Novel quinolines bearing a biologically active trimethoxyphenyl moiety as a new class of antitumor agents

Abstract

The present paper describes the synthesis of some novel 2-amino-4-substituted aryl-5-oxo-1-(3,4,5-trimethoxy)-l,4,5,6,7,8-hexahydroquinoline-3-carbonitriles 6a–s starting with 3-(3,4,5-trimethoxyanilino)cyclohex-2-enone 3. All the newly synthesized compounds were evaluated for their in vitro antitumor activity. Compounds 6j, 6ρ and 6q showed higher activity with IC₅₀ values 10, 10, 15 μg/mL, respectively, when compared with doxorubicin as a reference drug (IC₅₀ value 37.5 μg/mL).

Key words

Antitumor activity - Cyclohexane-l,3-dione - Quinoline derivatives - Synthesis - 3,4,5-Trimethoxyaniline

• References

• 1 Balkenhohl F, Bussche-Hunnefeld C, Lansky A, Zechel C. Combinatorial Synthesis of Small Organic Molecules. Angew Chem Int Ed Eng. 1996; 35: 2288-337
• 2 Nefzi A, Ostresh JM, Houghten RA. The current status of heterocyclic combinatorial libraries. Chem Rev. 1997; 97: 449-
• 3 Loughlin WA. Combinatorial synthesis: a heterocyclic chemist’s perspective. Aust J Chem. 1998; 52: 875-93
• 4 Chen YL, Huang CJ, Huang ZY, Tseng CH, Chang FS, Yang SH et al. Synthesis and antiproliferative evaluation of certain 4-anilino-8-methoxy-2-phenylquinoline and 4-anili-no-8-hydroxy-2-phenylquinoline derivatives. Bioorg Med Chem. 2006; 14: 3098-105
• 5 Ghorab MM, Ragab FA, Hamed MM. Design, synthesis and anticancer evaluation of novel tetrahydroquinoline derivatives containing sulfonamide moiety. Eur J Med Chem. 2009; 44: 4211-7
• 6 Gopal M, Shenoy S, Doddamani LS. Antitumor activity of 4-amino and 8-methyl-4-(3diethylaminopropylamino)pyrimi-do[4′,5′ : 4,5]-thieno(2,3-b)quinolines. J Photochem Photobiol B. 2003; 72: 69-78
• 7 Zhao YL, Chen YL, Chang FS, Tzeng CC. Synthesis and cytotoxic evaluation of certain 4-anilino-2-phenylquinoline derivatives. Eur J Med Chem. 2005; 40: 792-7
• 8 Kim YH, Shin KJ, Lee TG, Kim E, Lee MS, Ryu SH et al. G2 arrest and apoptosis by 2-amino-N-quinoline-8-yl-benze-nesulfonamide (QBS), a novel cytotoxic compound. Biochem Pharmacol. 2005; 69: 1333-41
• 9 Ghorab MM, Ragab FA, Noaman E, Heiba HI, El-Hossary EM. Utility of 4-(5,5-dimethyl-3-oxo-cyclohex-l-enylami-no)-benzene-sulfonamide in the synthesis of novel quino-lines as possible anticancer and radio protective agents. Arzneimittelforschung. 2007; 58 (1) 35-41
• 10 Ghorab MM, Ragab FA, Noaman E, Heiba HI, El-Hossary EM. Synthesis of some novel quinolines and pyrimido[4,5-b] qui-nolines bearing sulfonamide moiety as potential anticancer and radio protective agents. Arzneimittelforschung. 2007; 57 (12) 795-803
• 11 Romagnoli R, Baraldi PG, Carrion MD, Cruz-Lopez O, Cara CL, Tolomeo M et al. Synthesis and biological evaluation of 2-amino-3-(3′,4′,5′-trimethoxybenzoyl)-6-substituted-4,5,6,7-tetrahydrothieno[2,3-c]pyridine derivatives as antimitotic agents and inhibitors of tubulin polymerization. Bioorg Med Chem Lett. 2008; 18: 5041-5
• 12 Tron GC, Pirali T, Sorba G, Pagliai F, Busacca S. Genazzani AA. J Med Chem. 2006; 49: 3033-44
• 13 Cushman M, Nagarathnam D, Gopal D, He HM, Lin CM, Hamel E. Synthesis and evaluation of analogs of (Z)-l-(4-methoxyphenyl)-2-(3,4,5-trimethoxyphenyl)ethene as potential cytotoxic and antimitotic agents. J Med Chem. 1992; 35: 2293-306
• 14 El-Merzabani MM, El-Aaser AA, El-Dueini AK, El-Masry AM. A bioassay of antimitotic alkaloids of Catharanthus ro-seus. Planta Med. 1979; 36: 87-90
• 15 Raffa D, Daidone G, Maggio B, Cascioferro S, Plescia F, Schillaci D. Synthesis and antileukemic activity of new 3-(5-methylisoxazol-3-yl) and 3-(pyrimidin-2-yl)-2-styrylquin-azolin-4(3H)-ones. IL Farmaco. 2004; 59: 451-5
• 16 Takemoto DJ, Dunford C, McMurray MM. The cytotoxic and cytostatic effects of the bitter melon (Momordica char-antia) on human lymphocytes. Toxicon. 1982; 20: 593-9
• 17 El-Merzabani MM, El-Aaser AA, Attia MA, El-Duweini AK, Ghazal AM. Screening system for Egyptian plants with potential anti-tumour activity. Planta Med. 1979; 36: 150-5