Vinylic sulphoxides from penicillins

The chemical manipulation of the aminosucrar, daunosamine, has resulted in the development of new interesting doxorubicin analogues, namely 4'-epi-and 4'-deoxydoxorubicin, whereas the total synthesis of new aglycones has Drovided new structural types of the anthracyclines. In the field of beta-lactams, efforts aimed to the discovery of original anti-infective compounds have led to the synthesis of novel "penem" derivatives starting from methyl penicillinate.In this paper I shall deal with two major lines of investigation existing in our laboratory, namely the development of new antitumour anthracyclines and of novel bioactive B-lactam derivatives by partial or total synthesis.Although the anthracycline glycosides and the corresponding aqlycones had been known for ten years mainly through the pioneering work of H. Brockmann, W.D. Ollis and W. Prelog, their interest was restricted to the unique structural features of this class of microbial piqments. The discovery of daunorubicin in 1962 and of doxorubicin (Adriamycin) in 1967 in our laboratory brouqht these compounds to the attention of the scientific and medical world aivinq rise to significant improvements in cancer chemotherapv. Doxorubicinis amajor antitumour drug,more than one million and half patients havinq received medical treatment including the compound since 1969. Doxorubicin, alone or in combination, is active on soft tissue and osteoaenic sarcomas, maliqnant lymphomas, breast cancer, bronchogenic carcinoma, acute leukemias, cancer of bladder, qastric tumour. Dose limiting side effects are hematological and qastrointestinal toxicity (which is reversible) and a cumulative dose-dependent cardiotoxicity that limits the overall dosage to 450-550 mg/m2. In 1972 we started a comprehensive programme aimed at the discovery of new related compounds endowed with lower toxicity and wider spectrum of activity than the parent drugs, daunorubicin and doxorubicin. Our work, as well as that of others, along these lines up to 1979 has been reviewed in a book (1). I shall deal therefore with some major points of the anthracycline research representinq selected lines of investigation, namely (a) the chemical modification of the aminosugar, daunosamine, (b) the synthesis of stereochemical variants of the antitumour anthracyclines and (c) the total synthesis of new derivatives modified in the substitution of the aglycone moiety.Daunosamine (I) was first isolated by acid hydrolysis of daunorubicin, and its structure determined by chemical deuradation (2). It was obviously available by fermentation followed by hydrolysis of the recovered qlvcosides and therefore was soon recognised in our laboratory as a convenient substrate for che-

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