2.1 3-Quinoline derivatives

Several quinoline derivatives, isolated from natural sources or prepared synthetically, are important for medicinal chemistry and biomedical use. The quinoline derivatives that intercalate DNA are of growing interest in the field of anticancer drugs. A number of research programs directed toward developing new approaches to a variety of heterocyclic ring systems for anticancer activity, especially those containing 3-quinoline derivatives have been widely reported.

Ghorab et al. (2015) reported a series of 3-quinoline derivatives. Compounds were synthesized via reaction of 3-aminoquinoline with ethyl cyanoacetate followed by reaction with substituted aldehydes. The structures of the newly synthesized compounds were confirmed by elemental analyses, and spectroscopic techniques. All the newly synthesized compounds were evaluated for their cytotoxic activity against a human tumor breast cancer cell line (MCF7). It was found that the compounds 2-Cyano-3-(4-hydroxy-3-methoxyphenyl)-N-(quinolin-3-yl) acrylamide (11), 3-Oxo-N-(quinolin-3-yl)-3H-benzol[f]chromene-2-carboxamide (12), 2-Cyano-3- (4-fluorophenyl-N-(quinolin-3-yl) acrylamide (13) and 2-Cyano-5-(4-(dimethylamino) phenyl)- N-(quinolin-3-yl) penta-2,4-dienamide (14) exhibited higher activity with IC₅₀ values of 29.8, 39.0, 40.0, 40.4 μmol L⁻¹, respectively. These compounds showed remarkable cytotoxic activity compared to doxorubicin as a positive control (Fig. 1).

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Figure 1

Structures of 3-quinoline derivatives (11–14) show cytotoxic activity against breast cancer cell line (MCF7).

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2.2 4-Quinoline derivatives

Reyes et al. (2010) synthesized a series of 4-quinoline substituted aminopyrimidine and 2-methylimidazo[1,2-a]pyridine derivatives. The synthesized compounds were evaluated for their cytotoxic activity against U251 (glioma), PC-3 (prostate), K562 (leukemia), HCT-15 (colon), MCF7 (breast) and SK-LU-1 (lung) cancer cell lines. Results showed that quinolin-4-yl-substituted compound (15), persists cytotoxic activity and is the most effective and selective against CDK1/CycA than against CDK2/CycB, while quinolin-3-yl-substituted compound is devoid of any cytotoxic activity (Fig. 2). This result constituted a new lead of quinolin-4-yl-substituted compounds for their cytotoxic and CDK inhibitory activity from which more compelling and selective inhibitors can be designed.

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Figure 2

Structure of compound 4-(Quinolin-4-yl)-N-p-tolylpyrimidin-2-amine (15), possessing cytotoxic and CDK inhibitory activity.

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3.1 N-alkylated, 2-oxoquinoline derivatives

N-alkylated quinoline derivatives exhibited a wide spectrum of pharmacological activities, such as antiplasmodial, cytotoxic, antibacterial, antiproliferative, antimalarial, and anticancer activity. The incorporation of oxygen at second position in quinoline (i.e. 2-Oxoquinoline) may alter the biological response of quinoline (Ryckebusch et al., 2003). Sagheer et al. (2013) reported N-alkylated, 2-oxoquinoline derivatives as cytotoxic agents. The quinoline was N-alkylated by the bromoacetic acid and then oxidized with an alkaline potassium ferricyanide solution to get N-alkylated quinolone. Six new quinoline derivatives (16–21) with high purity were synthesized and tested for their cytotoxic activity on the HEp-2 cell line (tumor of the larynx) with inhibitory concentration percent of (IC%) range (Fig. 3). The results of cytotoxic studies showed that all the synthesized compounds have IC₅₀ (%) value in the range of 49.01–77.67%. The result of cytotoxicity confirms the anticancer activity of N-alkylated, 2-oxoquinoline derivatives.

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Figure 3

Structure of compounds N-alkylated, 2-oxoquinoline derivatives (16–21) shows good cytotoxic activity on the HEp-2 cell line (tumor of larynx).

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3.2 2,3-Disubstituted quinoline derivatives

Recently, photodynamic therapy is an emerging method of non-invasive treatment of cancer in which drugs such as Photofrin show localized toxicity on photoactivation at the tumor cells leaving the healthy cells unaffected. There has been increased interest in the discovery and investigation of compounds that damage DNA upon irradiation, also known as photonucleases, exhibited a large potential for therapeutic applications chiefly in cancer disease (Armitage et al., 1998). Importantly, the type and the efficiency of the photo cleavage reaction will depend on the binding affinity and the binding site that the photonuclease occupies. A number of 2,3-disubstituted quinoline oxime derivatives have been reported for their anticancer activity by means of DNA cleavage activity in cancerous cells.

Bindu et al. (2012) reported the simple, convenient and high yielding synthesis of 2-chloro-3-formyl quinoline oxime esters derivatives. The electrophoretic data showed concentration and substitution dependent nucleolytic activities of 2-chloro-3-formyl quinoline oxime esters. The DNA photo cleavage studies were performed by neutral agarose gel electrophoresis at different concentrations (40 μM and 80 μM) which indicated that few of quinoline oxime esters (22–27) converted into supercoiled pUC19 plasmid DNA to its nicked or linear form (Fig. 4). The structure activity studies concluded that the electron donating groups are highly reactive radical and thus possessed remarkable anticancer activity, while the molecules having halogen and nitro groups were less active. These electrons donating groups abstracts hydrogen atoms efficiently at C-40 of 2-deoxyribose in B-DNA.

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Figure 4

Structure of compounds 2-chloro-3-formyl quinoline oxime esters derivatives having good anticancer properties.

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In the continuous search of new 2,3-disubstituted quinoline derivatives for anticancer activity, Broch et al. (2010) designed and synthesized new quinoline derivatives. The synthesized compounds were evaluated for their in vitro antiproliferative activity toward a human fibroblast primary culture and two human solid cancer cell lines (MCF-7 breast and PA 1, ovarian carcinoma). Results showed that the dimeric analogous (2,2′ Dimethoxy-3,7′-biquinoline 28 and 2,2′-Diethoxy-3,7′-biquinoline 29) were slightly active toward PA1 and MCF-7 cell lines with IC₅₀ values in the range of 36–54 μM, and possessed better cytotoxicity toward these two human solid cancer cell lines as compared to trimeric compound (2,2′,2′’-triethoxy-3,7′–3′,7′′-terquinoline 30). The trimeric analogue (30) showed mild activity against the PA1 cell line with an IC₅₀ value of 50 μM. The proposed reason for better activity of dimeric analogues is due to its enhanced solubility over trimeric analogues, and thus better cellular penetration (Fig. 5). The SAR studies showed that the introduction of various substituents on the heteroaromatic nucleus improved the solubility of compounds and results better biological profile.

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Figure 5

Structures of dimeric (28, 29) and trimeric (30) analogues of 2,3-disubstituted quinoline derivatives having improved cytotoxicity against PA1/MCF-7 and PA1 cell line respectively.

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3.3 2,4-Disubstituted quinoline derivatives

Quinoline ring having 2,4-disubstitution plays an important role in the search of new anti-cancer agents as these derivatives have shown excellent results through different mechanism of action such as growth inhibitors by cell cycle arrest, apoptosis, inhibition of angiogenesis, disruption of cell migration, and modulation of nuclear receptor responsiveness (Lu et al., 2008).

Kouznetsov et al. (2012) reported a series of 2,4-disubstituted quinoline compounds, for their cytotoxic activity. The studies were further extended by the same research group Ilango et al. (2015). Various 2,4-disubstituted quinolines derivatives were synthesized from the reaction of aniline with benzaldehyde and pyruvic acid to formed 2-phenylquinolin-4-carboxylic acid, which converted to 2-phenylquinolin-4-carbonyl chloride, and on the subsequent reaction with substituted amines gave 2-phenylquinoline-4-substituted phenylcarboxamide. The syntheses of compounds were confirmed by spectroscopic techniques. The results of spectroscopy confirmed the synthesis of desired compounds with adequate purity.

The newly synthesized compounds were screened for cytotoxic activity by Trypan blue dye exclusion technique using Neubauer Hemocytometer. The Ara-c in a concentration of 10 μg/ml was used as standards. Among the synthesized compounds, nine compounds showed % mortality above 50. However, three compounds were found to have a 70% mortality when compared with Ara-c against the tumor cells. In spite of cytotoxic activity, all the newly synthesized compounds also showed good antibacterial and antifungal activities. Among newly synthesized derivatives, compounds N-2-diphenyl quinolin-4-carboxamide (31) and N-p-tolylquinolin-4-carboxamide (32) were found to possess maximum cytotoxicity (Fig. 6). The proposed reason for the superior cytotoxicity of these two compounds was the presence of bulky aryl groups at 2 and 4 positions which enhanced the activity of synthesized quinoline derivatives. The research group also proposed that the incorporation of the amido group in quinoline derivatives enhanced their cytotoxic and antimicrobial activities, but the presence of electron donating and electron withdrawing groups on the two aryl rings did not make any significant difference in their activity.

