Antitumor Agents. I. DNA Topoisomerase II Inhibitory Activity and the Structural Relationship of Podophyllotoxin Derivatives as Antitumor Agents

• Published in: Chemical & pharmaceutical bulletin Vol. 40; no. 10; pp. 2720 - 2727
• Main Authors: TERADA, Tadafumi, FUJIMOTO, Katsuhiko, NOMURA, Makoto, YAMASHITA, Jun-ichi, KOBUNAI, Takashi, TAKEDA, Setsuo, WIERZBA, Konstanty, YAMADA, Yuji, YAMAGUCHI, Hideo
• Format: Journal Article
• Language: English
• Published: Tokyo The Pharmaceutical Society of Japan 1992; Maruzen; Japan Science and Technology Agency
• Subjects: Animals; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; antitumor agent; Chemistry; cytotoxicity; desoxypodophyllotoxin; DNA topoisomerase II; Exact sciences and technology; Heterocyclic compounds; Heterocyclic compounds with o, s, se, te hetero atom and condensed derivatives; in vitro; in vivo; Leukemia P388 - drug therapy; Mice; Organic chemistry; Podophyllotoxin - analogs & derivatives; Podophyllotoxin - chemistry; Podophyllotoxin - pharmacology; podophyllotoxin derivative; Preparations and properties; Sarcoma, Experimental - drug therapy; structural relationship; Structure-Activity Relationship; synthesis; Topoisomerase II Inhibitors; tubulin polymerization; Antineoplastic agent; Rodentia; Enzyme inhibitor; Lactone; Tetracyclic compound; Oxygen heterocycle; In vitro; In vivo; Vertebrata; Mammalia; Structure activity relation; Mouse; Animal; Aromatic compound
• ISSN: 0009-2363; 1347-5223
• DOI: 10.1248/cpb.40.2720

Various podophyllotoxin derivatives from desoxypodophyllotoxin (DPT) were synthesized to examine the structural relationships between the biological significance (cytotoxic effect, effects on DNA topoisomerase II and tubulin polymerization) in vitro and antitumor activity in vivo (L 1210).An intact 6, 7-methylenedioxy group of DPT is necessary to inhibit tubulin polymerization and topoisomerase II. 4'-Phenolic hydroxyl group of DPT is essential to inhibit DNA topoisomerase II and the inhibitory effect on DNA topoisomerase II contributes to a high cytotoxicity.The introduction of an aminoalkoxy group at 1-position of DPT enhances the inhibitory activity against DNA topoisomerase II and cytotoxic effect, causing the inhibitory activity against tubulin polymerization to disappear. The results of antitumor test in mice bearing L 1210 on podophyllotoxin derivatives suggest the following : 1) the strong cytotoxic effect itself is not a good indication of antitumor activity in vivo as long as it is associated with inhibition of tubulin polymerization. DNA topoisomerase II inhibitory effect contributes to an antitumor activity in vivo; 2) detailed measurements of cytotoxicity and inhibition on DNA topoisomerase II and tubulin polymerization in vitro are necessary to evaluate podophyllotoxin derivatives.