Antitumor Agents. 174. 2‘,3‘,4‘,5,6,7-Substituted 2-Phenyl-1,8-naphthyridin-4-ones:  Their Synthesis, Cytotoxicity, and Inhibition of Tubulin Polymerization

Abstract

Two series of 2',3',4',5,6,7-substituted 2-phenyl-1,8-naphthyridin-4-ones and 2-phenylpyrido[1,2-alpha]pyrimidin-4-ones have been synthesized and evaluated as cytotoxic compounds and as inhibitors of tubulin polymerization. Most 2-phenyl-1,8-naphthyridin-4-ones showed potent cytotoxic and antitubulin activities, whereas 2-phenylpyrido[1,2-alpha]pyrimidin-4-ones showed no activity in either assay. In general, a good correlation was found between cytotoxicity and inhibition of tubulin polymerization in the 2-phenyl-1,8-naphthyridin-4-one series. The 2-phenyl-1,8-naphthyridin-4-ones (44-49) with a methoxy group at the 3'-position showed potent cytotoxicity against most tumor cell lines with GI50 values in the low micromolar to nanomolar concentration range in the National Cancer Institute's 60 human tumor cell line in vitro screen. Introduction of substituents (e.g. F, Cl, CH3, and OCH3) at the 4'-position led to compounds with reduced or little activity and substitution at the 2'-position resulted in inactive compounds. The effects of various A-ring substitutions on activity depend on the substitution in ring C. Compounds 44-50 were potent inhibitors of tubulin polymerization, with activity nearly comparable to that of the potent antimitotic natural products colchicine, podophyllotoxin, and combretastatin A-4. Compounds 44-49 also inhibited the binding of radiolabeled colchicine to tubulin, but the inhibition was less potent than that obtained with the natural products. Further investigation is underway to determine if substitution at the 3'-position and multisubstitutions in ring C will result in compounds with increased activity.

Cytotoxic Activity and Three-Dimensional Quantitative Structure Activity Relationship of 2-Aryl-1,8-naphthyridin-4-ones

“…The effects of substitutions at the C5, C6 and C7-positions depend on the substitution at the C2-position in 1,8-naphthyridin, which is consistent with the previously reported trend (Chen et al, 1997). The introduction of a naphthyl group at C2-position increased cytotoxicity and methoxy substituted compounds at both the C2`and C4`-positions were more active than those substituted at the C3`and C4`-positions in 1,8-naphthyridin.…”

“…For example, vinca alkaloids inhibit tubulin polymerization into microtubules and taxoids promote microtubule assembly (Rowinsky and Donehower, 1992;Verwij et al, 1994). Colchicine is another antimitotic agent, but it is not used clinically due to its high toxicity (Hastie, 1991;Chen et al, 1997).…”

“…To find more potent antimitotic compounds, some researchers have synthesized new flavonoid analogues, such as 2-arylquinolin-4-ones (Xia et al, 1998;Lai et al, 2005;Nakamura et al, 2005), 2-arylnaphthyridin-4-ones (Chen et al, 1997;Zhang et al, 1999), and 2-arylquinazolin-4-ones (Hamel et al, 1996;Hour et al, 2000;Xia et al, 2001). Some of these compounds, especially 2-arylnaphthyridin-4-ones, exhibit potent cytotoxicity; thus, we synthesized a series of substituted 2-arylnaphthyridin-4-one analogues and conducted cytotoxicity assays in human tumor cell lines (Chung, 2004).…”

Anticancer Drug Design Based on Plant-Derived Natural Products¹

“…Another structurally related series, the 2-aryl-1,8-naphthyridin-4-ones (general structure 65 and 66-81), contain a second nitrogen at position 8 in the aromatic A ring. Compounds with meta-substituted phenyls (methoxy-, chloro-, or fluoro-) or ·-naphthyl groups at the C-2 position showed potent cytotoxicity in NCI)s 60 humor tumor cell line panel with GI 50 values in the low micromolar to nanomolar range (tables 6, 7) [15,16]. The tumor cell line selectivity varied with the various substituents.…”

Synthesis, Photochemical Synthesis and Antitumor Evaluation of Novel Derivatives of Thieno[3',2':4,5]thieno[2,3-c]quinolones.

“…In comparison with antitumor activity of other quinolones 2,[26][27][28][29][30] the substances tested in these experiments are very strong inhibitors of tumor cell proliferation at very small concentrations.…”