Synthesis and biological evaluation of sparsomycin analogues

Abstract

In 1962, Owen, Dietz, and Camiener reported the isolation of a new antitumor antibiotic from the culture filtrate of Streptomyces sparsogenes. The structure of the crystalline antibiotic, named sparsomycin, remained elusive until 1970, when Wiley and MacKellar reported results of spectroscopic and degradation studies which elucidated the structure. In addition to the molecular structure, investigators have examined the mechanism of action, toxicity, and related analogues, striving to establish sparsomycin or a synthetic analogue's usefulness as an effective chemotherapeutic agent. The initial pharmacological evaluation of sparsomycin revealed it possessed activity against KB human epidermoid carcinoma cells, a variety of gram-negative and gram-positive bacteria, and fungi. This broad spectrum of activity prompted a closer examination of the biochemical mechanisms. These studies revealed sparsomycin interfered with protein synthesis by inhibiting peptide bond formation near the enzyme peptidyl transferase. Ottenheijm, Liskamp, and Tijhuis reported the first total synthesis of sparsomycin in 1979, which provided access to greater quantities of the material for investigational use. Sparsomycin was selected for use by cancer patients in phase I clinical trials, but was found to cause ocular toxicity which hindered its development as an antitumor agent. In an effort to reduce or eradicate the toxic effects while maintaining the antitumor activity, analogues of sparsomycin were prepared. Using the sparsomycin analogues which were synthesized, studies were performed to determine the effect alteration of key structural parameters had on the efficacy of the compounds. Previous investigators examined analogues which incorporated modifications of the uracil ring, the unique mono-oxodithioacetal moiety, and the stereochemical configuration of the chiral centers. Vince and Lee reported there was an apparent requirement for the Q-configuration at the asymmetric carbon atom. Overall, however, the small number of sparsomycin analogues prepared and evaluated limited the definitive statements concerning the functional groups required for antitumor activity. In order to expand and clarify the structure-activity relationships, three series of new sparsomycin analogues were prepared for this project. The compounds of Series I and II, distinguished by the inclusion or exclusion of a hydroxymethyl functional group, were designed to elucidate the effect on activity of replacing the mono-oxodithioacetal side chain of sparsomycin with 4-substituted benzyl groups. The Series III analogues, which excluded the hydroxymethyl functional group, featured a 4-substituted benzyl amide group in place of the mono-oxodithioacetal moiety of sparsomycin, and were designed to investigate the potential interaction of an amide oxygen in contrast to the sulfoxide oxygen of sparsomycin. The target compounds synthesized for this project were experimentally examined to quantitate their effects on [ 75 Se]-selenomethionine…