Synthesis, tissue distribution and cytostatic properties of two new daunorubicin derivatives of 2-thiouracil containing a guanidine bridge.
In further attempts to utilize the affinity of 2-thiouracil for melanin-producing tissues in the design of drugs active against malignant melanomas, guanidine-bridged adducts of the anthraquinone drug daunorubicin (1a) with 2-thiouracil were prepared (Scheme 3). The expected adduct (4), and a by-product in its preparation (5) (Scheme 3), were inactive against murine melanoma, in vivo, and did not show affinity for melanin-producing tissues. They were efficient DNA intercalating agents, but were much less cytostatic than daunorubicin against Cloudman melanoma, and were inactive, in vitro, against human cervical carcinoma MS 751. The coupling chemistry employed may have application in current attempts to effect binding of drugs to high molecular weight targeting antigens.
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000493:pharmacokinetics* / Q000494:pharmacology; D055598:Chemical Phenomena; D002621:Chemistry; D003630:Daunorubicin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D004317:Doxorubicin / Q000494:pharmacology; D006146:Guanidines / Q000138:chemical synthesis / Q000493:pharmacokinetics; D007273:Injections, Intramuscular; D008297:Male; D008546:Melanoma, Experimental / Q000188:drug therapy / Q000378:metabolism; D051379:Mice; D008811:Mice, Inbred DBA; D013889:Thiouracil / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D014018:Tissue Distribution; D014407:Tumor Cells, Cultured / Q000187:drug effects
D000970:Antineoplastic Agents; D006146:Guanidines; D013889:Thiouracil; D004317:Doxorubicin; D003630:Daunorubicin