| Streptonigrin (SN) is a highly potent anti-cancer drug which exhibits a broad spectrum of activity against various tumors and is known to mediate its antineoplastic action by the extensive degradation of DNA. In the past decade various analogues of SN had been synthesized and a structure activity relationship has been developed. However, the literature is devoid of a unifying rationale amongst these analogues in terms of the activities associated with them.;We also examined the mechanism of DNA degradation by SN and its analogues. Some diagnostic leads were obtained concerning the crucial roles played by the reducing agent NADH and the metal ion. It was learned that the reductant does not reduce the para quinone moiety of the drug to a hydroquinone as proposed by Lown; the reduction transforms the drug into an unstable intermediate, which we believe to be the semiquinone. Similarly, we also found that the metal ion does not participate in the redox cycle; it simply seems to form a drug(reduced)-metal complex which intercalates with DNA and causes extensive degradation of the latter.;After making a careful examination of the previous work we were able to formulate a Redox Potential Theory (RPT) which nicely correlates the in vitro activities of the analogues with their structures. On the basis of this RPT we synthesized a large variety of new SN analogues whose activities confirm the above postulate. These analogues comprise of 2,3-disubstituted-1,4-naphthalenediones, 6,7-disubstituted-5,8-quinoline, isoquinoline, quinoxoline, quinazoline, phthalazinediones, and 2-(o-nitrophenyl)-6,7-disubstituted-5,8-quinolinediones. The result of these further studies has been to reveal substances which have substantially greater in vitro activity than those of previously known analogues and of SN itself. |