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Figure 6

Structure of compounds N-2-diphenyl quinolin-4-carboxamide (31) and N-p-tolylquinolin-4-carboxamide (32) shows best cytotoxicity among 2, 4-disubstituted quinoline compounds.

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3.4 3,5-Disubstituted quinoline derivatives

3,5-Disubstituted quinolines have been reported as potent c-Jun N-terminal kinase (JNKs) inhibitors and lead to produced anticancer activity. Three distinct genes encoding JNKs have been identified (jnk1, jnk2, and jnk3). JNK3 has been shown to mediate neuronal apoptosis and make inhibiting this isoform a promising therapeutic target for neurodegenerative diseases such as Parkinson’s disease, Alzheimer’s disease, and other CNS disorders. Currently JNK3 becomes primary target for number of therapeutics for anticancer activity (Zhang et al., 2005; Kuan et al., 2003). Jiang et al. (2007) reported the synthesis of a novel series as potent c-Jun N-terminal kinase (JNK) inhibitors with selectivity against p38. The structures of 3,5-disubstituted quinolines were derived from 4-(2,7-phenanthrolin-9-yl)phenol. The X-ray crystal structure of inverse sulfonamide t-butyl analogue (33) in JNK3 revealed an unexpected binding mode for this new scaffold with protein and possessed a remarkable inhibition (0.15 μM IC₅₀) against JNK3 and devoid of inhibition against p38 (Fig. 7).

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Figure 7

Structure of inverse sulfonamide t-butyl analogue (33) showing unexpected JNK3 binding capability with remarkable inhibitory activity (0.15 μM IC₅₀) against p38 cell line.

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3.5 3,8-Disubstituted quinoline derivatives

Scolopendra subspinipes has been traditionally used for treating febrile seizure, malignant tumor, neuralgia or diphtheria in oriental countries. The inventors have extracted a novel quinoline compound from scolopendra subspinipes termed as jineol, and found that the extracted quinoline compound has cytotoxicity to a cancerous cell. This quinoline alkaloid has an oxygen atom at 3-carbon position and is rare in the nature. Nowadays jineol a new 3-hydroxy quinolinic compound has been discovered. It is known that the cyclic peptide structure of 3-hydroxy quinoline has an anticancer activity and its derivative 3-hydroxy quinoline-2-carboxylic acid, which can be obtained from a microorganism also showed anticancer activity (Matson et al., 1993). The amount of jineol (34) extracted from scolopendra subspinipes is very limited for commercial use (Fig. 8). Thus Cho et al. (2008), developed methods for synthesis of jineol and its derivatives thereof which showed anticancer activity. Jineol and its derivatives were synthesized by the reduction of starting material 2-amino-3-methoxybenzoic followed by acetylation then selective deacetylation. The reaction was further proceed by the oxidation and Friedlander condensation and hydrogenation yielded jineol 8-methyl ether or jineol 3-benzyl ether.

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Figure 8

Structure of jineol having anticancer activity.

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The researchers patented a number of jineol derivatives having structure at 3,8-dihydroxy-quinoline derivatives (35) (Fig. 9). Jineol was extracted from scolopendra subspinipes with an organic solvent, and purifying an anticancerous activating portion by chromatography. Jineol showed cytotoxic activity of the cells, such as A-549 non-small cell lung cancer, SKOV-3 ovarian cancer, SK-Mel-2 melanoma, XP-498 central nervous system cancer and HCT-15 colon cancer. This jineol was utilized to derive its derivatives. The synthesized compounds were characterized by spectroscopic techniques. The cytotoxic activity of jineol derivatives was performed by SRB assay against A-549, SKOV-3, SK-Mel-2, XP-498 and HCT-15 cancer cell lines. Results showed enhanced cytotoxic activity of jineol and its derivatives as compared to carboplatin, cisplatin and adriamycin.

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Figure 9

Structure of 3,8-dihydroxy-jineol derivatives (35) shows remarkable cytotoxic activity using SRB assay.

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3.6 4,7-Disubstituted quinolines derivatives

Bispo et al. (2015) reported a new and potent class of 7-chloro-4-quinolinylhydrazone derivatives (36) as anticancer agents (Fig. 10). The synthesized compounds were screened against cancer cell lines using the MTT assay. The results of anticancer activity showed that compounds exhibited good cytotoxic activity against at least three cancer cell lines (SF-295, central nervous system; HTC-8 colon and HL-60, leukemia), with IC₅₀ values between 0.314 and 4.65 μg/cm³. Results showed that the compounds having 2,6-dichloro hydrazone derivative were more active as compared to monochlo, while di or trimethoxy hydrazone derivatives were more active than monomethoxy. Results also showed that 3rd position substituted hydrazone showed best cytotoxic activity while N-methylation increased biological activity of quinoline. However, 7-chloro substitution on the quinoline ring decreased cytotoxic activity.

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Figure 10

Structure of 7-chloro-4-quinolinylhydrazone derivatives (36) shows improved cytotoxic activity using MTT assay.

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A plethora of the researcher’s findings suggests that 4-amino, 7-substituted-quinoline derivatives bear numerous biological activities. These include anticancer, antioxidant, anti-proliferative, and anti-inflammatory properties. Mcchesney et al. (1962) employed structure activity relationship of 4-aminoquinoline derivatives for antimalarial activity. Consideration has been given to the potential role of metabolic transformations in the in vivo activation of 8-aminoquinoline.

Ghorab et al. (2014) designed and synthesized nineteen compounds based on a 4-aminoquinoline scaffold. The synthesized compounds bear N-substituted at the 4-position by aryl or heteroaryl, quinolin- 3-yl, 2-methylquinolin-3-yl, thiazol-2-yl, dapsone moieties and bis-compounds. The synthesized compounds were assayed for in vitro using sulforhodamine B stain (SRB) method of the antiproliferative activity against the MCF-7 breast cancer cell line. Out of nineteen, seventeen compounds showed moderate activity than the reference drug doxorubicin, while compounds 7-(trifluoromethyl)-N-(3,4,5-trimethoxyphenyl)quinolin-4-amine (37), N-(7-(trifluoromethyl)quinolin-4-yl)quinolin-3-amine (38), 2-methyl-N-(7-trifluoromethyl)quinolin-4-yl) quinolin-3-amine (39) and N-(4-(4-aminophenylsulfonyl) phenyl)-7-chloroquinolin-4-amine (40) were reported almost twice to thrice as potent as doxorubicin (Fig. 11). The result of in vitro studies strongly recommended that the 4-amino, 7-substituted-quinoline derivatives possess antiproliferative activity.

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Figure 11

Structure of 4-amino, 7-substituted-quinoline derivatives (37–40) showing improve antiproliferative activity against the MCF-7 breast cancer cell line using sulforhodamine B stain (SRB) method, with respect to doxorubicin.

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Recently the combination of quinolines with chloroquine has been reported as the most apoptosis-inducing agent used against MCF-7 human breast cancer cells (Martirosyan et al., 2004). All differentiation-inducing quinolines caused growth suppression in MCF-7 and MCF10A cells by strong suppression of E2F1 which results cell cycle arrest.

Ferrer et al. (2009) reported a series of new [(7-Chloroquinolin-4-yl)amino]chalcone derivatives and were tested in vitro antiproliferative activity against human prostate LNCaP tumor cells. Compounds (2E)-3-(4-Chlorophenyl)-1-{3-[(7-chloroquinolin-4-yl)amino]phenyl}prop 2-en-1-one (4-chloro-3′-[(7-chloroquinolin-4-yl)amino]chalcone (41), (2E)-1-{3-[(7-Chloroquinolin-4-yl)amino]phenyl}-3-(3-fluorophenyl)prop-2-en-1-one (3′-[(7-chloroquinolin-4-yl)amino]-3-fluorochalcone (42) and (2E)-1-{3-[(7-Chloroquinolin-4-yl)amino]phenyl}-3-phenylprop-2-en-1-one (3′-[(7-chloroquinolin-4-yl)amino]chalcone, (43) exhibited potential inhibitors of human prostate cancer cell proliferation with IC₅₀ values of 7.93 ± 2.05, 7.11 ± 2.06 and 6.95 ± 1.62 μg/mL respectively (Fig. 12). Results showed that the presence of hydrogen or a halogen on position 3rd or 4th in the aromatic ring improved the antiproliferative activity of the reported compounds.

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Figure 12

Structure of compounds [(7-Chloroquinolin-4-yl)amino]chalcone (41–43) exhibits potential antiproliferative activity against prostate LNCaP tumor cells.

