The biological activity of 14 analogues of sparsomycin (1) was studied in cell-free systems of Escherichia coli, Saccharomyces cerevisiae, and Sulfolobus solfataricus by measuring the inhibition of protein synthesis. The inhibition of L1210 colony formation in soft agar and bacterial cell growth in solid as well as in liquid medium was also examined. Each analogue possesses not more than two structural modifications of the sparsomycin molecule. This enabled us to determine unambiguously several structural and stereochemical features that are required for an optimal biological activity in these assays. Sparsomycin, having the SCRS chirality, is the most potent of the four possible stereoisomers. The results obtained with compounds 5-7 indicate that the presence of an oxygen atom on the S (alpha) atom is essential. Substitution of the bivalent sulfur atom by a CH2 group (10) or of the SCH3 moiety by a Cl atom (12) affects the activity of the molecule partially. Compound 12 is surprisingly active against intact cells. Substitution of the C(6)-CH3 group by a H(14) reduces the activity of the molecule. Isomerization of the trans double bond into the cis double bond yields cis-sparsomycin (15), which is inactive. The hydrophobic derivatives 8, 9, and 11 are considerably more active than sparsomycin; thus the ribosomal binding site for sparsomycin may have a hydrophobic character.

m, 2), 2.50-2.30 (m, 2); 2H NMR (CHC1,) 6 2.33 (s, NC2H3); exact mass calcd for C11H31H17Nz (M') 267.1813, found 267.1806. Acknowledgment. We thank Dr. R. M. Koenig (Organon) for a generous gift of 5a. We gratefully acknowledge the technical assistance of L. Todisco (NEN) and R. Nugent (NEN) in the conversion of 5b to 5c and the help of Dr. P. Srinivasan (NEN) and L. Thomas (NEN) in obtaining the 3H NMR for 5c and the 2H NMR spectrum for 5d. We also thank Professor S. H. Snyder (Johns Hopkins) for performing receptor binding experiments on 5c and Professor H.-R. Schulten (University of Bonn) for obtaining the field-desorption mass spectrum of 5c. Finally we also gratefully acknowledge the technical assistance of M. Tutunjian (NEN) and R. Wellman (NEN) in performing the HPLC experiments on 5a, 5c, and 5d.

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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.

Aus den Ketocarbonsäuren (I) werden die Oxim‐carbonsäuren (IIa) hergestellt und in die Derivate (IIb) und (IIc) übergeführt.