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

Article abstract of DOI:10.1021/jm00369a012

Nine analogues of sparsomycin (1) 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 analogue possesses not more than two structural modifications of the sparsomycin molecule 1. Comparison of the activity of 1 with that of the stereomers, having R(C)S(S), S(C)S(S) and R(C)R(S) 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 two S-deoxo analogues, as well as two compounds having the β-sulfoxide function, indicate that the presence of an oxygen atom on the α-sulfur atom is essential. Isomerization of the trans double bond into the cis double bond yields isosparsomycin, 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.