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3.7 6,8-Disubstituted quinoline derivatives

The quinoline and 6,8-disubstituted quinoline skeletons are often used in the designs of many synthetic compounds with diverse pharmacological properties. Okten et al. (2013) described an easy route for synthesis of 6,8-disubstituted quinoline derivatives since 6,8-dibromoquinolines. The reaction starts with synthesis of 6,8-dibromoquinolines followed by metal bromine exchange leading to produce various 6,8-disubstituted quinoline derivatives. The synthesized compounds were characterized by spectroscopic techniques. The synthesized compounds were screened for antiproliferative activity against several tumor cell lines. The results showed that compound 6,8-dibromo-1,2,3,4-tetrahydroquinoline (44) showed comparable antiproliferative activity against HeLa (cervical epithelioid carcinoma cells), HT-29 (colon cells) and C6 (brain tumor cells) in a concentration of 10 μg/mL, 30 μg/mL and 30 μg/mL respectively with respect to 5-FU. Compound 6,8-dimethoxidequinoline (45) also showed significant activity against HT-29 cells in the concentration of 70 μg/mL with respect to 5-FU. The proposed reaction procedure avoids shortcoming of numerous conventional methods (i.e. Skraup, Friedlander, Doebner-von Miller, Pfitzinger, Conrad-Limpach, and Combes) including limited homogeny and substitution on the quinoline ring system (Fig. 13).

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Figure 13

Structure of compounds 6,8-dibromo-1,2,3,4-tetrahydroquinoline (44) and 6,8-dimethoxidequinoline (45) showing comparable antiproliferative activity against HeLa/HT-29/C6 and HT-29 cancer cell lines respectively.

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4.1 2,4,5-Trisubstituted quinoline derivatives

Enhancer of Zeste Homologue 2 (EZH2) is a member of the histone-lysine N-methyltransferase (HKMT) family, which methylates K9 and K27 of histone H3, leading to transcriptional repression of the affected target genes. EZH2 has been found to be over-activated or over-expressed in many cancer types including colon, prostate, breast, and lung cancer (Kleer et al., 2003). Recently EZH2 has become a choice of target for a number of researchers for the treatment of cancer. EZH2 inhibitors had been discovered by many pharmaceutical companies and academic institutes exposed in the treatment of cancer. To date, a number of EZH2 inhibitors (Fig. 14) have been reported (Nasveschuk et al., 2014; Bradley et al., 2014). Unfortunately, the known EZH2 inhibitors have very limited scaffold structures.

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Figure 14

Structure of typical EZH2 inhibitors.

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In the search of new potent EZH2 inhibitors Xiang et al. (2015) discovered a new class of 5-methoxyquinoline derivatives a congener of BIX-01294 (2-(hexahydro-4-methyl-1H-1,4-diazepin-1-yl)-6,7-dimethoxy-N-[1-(phenylmethyl)- 4-piperidinyl]-4-quinazolinamine, (Fig. 15). BIX-01294 is a well-known histone methyltransferase G9a/GLP inhibitor containing a 1-benzylpiperidin-4-ylamino group (Kubicek et al., 2007).

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Figure 15

Structure of compound 2-(hexahydro-4-methyl-1H-1,4-diazepin-1-yl)-6,7-dimethoxy-N-[1-(phenylmethyl)- 4-piperidinyl]-4-quinazolinamine (BIX-01294), a potent EZH2 inhibitors.

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5-Methoxyquinoline derivatives were prepared by cyclization of 2-bromo-5-methoxyaniline and malonic acid, using POCl₃ as catalyst and solvent. The intermediate 8-bromo-2,4-dichloro-5-methoxyquinoline was prepared which on subsequent reactions with n-BuLi in THF and CH₃OH followed on reaction with a variety of primary or secondary amines at the 4-position of the quinoline moiety and finally on nucleophilic substitution reaction with amines at the 2-position of the quinoline moiety in i-PrOH under microwave conditions, using TFA as an acid catalyst gave the desired series of compounds. The quinoline derivatives were assayed for their anticancer activity which was based on both enzymatic and cellular assays, in which the enzymatic activities were determined by the AlphaLISA (EZH2) method, and the cell growth inhibition potencies were evaluated on the HCT-15 (colon) and MD-MBA-231 (breast) cell lines by the MTT method. The results of these studies showed that compound 5-methoxy-2-(4-methyl-1,4-diazepan-1-yl)-N-(1- methylpiperidin-4-yl)quinolin-4-amine (46), displayed an IC₅₀ value of 1.2 μM against EZH2, decreased global H3K27me3 level in cells and also showed good anti-viability activities against both HCT15 and MD-MBA-231 tumor cell lines (Fig. 16). Studies also indicated that methoxy groups at the 5-position might be more important for the potency of the compounds, and single or double substitutions at other positions would not contribute to the potency. Selectivity studies of compound (46) were also done on different proteins, including SMYD3, G9a, SUV39H1, SETDB1, PRMT1 and SETD8. Results of selectivity showed that the compound (46) is highly selective for EZH2. Researchers concluded that the compound (46) could be a lead compound deserving further structural optimization due to the fact that it represents a new scaffold and possesses low molecular weight.

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Figure 16

Structure of compound 5-methoxy-2-(4-methyl-1,4-diazepan-1-yl)-N-(1- methylpiperidin-4-yl)quinolin-4-amine (46) showing good anti-viability activities against both HCT15 and MD-MB-231 tumor cell lines.

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4.2 2,4,6-Trisubstituted quinolines

DNA alkylating agents have been widely used in chemotherapy. Recently, the investigation of new alkylating agents for cancer chemotherapy via the designing of DNA-directed alkylating agents or prodrug becomes a key area to overcome the general drawbacks of alkylating agents. DNA-directed alkylating agents are generally synthesized by linking alkylating pharmacophores (such as N-mustard residue) to DNA-affinic molecules (such as DNA intercalating agents or DNA minor groove binder) (Gourdie et al., 1990). These agents showed higher cytotoxicity and better therapeutic efficacy than the corresponding untargeted alkylating agents. Studies on the structure–activity relationships of these conjugates suggest that the selection of the DNA-affinic molecule (carrier), N-mustard residue (alkyl or phenyl N-mustard) and the spacer (type and length) greatly affect their antitumor activity. For example, Tallimustine a proposed anticancer drug candidate for this new class of cytotoxic compounds. It was evaluated in Phases I and II clinical trials and expressed a promising anticancer activity both in vivo and in vitro (Pezzoni et al., 1991).

Till date a number of DNA-directed alkylating agents, having N-mustard residue have been reported. In the search of new N-mustard alkylating agents Kakadiya et al. (2010) reported a series of phenyl N-mustard quinoline conjugates as potent DNA-directed alkylating agents. In his study quinolines were chosen as a DNA-affinic molecule, as they are DNA minor groove binders. New N-mustard–quinoline conjugates were synthesized, using urea or hydrazinecarboxamide as stabilizing spacers. The new targets derivatives were subjected to antitumor evaluation against a variety of human tumor cell growth in vitro, therapeutic efficacy in vivo, and their capability of DNA interstrand cross-linking. Results showed that compounds having hydrazinecarboxamide as a linker showed increased cytotoxic activity in comparison with the corresponding compounds bearing a urea spacer. The therapeutic efficacy against human tumor xenografts in animal model study clearly exposed the complete tumor remission in nude mice bearing human breast carcinoma MX-1 xenograft by N-{4-[Bis(2-chloroethyl)amino]phenyl}-N0-(2-methyl-4-quinolinyl)urea (47); N-{4-[Bis(2-chloroethyl)amino]phenyl}-N0-[6-methoxy- 2-(3-methoxy-phenyl) -4-quinolinyl]urea (48); N-{4-[Bis(2-chloroethyl)amino]phenyl}-2-(6-methyl[1,3]- dioxolo[4,5-g]quinolin-8-yl)-hydrazinecarboxamide (49) and N-{4-[Bis(2-chloroethyl)amino]phenyl}-2-[6-(dimethylamino)- 2-methyl- 4-quinolinyl]-hydrazinecarboxamide (50). The study concluded that the both linkers were able to lower the chemically reactive N-mustard pharmacophore and thus the newly synthesized conjugates possessed a long half-life in rat plasma (Fig. 17).

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Figure 17

Structure of N-mustard–quinoline conjugates (47–50) showing improvement of anticancer activity against human breast carcinoma MX-1 xenograft.

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4.3 2,4,8-Trisubstituted quinoline derivatives

It is known that diverse polyfunctionalized quinoline molecules are used as potential anticancer agents. As a part of a medicinal chemistry program devoted to the search of new anticancer compounds, 2,4,8-trisubstituted quinoline derivatives could serve as models for the development of new antitumor drugs. It was reported that chemical modulation at the C-2 position of quinoline would alter the biological activity of the new quinoline compounds. The introduction of a hetaryl moiety in the C-2 position of the quinoline ring would possibly enhance the lipophilicity and DNA-quinoline binding properties of the prepared compounds and thus may augment the anticancer activity. Kouznetsov et al. (2012) accounted C-2 quinoline derivatives that possessed good cytotoxic activity. They identified structural similarities between sixteen C-2-substituted quinolines compounds and reported structures as anticancer. The synthesized compounds were tested in specific human cancer cell lines (MCF-7, H-460 and SF-268) and against nonspecific Vero cell lines and THP-1 monocyte macrophages, which indicated that 2-α-furyl- and 2-γ-pyridinyl quinoline derivatives 6-Methoxy-2-(thiophen-2-yl)quinoline (51); 8-Ethyl-4-methyl-2-(pyridin-4-yl)quinoline (52) and 8-Propyl-4-methyl-2-(pyridin-4-yl)quinoline (53) are active against the three specific cancer cell lines (MCF-7, H-460 and SF-268) and, at the same time, were devoid of cytotoxic effect on nonspecific Vero cell lines and THP-1 monocyte macrophages when compared to adriamycin and camptothecin as standard drugs (Fig. 18). Biological activity and SAR results were compared with different molecular descriptors determined in silico using online available software, in an attempt to show a relationship with the possible mode of action of these quinoline derivatives.

