Antitumor Agents 155. Synthesis and Biological Evaluation of 3',6,7-Substituted 2-Phenyl-4-quinolones as Antimicrotubule Agents

Abstract

A series of 3',6,7-substituted 2-phenyl-4-quinolones were designed and synthesized as antimitotic antitumor agents. All compounds showed cytotoxic effects (log GI50 < or = -4.0; log drug molar concentration required to cause 50% inhibition) against the growth of a variety of human tumor cell lines, including those derived from solid tumors such as non-small cell lung, colon, central nervous system, ovary, prostate, and breast cancers, when evaluated in the National Cancer Institute's 60 human tumor cell line in vitro screen. The most potent compound (26) demonstrated strong cytotoxic effects with GI50 values in the nanomolar or subnanomolar range in almost all the tumor cell lines. Compound 26 was also a potent inhibitor of tubulin polymerization and radiolabeled colchicine binding to tubulin, with activity comparable to those of the potent antimitotic natural products colchicine, podophyllotoxin, and combretastatin A-4.

Synthesis and Biological Evaluation of Some Polymethoxylated Fused Pyridine Ring Systems as Antitumor Agents

“…Some 2-aminoquinazolines, their aza analogues, and the other fused pyridine analogues such as 5-deazaaminopetrin [17] and quinolones [18] interfere with the folic acid synthesis. These findings rationalized the design and synthesis of some pyrazolo [4,3-c]pyridine, pyrido [4,3-d]pyrimidine, pyrano [3,2-c]pyridine, and pyrido[3,2-c]pyridine targets carrying an arylidene moiety to be evaluated as antitumor agents which may exert their activity through folic acid synthesis inhibition.…”

Novel antitumor agents from higher plants

“…65 Synthetic 2-phenyl-4-quinolones (e.g., 62-65) contain a ring nitrogen instead of the oxygen found in the natural compounds and showed promising cytotoxic activity. 66 In a series of 3Ј,6,7-substituted compounds, 67 several compounds, including 62 and 63, showed impressive differential cytotoxicity against human tumor cell lines and were potent inhibitors of tubulin polymerization with activity nearly comparable to those of the potent antimitotic natural products colchicine (86), podophyllotoxin (14), and combretastin A-4. The most potent compound 2-(3Ј-methoxyphenyl)-6-pyrrolinyl-4-quinolone (62) had GI 50 values in the nanomolar or subnanomolar range (average log GI 50 ϭ Ϫ8.73).…”

Anticancer Drug Design Based on Plant-Derived Natural Products¹

“…Changes in the N-substituent at C(7) are also generally well tolerated in regards to antitubulin activity, and many derivatives have been reported [2,6,8,10,14,[45][46][47]55]. Thiocolchinoids with substituted benzyl amines (40)(41)(42)(43) and aroyl amides (44-46) had comparable antitubulin activity and comparable or greater cytotoxicity to those of thiocolchicine; the thiocolchicine derivative with a 4)-cyanobenzamide substituent at C(7) (44) was the most potent compound [55]. In additional modifications, we compared 26 analogs where ketone (47, thiocolchicone), hydroxy (48), and ester (49,50) groups had replaced the C-7 acetamido group [53].…”

“…The synthetic target compounds contain a ring nitrogen instead of the oxygen found in the natural compounds. The initially synthesized 2-phenyl-4-quinolones [35] showed promising activity, and subsequent studies investigated many substituents and substitution patterns in the A and C rings [39,40]. Several compounds showed impressive differential cytotoxicity against human tumor cell lines and were potent inhibitors of tubulin polymerization with activity nearly comparable to those of the potent antimitotic natural products colchicine (25), podophyllotoxin (13), and combretastin A-4.…”