Tricyclodecenetetracarboxydiimides and their antitumor activity

Zhubanov, B. A.; Boiko, G.I.; Abdulin, K. A.; Umerzakova, M. B.; Ibraeva, Zh. K.

doi:10.1007/bf00766364

Pharm Chem J

1991

DOI: 10.1007/bf00766364

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Tricyclodecenetetracarboxydiimides and their antitumor activity

B. A. Zhubanov

G.I. Boiko

K. A. Abdulin

et al.

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1997

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“…Even though mitindomide has been shown to slowly (over 12 hr) promote DNA-interstrand cross-linking (4), the mechanism by which mitindomide or its analogs exert their antitumor effects has never been identified. Problems with low aqueous solubility of mitindomide (3,5,6) led to the development of a number of more soluble N-substituted analogs (3,4,(7)(8)(9), some of which also displayed good antitumor activity. The N-substituted mitindomide analog fetindomide (NSC 373965) has been shown (10) to hydrolyze to mitindomide, suggesting that mitindomide is the active form of fetindomide.…”

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confidence: 99%

Mitindomide Is a Catalytic Inhibitor of DNA Topoisomerase II That Acts at the Bisdioxopiperazine Binding Site

et al. 1997

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SUMMARYThe antitumor drug mitindomide (NSC 284356) was shown to inhibit the decatenation activity of human and Chinese hamster ovary (CHO) topoisomerase II [DNA topoisomerase (ATP-hydrolyzing), EC 5.99.1.1]. Mitindomide did not induce the formation of topoisomerase II-DNA covalent cleavable complexes in CHO cells. These results taken together indicate that mitindomide is a catalytic/noncleavable complex-forming-type inhibitor of topoisomerase II. The growth inhibitory effects of mitindomide and dexrazoxane toward a sensitive parent CHO cell line and the dexrazoxane-resistant DZR cell line, which is highly (500-fold) resistant to the bisdioxopiperazine dexrazoxane, were measured. The DZR cell line was shown to be 30-fold cross-resistant to mitindomide. Mitindomide, like dexrazoxane, was shown to inhibit cleavable complex formation by the topoisomerase II poison etoposide. The attenuated inhibition of etoposide-induced cleavable complexes in DZR compared with CHO cells was, likewise, very similar for dexrazoxane and mitindomide. Together these results suggest that mitindomide acts at the same site on topoisomerase II as does dexrazoxane and other bisdioxopiperazines. Various molecular parameters obtained by molecular modeling were compared for mitindomide and dexrazoxane. Mitindomide, which is conformationally very rigid, has highly coplanar imide rings, as does dexrazoxane in the solid state. Other molecular parameters, such as the imide nitrogen-to-imide nitrogen bond distances, and polar and nonpolar surface areas were also very similar. Thus, it is concluded that mitindomide exerts its antitumor effects through its inhibition of topoisomerase II by binding to the bisdioxopiperazine binding site.Mitindomide (NSC 284356) (Fig. 1) and a number of its analogs have been shown to have good antitumor activity (1-3). Even though mitindomide has been shown to slowly (over 12 hr) promote DNA-interstrand cross-linking (4), the mechanism by which mitindomide or its analogs exert their antitumor effects has never been identified. Problems with low aqueous solubility of mitindomide (3, 5, 6) led to the development of a number of more soluble N-substituted analogs (3, 4, 7-9), some of which also displayed good antitumor activity. The N-substituted mitindomide analog fetindomide (NSC 373965) has been shown (10) to hydrolyze to mitindomide, suggesting that mitindomide is the active form of fetindomide.The bisdioxopiperazine dexrazoxane (Fig. 1), like mitindomide, is also a bis imide. We and others have shown that the bisdioxopiperazines dexrazoxane (ICRF-187; Zinecard, ADR-529) (Fig. 1), ICRF-159 (razoxane, the racemic form of dexrazoxane), and ICRF-193 (Fig. 1) are strong inhibitors of mammalian topoisomerase II (11,12). Razoxane was developed originally as an antitumor agent (13). Dexrazoxane is, however, now clinically used for the prevention of doxorubicininduced cardiotoxicity (14), and presumably acts through its EDTA-like hydrolysis product (15) by inhibiting iron-dependent oxygen free radical formation.Topoisomerase II...

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Mitindomide Is a Catalytic Inhibitor of DNA Topoisomerase II That Acts at the Bisdioxopiperazine Binding Site

et al. 1997

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Tricyclodecenetetracarboxydiimides and their antitumor activity

Cited by 1 publication

References 2 publications

Mitindomide Is a Catalytic Inhibitor of DNA Topoisomerase II That Acts at the Bisdioxopiperazine Binding Site

Mitindomide Is a Catalytic Inhibitor of DNA Topoisomerase II That Acts at the Bisdioxopiperazine Binding Site

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