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Figure 18

Structures of compounds 6-Methoxy-2-(thiophen-2-yl)quinoline (51); 8-Ethyl-4-methyl-2-(pyridin-4-yl)quinoline (52) and 8-Propyl-4-methyl-2-(pyridin-4-yl)quinoline (53) show excellent cytotoxicity against the specific human cancer cell lines (MCF-7, H-460 and SF-268).

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4.4 2-Substituted-4-amino-6-halogenquinoline derivatives

Gefitinib and pelitinib the 4-aminoquinazoline and 4-aminoquinoline skeletons respectively, are considered to be the promising nucleus for antitumor drug development. As a result, a great number of novel 4-aminoquinazoline and 4-aminoquinoline derivatives have been developed in succession. Two series of novel 2-substituted-4-amino-6-halogenquinolines were designed, synthesized and evaluated by Jiang et al. (2012) for their antiproliferative activity against H-460 (lung), HT-29 (colon), HepG2 (liver) and SGC-7901 (stomach) cancer cell lines in vitro. The pharmacological results indicated that most compounds with 2-arylvinyl substituents exhibited good to excellent antiproliferative activity. Among them, the compound (E)-N¹-(6-Chloro-2-(4-methoxystyryl)quinolin-4-yl)-N²,N²-dimethylethane-1,2-diamine (54) (with a 4-methoxystyryl group at the C-2 position and a dimethylaminoalkylamino substituent at the C-4 position) was considered promising lead for further structural modifications with IC₅₀ values of 0.03 μM, 0.55 μM, 0.33 μM and 1.24 μM, against H-460, HT-29, HepG2 and SGC-7901 cancer cell lines respectively which was 2.5- to 186-fold more active than gefitinib (Fig. 19). The prelude SARs showed that the improved activity depended strongly on the introduction of an ethylene linkage between the nucleus and aryl moiety.

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Figure 19

Structure of compound (E)-N¹-(6-Chloro-2-(4-methoxystyryl)quinolin-4-yl)-N²,N²-dimethylethane-1,2-diamine (54) shows improve antiproliferative activity over H-460, HT-29, HepG2 and SGC-7901 cancer cell lines.

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4.5 2,8-Bis(trifluoromethyl)-4-substituted quinoline derivatives

Meshram et al. (2012) synthesized various 2,8-bis(trifluoromethyl)-4-substituted quinoline derivatives since 4-substituted iodoquinoline on reaction with boronic acids in the presence of a palladium catalyst under basic conditions or by the use of Triton B as a base. Synthesized compounds were characterized by spectroscopic techniques. Cell proliferation or viability of the synthesized compounds were assayed via MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrasolium bromide] assay against the HL-60 (myeloid leukemia) and U937 (leukemia monocyte lymphoma) cell lines using etoposide as a reference drug. Results of cytotoxicity studies showed that synthesized quinoline derivatives were toxic to human HL-60 and U937 cell lines in the concentration of 100–200 μg/ml. Compound (55) [4-(3,5-dimethyl-1H-pyrazol-4-yl)-2,8-bis (trifluoromethyl) quinoline] was found to be a most potent antiproliferative agent (Fig. 20). This compound possessed IC₅₀ value 19.88 ± 3.35 μg/ml and 43.95 ± 3.53 μg/ml in HL-60 and U937 cell lines respectively.

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Figure 20

Structure of compound 4-(3,5-dimethyl-1H-pyrazol-4-yl)-2,8-bis (trifluoromethyl) quinoline (55) shows highest anticancer activity against HL-60 and U937 cell lines.

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4.6 4-Anilino-8-hydroxy-2-phenylquinoline derivatives

Chen et al. (2006) reported the synthesis and antiproliferative evaluation of certain 4-anilino-8-methoxy-2-phenylquinoline and 4-anilino-8-hydroxy-2-phenylquinoline derivatives. The results showed that the antiproliferative activity of 4′-COMe-substituted derivatives decreased in an order of 6-OMe (3.89 μM) > 8-OMe (10.47 μM) > 8-OH (14.45 μM), signifying that the position of substitution at the quinoline ring was crucial. For 3′-COMe derivatives, the antiproliferative activity of 8-OH (4-(3-Acetylanilino)-8-hydroxy-2-phenylquinoline) (56, 1.20 μM) was found to be more potent than its 8-OMe counterpart (8.91 μM), indicating that a H-bond donating substituent was more favorable than that of a H-bonding accepting group. Similarly, for 8-OH derivatives, the antiproliferative effect of -COMe (56) was more potent than its oxime derivative (2.88 μM), which in turn was more potent than the methyloxime counterpart (5.50 lM) (Fig. 21). In continuation, the studies showed that the compound (56) was principally active against the growth of certain solid cancer cells, such as HCT-116 (colon cancer), MCF7 and MDA-MB-435 (breast cancer) with GI50 values of 0.07, <0.01 and <0.01 μM, respectively.

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Figure 21

Structure of compound 4-(3-Acetylanilino)-8-hydroxy-2-phenylquinoline (56) shows significant antiproliferative activity against HCT-116, MCF7 and MDA-MB-435 cancer cell lines.

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4.7 8-Hydroxy-2-methyl-7- substituted quinoline derivatives

Nowadays, researchers are focusing on biologically active quinoline analogues and fluorescent compounds capable of staining cancer cells. Researchers are trying to increase the lipophilicity of quinoline derivatives to enhance the permeability of the derivatives through the cell membranes, while their antiproliferative activities render them interesting as leading structures for anticancer agents or (in case of non-active compounds) as dying agents (Li et al., 2007). Spaczyńska et al. (2014) reported a series of 8-hydroxy-2-methyl-quinolone derivatives with benzylamide substitution and characterized by spectroscopic techniques. Compounds were investigated for fluorescent properties. Compounds 8-Hydroxy-2-methylquinoline-7-carboxylic acid (3- phenylbutyl)-amide (57) and 8-Hydroxy-2-methylquinoline-7-carboxylic acid phenethylamide (58) showed highest fluorescence, while remaining compounds also possessed remarkable fluorescence. The results of fluorescence studied showed that compounds having an unsubstituted aryl system or substituted —CH₃ or —F showed the best fluorescence intensity while substitution with —OCH₃ or —OH in the aryl ring decreased fluorescence. Synthesized compounds were also utilized for biological assays and were tested by the MTS assay against the wild type of human colon adenocarcinoma cell line (HCT116) and mutants with disabled TP53 gene (HCT116 p53). The synthesized compounds were also screened for their cytotoxicity against murine melanoma cell line (B16-F10) and normal human dermal fibroblasts. The compound 2-Hydroxybenzoic acid N’-(8-hydroxy-2-methylquinoline-7-carbonyl)-hydrazide (59) was found to possess highest cytotoxic activity and was active in inhibiting the proliferation of all tumor cell lines and possessed highest cytotoxic activity but very poor fluorescence, too weak for observations (Fig. 22).

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Figure 22

Structure of 8-hydroxy-2-methyl-quinolone derivatives (57–59) possesses highest cytotoxicity against B16-F10, NHDF cell lines but with very poor fluorescence.

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4.8 Thiosemicarbazones based on quinoline scaffold

Thiosemicarbazones exhibit potent anticancer activity through the blocking of ribonucleotide reductase or by specific redox activity. Serda et al. (2010) showed that reduction of complex of Fe³⁺-thiosemicarbazone lead to generation of reactive oxygen species (ROS) which may also be responsible for inhibition of ribonucleotide reductase as they are able to quench the tyrosyl radical of the R2 subunit of ribonucleotide reductase. Quinoline and its derivatives were also reported as a potent antiproliferative scaffold. Number of thiosemicarbazones based on quinoline compounds has been synthesized using microwave assisted techniques.

Microwave assisted chemistry carried most of the steps in efficient manner and green technique and also provide good (above 80%) yields of the main product. The proposed technique is time and cost efficient and allows obtaining a relatively wide group of compounds for biological tests. Structures of all new compounds were confirmed with spectroscopic techniques. The antiproliferative activity of thiosemicarbazones based quinoline compounds (60 and 61) was assessed by the MTT assay against the HCT116 (human colon carcinoma) cell line (Fig. 23). Tested compounds exhibited improved antiproliferative activities against HCT116 cancer cells.

