Structure-activity relationships of sparsomycin and its analogues. Octylsparsomycin: the first analogue more active than sparsomycin.

Nine analogues of sparsomycin were synthesized, and their cytostatic activity was studied in an in vitro clonogenic L1210 assay by measuring the inhibition of colony formation. The activity of an analogue, expressed as an ID50 value, was compared to that of sparsomycin. Each possesses not more than two structural modifications of the sparsomycin molecule 1. Comparison of the activity of with that of the stereomers, having RCSS, SCSS, and RCRS chirality, respectively, shows that the S configuration of the chiral carbon atom is essential for an optimal activity, whereas the R chirality of the sulfoxide sulfur atom of sparsomycin is of importance. Study of the ID50 values of the S-deoxo analogues, as well as the compounds having the beta-sulfoxide function, indicate that the presence of an oxygen atom on the alpha-sulfur atom is essential. Isomerization of the trans double bond into the cis double bond yields isosparsomycin, (Scheme II), which has a low activity. The cytostatic activity of sparsomycin seems to be related to its lipophilicity: octylsparsomycin was shown to be three times as effective as sparsomycin.