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Microtubules are dynamic structures, which play a crucial role in cellular division and are recognized as an important target for anti-cancer therapy (Jordan & Wilson, 2004). A number of naturally occurring compounds, e.g., paclitaxel, epithilone A, vinblastine, dolastatin 10, combretastatin A-4 (CA4) and colchicine (COL, cf. Figure 1), exhibit anti-cancer properties by interfering with tubulin de/polymerization dynamics, resulting in mitotic arrest.
Figure 1. Natural tubulin polymerization inhibitor colchicine
Reports showed that drugs binding to COL domain underwent research as vascular-disrupting agents for cancer therapy; e.g., clinical candidates of microtubule inhibitor, CA4 phosphate (CA4P, Zybrestat) and AVE-8062 (Ombrabulin), act as vascular disrupting agent (VDA), which rapidly depolymerize microtubules of newly formed vasculatures and subsequently shut down the blood supply to tumours (Dark et al., 1997; Gaya & Rustin, 2005; Hinnen & Eskens, 2007; Lippert, 2007; Patterson & Rustin, 2007; Siemann, 2006; Siemann et al., 2005, 2009; Tozer et al., 2005, 2008). Sulphonamide-containing small-molecule compound, ABT-751, showed efficacious anti-mitotic activity, by tubulin polymerization inhibition, and underwent clinical trials (Fox et al., 2008; Mauer et al., 2008). Current available clinically used chemotherapeutic microtubule inhibitors present high toxicity, and potential is limited by multidrug resistance (MDR) development. There was great interest in identifying novel microtubule inhibitors, which overcame various resistance models and exhibited improved pharmacology profiles (Chaplin et al., 2006; Hsieh et al., 2005; Li & Sham, 2002; Liou et al., 2007, 2008; Mahindroo et al., 2006; Prinz et al., 2009; Reddy et al., 2008; Romagnoli et al., 2008; Simoni et al., 2008; Tron et al., 2006). Quinolines are a pharmacologically active class of heterocyclic compounds (Joule et al., 1995). Microtubule-inhibitors analysis indicated that 3,4,5-trimethoxyphenyl/3,4,5-trimethoxybenzoyl and p-methoxyphenyl groups play an important role in bioactivity. Nien et al. (2010) explored core quinoline, coupled with group 3,4,5-trimethoxybenzoyl, as tubulin polymerization inhibitors (cf. Figure 2a–c) .
Figure 2. (a) quinoline 1: R = 2-(3’,4’,5’-trimethoxybenzoyl); X = H; 2: R = 3-(3’,4’,5’-trimethoxybenzoyl); X = H; 3: R = 4-(3’,4’,5’-trimethoxybenzoyl); X = H; 4: R = 5-(3’,4’,5’-trimethoxybenzoyl); X = H; 5: R = 6-(3’,4’,5’-trimethoxybenzoyl); X = H; 6: R = 7-(3’,4’,5’-trimethoxybenzoyl); X = H; 7: R = 8-(3’,4’,5’-trimethoxybenzoyl); X = H; 8: R = 2-(3’,4’,5’-trimethoxybenzoyl); X = 6-O–CH3; 9: R = 4-(3’,4’,5’-trimethoxybenzoyl); X = 8-O–CH3; 10: R = 6-(3’,4’,5’-trimethoxybenzoyl); X = 2-O–CH3; (b) 11: 5-amino-6-methoxy-2-(3’,4’,5’-trimethoxybenzoyl)quinoline; (c) 12: Y = O–; 13: Y = CH3 (I–); (d) 2-aroyl-5,6,7- 14: R = 4’-methoxy; 15: R = 3’-fluoro-4’-methoxy; (e) 4-aroyl-6,7,8- 16: R = 4’-methoxy; 17: R = 3’-fluoro-4’-methoxy; 18: R = 4’-N,N-dimethylamino; (f) 2-aryl-5,6,7-TMQs 19: R = 4’-methoxy; 20: R = 3’-fluoro-4’-methoxy