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Figure 23

Structure of thiosemicarbazones based quinoline compounds (60, 61) shows good antiproliferative activity against the HCT116 cell line by MTT assay.

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5.1 2,3-Disubstituted-6,7-dimethoxy (dihydroxy) quinoline derivatives

RAF (rapidly-growing fibrosarcoma) kinases are serine/threonine kinases, and they are part of the mitogen activated protein kinase signal transduction cascade. This cascade is vital for numerous cellular fates, including cell growth, differentiation, proliferation and survival (Weber et al., 2000). Imatinib a diarylamides derivative was used in the treatment of gastrointestinal stromal tumors, thyroid cancer, breast cancer, meningioma, ovarian cancer, and nonsmall cell lung cancer in combination with other drugs (Wellbrock et al., 2004). Gamal et al. (2014) synthesized a new series of diarylamide derivatives possessing dimethoxy(dihydroxy)quinoline nucleus. The synthesized compounds were tested for in vitro antiproliferative activities over NCI-58 cancer cell line panel of nine different cancer types. Compounds 3,4-dichloro-N-(4-(6,7-dimethoxy-2- methylquinolin-3-yloxy)phenyl)benzamide (62); N-(4-(6,7-dimethoxy-2-methylquinolin-3-yloxy)phenyl)-2,3- dihydrobenzo[b][1,4]dioxine-5-carboxamide (63); 3-(Trifluoromethyl)-N-(4-(6,7-dimethoxy-2-methylquinolin-3-yloxy) phenyl)benzamide (64); 4-Chloro-3-(trifluoromethyl)-N-(4-(6,7-dimethoxy-2- methylquinolin-3-yloxy)phenyl)benzamide (65); N-(4-(6,7-dimethoxy-2-methylquinolin-3-yloxy)phenyl)-3,5- bis(trifluoromethyl)benzamide (66) showed the most promising results among all the synthesized compounds at a single-dose concentration of 10 mM over 58 cell line panel. These compounds (62–66) were further tested in 5-dose testing mode in order to determine their IC₅₀ values, and the results were compared with those of imatinib and gefitinib which showed that the five compounds were more potent than imatinib against all the cell lines of nine different cancer types (Table 2). Compound 66 showed the highest inhibited activity and was further tested against C-RAF kinase inhibition. Results of C-RAF kinase inhibition showed 76.65% inhibition at 10 mM. So it can be concluded that C-RAF kinase inhibition is a possible mechanism of the antiproliferative activity of this compound. The structure activity relationship (SAR) studies of synthesized compounds indicated that 6,7-dimethoxyquinoline scaffold was more favorable for activity than 6,7-dihydroxyquinoline. The O linker was optimal for the activity too. Taken together, they can give information about the pharmacophore of this series of compounds.

Table 2 Structures of the 2,3-disubstituted-6,7-dimethoxy (dihydroxy) quinoline derivatives (60–64) with their IC₅₀ values (μM) over the most sensitive cell line of each subpanel.

Com. No.	R	X	Ar	Cancer cell lines
				RPMI-8226a	HOP-92b	HCT-116c	SF-295d	SK-MEL-5e	OVCAR-4f	A498g	PC-3h	BT-549i
62	CH3	O		3.70	16.10	4.26	1.59	4.99	5.26	20.60	4.77	3.91
63	CH3	O		2.98	3.93	3.42	2.91	2.92	3.32	2.06	2.49	1.71
64	CH3	O		3.67	3.08	3.22	2.73	2.45	3.68	1.78	2.85	3.31
65	CH3	O		5.43	13.60	4.18	2.28	10.60	5.58	2.42	4.30	8.86
66	CH3	O		1.57	1.82	1.56	1.64	2b.76	4.53	1.13	1.66	3.02
Imatinib				6.31	12.59	12.59	19.95	12.59	19.95	19.95	19.95	15.85
Gefitinib				6.31	0.32	3.16	10.00	3.16	6.31	0.63	5.01	3.16

a Leukemia cell line.

b Non-small cell lung cancer cell line.

c Colon cancer cell line.

d CNS cancer cell line.

e Melanoma cell line.

f Ovarian cancer cell line.

g Renal cancer cell line.

h Prostate cancer cell line.

i Breast cancer cell line.

5.2 6,7-Substituted-5,8-quinolinequinone derivatives

5,8-Quinolinequinones derivatives reported to possess a wide spectrum of biological properties that include anti-tumor, anti-inflammatory and anti-bacterial activities (Cheng et al., 2008; Castellano et al., 2008). Streptonigrin, isolated from the bacterium Streptomyces flocculus showed antitumor activity, having 5,8-quinolinequinones nub, which was one of the first compounds to be systematically modified in an attempt to correlate specific structural features with anti-cancer properties (Fig. 24) (Rao et al., 1963). Earlier structure–activity studies (SARs) concluded that the 7-aminoquinolinequinone-moiety of streptonigrin was crucial for anti-tumor activity; however, further studies showed that the addition of electron-withdrawing groups at the 6- and/or 7-positions of the quinolinequinone results enhanced rates of DNA degradation (Rao et al., 1974; Lown et al., 1976; Shaikh et al., 1986). Unfortunately, the high toxicity of streptonigrin has limited its therapeutic value (Davis et al., 1978; Bolzán et al., 2001).

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Figure 24

Structure of streptonigrin, having antitumor activity, with 5,8-quinolinequinones nub.

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Mulchin et al. (2010) reported a series of 6,7-substituted 5,8-quinolinequinones derivatives and identified their anti-cancer, anti-inflammatory or tuberculostatic activity. The starting material of synthesis was 8-hydroxyquinoline or 8-hydroxy-2-methyl-quinoline, which on the subsequent reaction with sodium chlorate gave oxidative product dichloro-quinones. These dichloro-quinones were then treated with a variety of amine nucleophiles to give the 6 and/or 7-substituted 5,8-quinolinequinolines products in good (65–96%) yield. The anti-cancer activity of the synthesized compounds was measured against HL60 cells (IC₅₀) and human T-cells (IC₅₀) from healthy volunteers using the MTT assay. These quinolinequinones showed promise as anti-cancer activity. Results showed that the introduction of a sulfur group at the 7-position of the quinolinequinone (6-methylamino-7-methylsulfanyl-5,8-quinolinequinone (67) and 6-amino-7- methylsulfonyl-5,8-quinolinequinone (68)) led to the discovery of a number of biologically active compounds that exhibited selectivity for leukemic cells over T-cells, a highly desirable property for an anti-cancer drug, while a di-chloro or di-thiol-substituted quinolinequinone gave better anti-inflammatory activity (Fig. 25).

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Figure 25

Structure of 6,7-substituted 5,8-quinolinequinones derivatives (67, 68) shows significant anticancer activity against HL60 cells and human T-cells.

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6.1 1,2-Quinoline-platinum complex

The compound belonging to a series of platinum(II) complexes bearing piperidine (pip) as a ligand, exhibited notable antitumor activity (Da et al., 2001; Solin et al., 1982). Thanh et al. (2014) reported a [PtCl₂(pip)(quinoline)] complex, in which the quinoline ligand is replaced by an N,O-bidentate quinaldate ligand and quinoline-piperidine ligands are arranged in cis positions. The researchers also reported a new chlorido(piperidine-κN)- (quinoline-2-carboxylato-κ²N,O)platinum(II) compound (69) in which the quinoline ring of the quinaldate ligand occupies a transposition with respect to the piperidine ring (Fig. 26). The compound was synthesized in two steps. In a first step the quinaldic acid in its ionic form coordinates with PtII via the O atom of the carboxylate group first and in a cis position with respect to piperidine based on the trans effect, while in a second step, the quinaldic acid coordinates with PtII also via its N atom, resulting in the cyclic complex.

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Figure 26

Structure of compound chlorido(piperidine-κN)- (quinoline-2-carboxylato-κ²N,O)platinum(II) (69), shows significant cytotoxicity against human cancer cells of HepG2, RD, MCF7 and Fl.

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The cytotoxic activity of the synthesized compound (69) was tested and recorded for four human cancer cells of HepG2, RD, MCF7 and Fl. The IC₅₀ values of the reported compound were found to be 4.46, 2.59, >10 and 5.60 μg ml⁻¹ respectively.

6.2 Pyrroloquinolines derivatives

Lee et al. (2004) identified a novel series of substituted pyrroloquinolines that selectively inhibited the function of P-glycoprotein (Pgp) without modulating multidrug resistance-related protein 1 (MRP 1). The synthesized compounds were screened for their toxicity toward drug-sensitive tumor cells (i.e. MCF-7, T24) and for their ability to antagonize Pgp mediated drug-resistant cells (i.e. NCI/ADR) and MRP 1 mediated resistant cells (i.e. MCF-7/VP). The results showed that the dihydropyrroloquinolines inhibited Pgp to varying degrees, without any significant inhibition of MRP 1. The compound Pgp-4008 (70) was found to be most potent in inhibition of Pgp in vitro (Fig. 27).

