Treatment failure due to drug resistance remains a serious problem in cancer therapy and a need continues to exist for new agents capable of overcoming cellular drug resistance. Among clinical drugs, adriamycin (doxorubicin), an anthracycline antibiotic, evidences the broadest antitumor spectrum and is one of the most widely used agents in chemotherapy. Yet a number of high-morbidity carcinomatous tumors are intrinsically insensitive to its cytotoxic effects, while other tumors can become resistant as a result of therapy with adriamycin or other cytotoxic agents (pleiotropic or multidrug resistance). Recently we have identified two exciting therapeutic leads, represented by hybrid nitrosoureidoanthracyclines and novel lipophilic N-alkylanthracyclines, for bypassing anthracycline and multidrug resistance. For each analogue-type, prototype compounds have been found which are therapeutically superior to adriamycin and less toxic in normally-responsive murine tumor model systems, and which retain activity in one or more in vitro and/or in vivo test systems normally exhibiting resistance to adriamycin cytotoxicity. The present proposal seeks to conduct detailed systematic structure-activity studies with these analogue-types in an attempt to identify optimally active congeners for potential clinical evaluation against adriamycin-resistant cancers. The specific objectives of this project are: (1) to prepare key intermediates for the preparation of structurally-modified N-alkylanthracyclines and nitrosoureidoanthracyclines (these intermediates are often common to the derivation of both analogue-type products); (2) to prepare various N-alkylanthracyclines modified at the aglycone 4-position, the side-chain 14-position, and the 3'-amino and/or 4'-hydroxyl position of the parent anthracycline glycoside; or in which the natural daunosamine glycoside is replaced by other N-alkyl-substituted aminoglycoside functions; (3) to prepare similarly modified nitrosoureidoanthracyclines, with special attention directed towards products wherein an adjacent nitrosoureido and hydroxyl function are in the more desirable trans geometric arrangement for enhanced chemical stability; (4) to evaluate these target compounds in appropriate in vitro growth inhibition and colony-formation assays and in vivo experimental murine tumor assays to determine their biological activities and to provide early indication of their ability to overcome resistance to adriamycin; additionally, active products will be evaluated for their relative DNA binding ability and potential for inhibition of nucleic acid synthesis, factors which may provide early insight on their mechanistic effects; (5) to provide samples of compounds of greatest interest to collaborating investigators for biochemical studies relating to mechanisms of drug action (alkaline elution assays, DNA unwinding assays, DNA topoisomerase II inhibition assays, DNA crosslinking and repair of damage assays) and for determination of activity profiles against human xenograft tumor models; and (6) to correlate data on structural modifications vs. biological effects in order to select promising agents for further preclinical development.
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