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Figure 27

Structure of compound Pgp-4008 (70), most potent in inhibition of Pgp in vitro.

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6.3 Indolo[2,3-b]quinoline derivatives

5,11-Dimethyl-5H-indolo[2,3-b]quinoline (DiMIQ, 71), the synthetic analogue of indolo[2,3-b]quinoline, reported high cytotoxic activity and inhibits the proliferation of mouth carcinoma KB cells (at a concentration of 1 mM) (Czoch et al.,1994) (Fig. 28). Moreover, its activity is similar to the cytotoxic activity of doxorubicin (0.8 mM against KB cells) a marketed anticancer drug (Kaczmarek et al., 1999). Unfortunately, DiMIQ (71) has limited practical applicability in the treatment of cancer, possibly due to its high toxicity, lack of selectivity and very low solubility in aqueous solutions, especially at neutral pH. The high toxicity and low bioavailability of DiMIQ (71), prompted researchers to look for new analogues which would conform to the high requirements necessary for anticancer drugs: potent and selective activity and low side effects.

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Figure 28

Structure of compound 5,11-dimethyl-5H-indolo[2,3-b]quinoline (DiMIQ, 71), a indolo derivative shows high cytotoxic activity and inhibits the proliferation of mouth carcinoma KB cells.

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In the search of new DiMIQ congeners, Sidoryk et al. (2015) reported new indolo[2,3-b]quinoline derivatives containing guanidine, amino acid or guanylamino acid substituents. Results revealed that the attachment of the guanidine, or guanylamino acid chain directly to the DiMIQ or 6H-indolo[2,3-b]quinoline moiety significantly perked up its selective cytotoxicity against almost all cancer cell lines, while decreasing this activity against the normal cell line. Compounds N-guanyl-N-(5,11-dimethyl-5H-indolo[2,3-b]quinolin-9-yl)- amine dihydrochloride (72) and N-guanyl-N-[6-(2-dimethylaminoethyl)-11-methyl-6Hindolo[ 2,3-b]quinolin-9-yl]-amine tetrahydrochloride (73) showed highest in vitro cytotoxicity and possessed selectivity between normal and cancer cell lines (Fig. 29). The cytotoxicity of compound (72) was found to be about 600-fold lower against normal fibroblasts than against A549 and MCF-7 cancer cell lines. The mechanism of action of synthesized compounds was also studied for guanidine derivatives, which showed that compounds (72 and 73) were very effective inducers of apoptosis. The results of mechanism of action studies proved that the compounds (72 and 73) produced antiproliferative activity through DNA interactions probably lead to the inhibition of DNA synthesis and consequent arrest the cells in S cell cycle phase. Compound (72), interacted more strongly with DNA than that of compound (73), and was also more efficient in the induction of apoptosis. The studies concluded that the conjugates containing the guanidine group directly linked to the core structure confirmed highly potent and selective anticancer activity.

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Figure 29

Structure of indolo[2,3-b]quinoline derivatives (72, 73) shows remarkable cytotoxicity against A549 and MCF-7 cancer cell lines.

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6.4 Anilinofuro[2,3-b]quinoline derivatives

Chen et al. (2005) synthesized 4-anilinofuro[2,3-b]quinoline and angular 4-anilinofuro[3,2-c]quinoline derivatives and evaluated in vitro against the full panel of NCI’s 60 cancer cell lines. Compound 1-(4-(furo[2,3-b]quinolin-4-ylamino)phenyl)ethanone (74) was found to be the most cytotoxic with a mean GI50 value of 0.025 μM (Fig. 30). The results showed that substitution at either furo[2,3-b]quinoline ring (2a, 2b, and 5b) or 4-anilino moiety (3–7) decreased cytotoxicity.

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Figure 30

Structure of compound 1-(4-(furo[2,3-b]quinolin-4- ylamino)phenyl) ethanone (74) shows most cytotoxicity against NCI’s 60 cancer cell lines.

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6.5 Indolo-, pyrrolo-, benzofuro and 6-anilinoindolo quinoline derivative

Chen et al. (2002) synthesized certain indolo-, pyrrolo-, and benzofuro-quinolin-2(1H)-ones and 6-anilinoindoloquinoline derivatives and evaluated in vitro against a three-cell line panel consisting of MCF7 (Breast), NCI-H460 (Lung), and SF-268 (CNS). The results have shown that cytotoxicity decreased in the order of 6-anilinoindoloquinolines > indoloquinolin-2(1H)-ones > pyrroloquinolin-2(1H)-ones > benzofuroquinolin-2(1H)-ones. Among them, 1-(3-(11H-indolo(3,2-c)quinolin-6ylamino)phenyl) ethanone oxime hydrochloride (75) and its 2-chloro derivative (76) were most active, with a mean GI₅₀ values of 1.70 and 1.35 mM, respectively (Fig. 31). Both compounds (75, 76) were also found to inhibit the growth of SNB-75 (CNS cancer cell) with a GI₅₀ value of less than 0.01 mM.

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Figure 31

Structure of compounds 1-(3-(11H-indolo(3,2-c)quinolin-6ylamino)phenyl) ethanone oxime hydrochloride (75) and its 2-chloro derivative (76) shows cytotoxicity against MCF7, NCI-H460, SNB-75 and SF-268 cancer cell lines.

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Atwell et al. (1972) synthesized acridine derivatives having an amino group at position 9 of acridine, and found that some of them had the effect of inhibiting leukemia. Cain et al. (1974) reported the interrelation between the anticancer effect of the acridine derivatives and the specific kind of alkylamino group at position 9 of acridine, and found that the most effective derivative is N-(4-(9-acridinylamino)-3-methoxyphenyl)-methanesulfonamide (amsacrine). Yamato et al. (1988) obtained a patent for compounds having indenoquinoline, benzofuroquinoline or benzothienoquinoline in lieu of the acridine skeletal structure of amsacrine, the process for the preparation thereof. In the present structure X was O, S or CH₂ (77) (Fig. 32). These compounds showed intensive antiproliferative activity. The antiproliferative activity was determined by measuring the 50% growth inhibition (ED₅₀) of KB-cells. The numbers of surviving cells were counted by a Kohlter’s counter, and the counted number was compared to that of the control to find the concentration of the drug for inhibiting the growth by 50%, thus found concentration being estimated as the ED₅₀ value. In vivo activity showed the prolonging life of P-388 murine leukemia cell line with cancer and these synthesized compounds were found to be devoid of any acute toxicity.

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Figure 32

Structure of compounds indenoquinoline, benzofuroquinoline or benzothienoquinoline derivatives (77) showing intensive antiproliferative activity against KB-cancer cells and prolonging the life of P-388 murine leukemia cell line with cancer.

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6.6 Indeno [1,2-c]quinoline derivatives

Although the quinoline ring is found in a wide variety of biologically active compounds and is frequently condensed with various heterocycles leads to produce remarkable active multifaceted. Synthesis and biological evaluation of the indeno [1,2-c] quinoline skeleton attracts limited attention. NSC 314622 (78) an indenoquinoline analogue, was first identified as a novel Topoisomerase I inhibitor with better pharmacokinetic features than camptothecin (Fig. 33) (Antony et al., 2003). Since then, a number of indenoisoquinolines analogues especially indeno [1,2-c]isoquinoline derivatives have been synthesized and proved to possess DNA Top I inhibitory activity. These compounds bind to a transient Top I DNA covalent complex and inhibited the resealing of a single-strand nick that the enzyme creates to relieve superhelical tension in duplex DNA (Hsiang et al., 1985; Hertzberg et al., 1989).

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Figure 33

Structure of indenoquinoline analogue (NSC 314622, 78) shows Topoisomerase I inhibitory activity.

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In the search of new, potent indeno[1,2-c]quinoline derivatives, Tseng et al. (2008) synthesized some new indeno[1,2-c]quinoline derivatives and reported their antiproliferative evaluation against the growth of six cancer cell lines including human cervical epithelioid carcinoma (HeLa), oral squamous cell carcinoma (SAS), hepatocellular carcinoma (SKHep), human stomach adenocarcinoma (AGS), prostate cancer (PC-3), and non-small cell lung cancer (A549). All indeno[1,2-c]quinoline derivatives were derived from isatin. The antiproliferative activity was measured by determining the concentration of substances that inhibited the growth of 50% of cells (GI₅₀). The results illustrated that the compound 9-Methoxy-6-(piperazin-1-yl)-11H-indeno[1,2-c]- quinolin-11-one O-3-aminopropyl oxime (79) was the most potent with GI50 values of 0.52, 0.74, 6.76, and 0.64 μM against the growth of HeLa, SKHep, AGS, and A549 cells, respectively. The study also showed that the potency of synthesized compounds was decreased in an order of aminoalkoxyimino > hydroxyimino > alkoxyimino > carbonyl. Flowcytometric analysis indicated that the compound 9-Methoxy-6-(piperazin-1-yl)-11H-indeno[1,2-c]- quinolin-11-one O-3-(dimethylamino)propyl oxime (80) can induce cell cycle arrest in S phase, and DNA polyploidy (>4n) followed by apoptosis (Fig. 34).

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Figure 34

Structure of indeno[1,2-c]quinoline derivatives (79–80) shows significant antiproliferative activity against HeLa, SKHep, AGS, and A549 cancerous cells.

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6.7 6,8-Diarylthieno[3,2-c]quinoline-2-carboxylate scaffold

The 6,8-diarylthieno[3,2-c]quinoline-based compounds continue to attract a great deal of attention in the research because of their rich biological activities including antibacterial (Castrillo et al., 2001), anticancer (Jarak et al., 2005) and anti-inflammatory agents (Cesare et al., 1999). Recently a number of thieno[3,2-c]quinoline derivatives were found to inhibit protein kinases in cancer cells (Beydoun et al., 2012; Pierre et al., 2011). Avetisyan et al. (2007) reported a series of substituted 2,4-dimethyl-thieno[3,2-c]quinolones derivatives, which were prepared via intramolecular cyclization and subsequent aromatization of 3-(2-chloroprop-2-en-1-yl)- and 3-(2-oxopropyl)-2-methylquinolin-4-thiols. Mphahlele et al. (2014) produced [(6,8-diarylthieno[3,2-c]quinoline)]-2-carboxylates derivatives via direct one-pot base-promoted conjugate addition–elimination of 6,8-dibromo-4-chloroquinoline-3-carbaldehyde with methyl mercaptoacetate and subsequent cyclization afforded methyl [(6,8-dibromothieno[3,2-c]quinoline)]-2-carboxylate followed by Suzuki-Miyaura cross-coupling with arylboronic acids to yield desired compounds. These synthesized compounds were screened for their cytotoxicity against the human breast cancer cell line MCF-7 using the MTT assay. Cytotoxicity of the synthesized compounds was also evaluated by measuring cell kinetics using the xCELLigence Real Time Cell Analysis (RTCA) system. Compounds Methyl [(6,8-Dibromothieno[3,2-c]quinoline)]-2-carboxylate (81); Methyl 6,8-bis(4-methoxyphenyl)thieno[3,2-c]quinoline-2-carboxylate (82) and Ethyl 6,8-bis(4-methoxyphenyl)thieno[3,2-c]quinoline-2-carboxylate (83) showed remarkable cytotoxic activity against human breast adenocarcinoma cell line (MCF-7 cells) either by using MTT assay or in Real Time Cell Analysis (Fig. 35). The compounds inhibited cancer cell growth in a dose- and time-dependent manner and their LC50 values, were accountable to compare to nocodazole, a well-established cytotoxic drug. The structure-activity relationship analysis suggested that the cytotoxicity of the synthesized compounds seems to be dependent on the electronic effects and lipophilicity of the substituent on the para position of the 6- and 8-phenyl rings. The structure-activity relationship analysis provided a guideline for the readers to design new derivatives with increased activity.

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Figure 35

Structure of [(6,8-diarylthieno[3,2-c]quinoline)]-2-carboxylates derivatives (81–83) showing remarkable cytotoxicity against MCF-7 cell line either by using MTT assay or in Real Time Cell Analysis.

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6.8 Thieno (2,3)-quinolone derivatives

Koruznjak et al. (2002) reported the novel synthesis scheme of thieno (39,29:4,5)thieno(2,3)-quinolone derivatives and performed their cytostatic activities against malignant cell lines: pancreatic (MiaPaCa2), breast (MCF7), cervical (HeLa), laryngeal (Hep2), colon (CaCo-2), melanoma (HBL), and human fibroblast cell lines (WI-38). All tested compounds exhibited strong inhibitory activities against all cell lines tested. The results showed that the compound (84), which bears the 3-dimethylaminopropyl substituent on quinolone nitrogen and methoxycarbonyl substituent on position 9, exhibited marked antitumor activity. On the contrary, compound (85), which also bears the 3-dimethylaminopropyl substituent on the quinolone nitrogen, but anilido substituent on position 9, exhibited less antitumor activity than the others (Fig. 36).

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Figure 36

Structure of compounds thieno (39,29:4,5)thieno(2,3)-quinolone derivatives (84 and 85). Compound (84) shows best anticancer activity while compound (85) shows least anticancer activity against MiaPaCa2, MCF7, HeLa, Hep2, CaCo-2, HBL and WI-38 cell lines.

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6.9 6H-indolo [2,3-b]quinoline derivatives

9-Anilinoacridine derivatives have been extensively studied as potential chemotherapeutic agents due to their capability of intercalating DNA, leading to the inhibition of topoisomerase II. Su et al. (1995) stated that further structural modification lead to the discovery of an improved broad spectrum antitumor agent, 3-(9-acridinylamino)-5-(hydroxymethyl)aniline (AHMA, 86), is capable of inhibiting the growth of certain solid tumors such as mammary adenocarcinoma, melanoma and lung carcinoma in mice (Fig. 37).

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Figure 37

Structure of compound 3-(9-acridinylamino)-5-(hydroxymethyl)aniline (AHMA, 86), capable of inhibiting the growth of certain solid tumors.

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These results promoted to synthesize and evaluate 4-anilinofuro[2,3-b]quinoline derivatives, which were structurally related to 9-Anilinoacridine derivatives.

Chen et al. (2004) synthesized and reported the anticancer evaluation of certain 11-substituted 6H-indolo[2,3-b]quinolines and their methylated derivatives. These 6H-indolo[2,3-b]quinoline derivatives were prepared from the commercially available 1,4-dihydroxyquinoline through alkylation, chlorination, nucleophilic reaction, and ring cyclization. The in vitro anticancer assay indicated that 5-methylated derivatives were more cytotoxic than their respective 6-methylated counterparts. Among them, 11-(4-methoxyanilino)-6-methyl-6H-indolo[2,3- b]quinoline (87) was the most cytotoxic with a mean GI₅₀ value of 0.78 μM and also exhibited selective cytotoxicities for HL-60 (TB), K-562, MOLT-4, RPMI-8226 and SR with GI₅₀ values of 0.11, 0.42, 0.09, 0.14, and 0.19 l μM, respectively (Fig. 38).

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Figure 38

Structure of compound 11-(4-methoxyanilino)-6-methyl-6H-indolo[2,3- b]quinoline (87) shows selective cytotoxicities for HL-60 (TB), K-562, MOLT-4, RPMI-8226 and SR cancer cells.

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The studies were further extended by Long et al. (2005) who had synthesized various 4-anilinofuro[2,3-b]quinoline and 4-anilinofuro (3,2-c) quinoline derivatives and evaluated their cytotoxic activity against various cancerous cell lines.

6.10 Tetrahydroquinoline and tetrahydropyrimidoquinoline derivatives

Studies clearly revealed that the quinoline and pyrimidine nucleuses are an important pharmacophore in various antitumor agents (Karthikeyan et al., 2015). Nowadays pyrimidine based potent anticancer drugs are available in the market, for example, gefitinib (IressaTM) (Wakeling et al., 2002) and erlotinib (TarcevaTM) (Moyer et al., 1997), and thus, it is considered as an attractive target for the design of new anticancer agents. Recently, several tetrahydroquinolines and their pyrimidine derivatives were synthesized and evaluated for their anticancer activity, and a number of tetrahydropyrimidoquinolines derivatives were reported for their anticancer activity (Faidallah and Rostomb, 2013; Alqasoumi et al., 2010).

Taking into consideration the above findings, and in an effort to identify novel potent anticancer leads through the combination of the two active anticancer moieties, Gedawy et al. (2015) prepared and reported several tetrahydroquinolines with different groups at C-2 and C-4 positions. Several tetrahydropyrimidoquinolin-4-amines and tetrahydropyrimidoquinoline-2,4-diamines with different aryl groups at position number 5 to substantiate were also reported and also marked their anticancer activity against both human colon carcinoma (HCT116) and human breast adenocarcinoma (MCF7) cell lines.

The results of in vitro anticancer activity showed that seven compounds 2-Oxo-4-(pyridin-2-yl)-1,2,5,6,7,8-hexahydroquinoline-3-carbonitrile (88); 2-Amino-4-(4-chlorophenyl)-8-isopropyl-5-methyl-5,6,7,8- tetrahydro-quinoline-3-carbonitrile (89); 2-Amino-4-(4-fluorophenyl)-8-isopropyl-5-methyl-5,6,7,8- tetrahydro-quinoline-3-carbonitrile (90); 5-(4-Chlorophenyl)-9-isopropyl-6-methyl-6,7,8,9-tetrahydropyrimido-[4,5-b]quinolin-4-amine (91); 5-(4-Fluorophenyl)-9-isopropyl-6-methyl-6,7,8,9-tetrahydropyrimido-[4,5-b]quinolin-4-amine (92); 5-(4-Chlorophenyl)-9-isopropyl-6-methyl-6,7,8,9-tetrahydropyrimido-[4,5-b]quinoline-2,4-diamine (93) and 5-(4-Fluorophenyl)-9-isopropyl-6-methyl-6,7,8,9-tetrahydropyrimido-[4,5-b]quinoline-2,4-diamine (94) possessed potent anticancer activity against both HCT-116 (colon) and MCF7 (breast) cell lines with IC₅₀ between 16.33 and 34.28 μM (Fig. 39). All these compounds were also reported more potent than imatinib (IC₅₀ = 34.40 lM) and tamoxifen (IC₅₀ = 34.30 lM). Out of these seven compounds, compound (94) was the most active against HCT-116 cell line with 2.1-fold more potent antitumor activity than imatinib, while compounds (88, 90 and 91) exhibited the highest anticancer activity against the MCF7 cell line, having 2–1.79-fold more potent anticancer activity than tamoxifen.

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Figure 39

Structure of novel tetrahydroquinoline (88–90), and tetrahydropyrimidoquinoline derivatives (91–94) possesses potent anticancer activity against both HCT116 and MCF7 cancer cell lines.

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On the basis of in vitro outcomes the researchers conclude that the anticancer activity of the synthesized quinoline and pyrimidoquinoline compounds appeared to be related to the cycloalkyl moiety fused to the pyridine ring, since the best activity was obtained by compounds bearing the branched cyclohexyl moiety (Compounds 91, 92, 93 and 94).

It was clear that the substituents in quinoline derivatives, at position 2 had a marked effect on the anticancer activity, since the compounds with carbonyl or amino groups possessed potent anticancer activity, while those with the chloro group at C-2 position were inactive. Thus, it was concluded that the tetrahydroquinolines and their fused pyrimidine derivatives represented a novel and promising class of anticancer agents, so researcher proposed further studies to explore the mechanism of action and to optimize the anticancer activity of these derivatives.

6.11 1,3,4-Thiadiazol, tetrazole and quinoline derivatives

1,3,4-Thiadiazol, tetrazole and quinoline derivatives have been reported as promising candidates for anticancer activity. Number of articles have been published for thiadiazol, tetrazole and quinoline containing compounds possessed anticancer activity. Understanding these facts Sheetal et al. (2012) reported N-[4-acetyl-5-(6, 7, 8-substituted-2-chloroquinolin-3-yl)- 4,5-dihydro-1,3,4-thiadiazol-2-yl]-acetamides compound possessed anticancer and anti-tubercular activity. The researchers extended their study and introduced a new heterocyclic compound had tetrazole moiety with quinoline derivatized with 1,3,4- thiadiazolidine ring. The synthesized N- (4-acetyl-4,5-dihydro - 5- (7,8,9- substituted - tetrazolo [1,5-a] - quinolin-4-yl) - 1,3,4-thiadiazol -2- yl) acetamides compounds were screened for their in vitro cytotoxic activity against two cell lines viz., human breast cancer cell line MCF7 and human cervix cancer cell line HeLa. The GI₅₀, LC₅₀ and TGI values were evaluated. The DNA cleavage study was also reported. Compounds (95 and 96) with halogen substituent at 7th position of the target molecules showed potent cytotoxicity against human cervix cancer cell line HeLa (Fig. 40). DNA cleavage studies revealed that most of these compounds showed partial cleavage and few of them showed complete cleavage of DNA.

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Figure 40

Structure of N- (4-acetyl-4,5-dihydro - 5- (7,8,9- substituted - tetrazolo [1,5-a] - quinolin-4-yl) - 1,3,4-thiadiazol -2- yl) acetamide derivatives (95 and 96) with halogen substituent at 7th position showing potent cytotoxicity against HeLa cancer cell line.

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6.12 Pyrimidoquinoline derivatives

Al-Said et al. (2011) reported in their study synthesis and investigation of the antiproliferative activity of new quinoline and pyrimidoquinoline derivatives containing a free sulfonamide moiety. Several compounds had been synthesized which exhibited significant anticancer activity. Quinoline compounds (97) having substituted benzamide, free amino group, butanamide, showed remarkable anticancer activity against Ehrlich Ascites Carcinoma (EAC) cells (Fig. 41). Docking of these synthesized compounds in the carbonic anhydrase active site suggested that the synthesized compounds may act as carbonic anhydrase inhibitors and this may contribute in part to their anticancer activity.

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Figure 41

Structure of pyrimidoquinoline derivatives (97) showing remarkable anticancer activity against Ehrlich Ascites Carcinoma (EAC) cells.

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6.13 Quinoline sulfonamide derivative

Quinoline and sulfonamide derivatives are important biologically active compounds that possess potent antitumor activity (Kouznetsov et al., 2006). Acetylation of histones in chromatin involved in the regulation of gene transcription and is tightly controlled by the balance of acetyltransferase (HATs) and deacetylase (HDAC) activities. HDACs mediate changes in nucleosome conformation are important in the regulation of gene expression and also are involved in cell cycle progression and differentiation. Alterations of HDACs were identified in tumor cells and contributed to the massive perturbations of gene expression in numerous tumors. HDAC inhibition leads to differentiation, cell cycle arrest and apoptosis in tumor cells (Hsi et al., 2004). Recently new set of sulfonamide derivatives have been reported as potent histone deacetylases inhibitors (HDACIs) (Finn et al., 2005; Ghorab et al., 2007).

6.14 6-Methoxy- 8- [(2-furanylmethyl)amino]- 4-methyl -5- (3 trifluoro-methylphenyloxy) quinoline derivatives

Cancer cells have a tendency to reduce capacity of gap junction inter-cellular communication (GJIC). The enhancement of GJIC induced apoptosis, decreased cell viability, and attenuated tumor growth.

Heiniger et al. (2010) reported a second generation of PQ analogues [PQ7 i.e. 6- methoxy- 8- [(2-furanylmethyl)amino]- 4-methyl -5- (3 trifluoro-methylphenyloxy) quinoline, 99] and examined its activates GJIC activity mediated tumor growth inhibitory activity in xenograft T47D mice (Fig. 42). Scrape load/dye transfer and colony growth assays were performed to measure GJIC and tumor formation of T47D breast cancer cells. Results showed that PQ7 (98) at 500 nM induced a 16-fold increased in the GJIC in T47D cells, and 50% decreased of colony growth with 100 nM concentration. PQ7-treated nu/nu mice showed a 100% regression of xenograft tumor growth of T47D cells. The authors concluded that the second-generation PQ7 (98) had a promising role in exerting anti-tumor activity in human breast cancer cells.

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Figure 42

Structure of compound PQ7 (6- methoxy- 8- [(2-furanylmethyl)amino]- 4-methyl -5- (3 trifluoro-methylphenyloxy) quinoline, 98) having promising anticancer activity against T47D breast cancer cells.

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6.15 N-2[4 Dimethylamino)ethyl]acridine-4-carboxamide derivatives

Acridine-4-carboxamides have been reported as a new generation of intercalators which are active against solid tumors and leukemia. A number of studies have been reported for their capacity to bind to DNA, for their DNA-damaging activity in whole cells and isolated nuclei, and for their inhibitory effect on RNA synthesis in a cell-free system (Atwell et al., 1987; Denny et al., 1990). A model of the acridine-4-carboxamide-DNA complexes were proposed by Wakelin and Denny (1990), suggesting intercalation of acridine ring between base pairs with the 4-carboxamide moiety located in the minor groove. The proposed structure of the substituent at position 4 seems to be the important factor in the stabilization of the drug-DNA complex as well as in the GC specificity of these acridines (Bailly et al., 1992). An antitumor drug N-[2-(dimethylamino)ethyl]acridine-4-carboxamide (DACA, 99) a acridine-4-carboxamide congener and its three close structural analogues N-[2-(hydroxyethylamino)ethyl]acridine-4-carboxamide (DACAH, 100), N-[2-(dimethylamino) ethyl]-9-aminoacridine-4-carboxamide (amino-DACA, 101), and N-[2-(hydroxyethylamino)ethyl]-9-aminoacridine- 4-carboxamide (amino-DACAH, 102) were further studied by the same research group to determine their ability to inhibit RNA synthesis in vitro and to form topoisomerase II-mediated DNA lesions in relation to cell-killing activity (Fig. 43). Results showed that the stabilization of the cleavable complex of topoisomerase II with DNA by acridine-4-carboxamides is not as important for the cytotoxic action of these compounds, but the compounds which can penetrate cell membrane easily and are able to form a strong intercalative complex with DNA, for example amino-DACA, may enhance DNA cleavage by topoisomerase II. The enhancement of DNA cleavage occurs only when used at low doses while at higher concentrations they act as catalytic inhibitors. The results also suggested that the compound having 4-carboxamide chain attached with N-2-(dimethylamino)ethyl moiety resulted in more efficient transport through cell membranes, higher cytotoxicity, and DNA-damaging activity. Thus compound amino-DACA, which easily penetrates the cell membrane, fully inhibited DNA break formation, whereas other analogues exhibited a lower degree of protection when used at high concentration.

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Figure 43

Structure of N-2[4 Dimethylamino)ethyl]acridine-4-carboxamide derivatives (99–102) having DNA cleavage property.

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