Structure-activity relationships of sparsomycin and its analogues. Octylsparsomycin: The first analogue more active than sparsomycin
article
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 (Table I). 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 2-4, 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 10 and 11, as well as the compounds 14 and 15 having the ??-sulfoxide function, indicate that the presence of an oxygen atom on the ??-sulfur atom is essential. Isomerization of the trans double bond into the cis double bond yields isosparsomycin (16, Scheme H), which has a low activity. The cytostatic activity of sparsomycin seems to be related to its lipophilicity: octylsparsomycin (19) was shown to be three times as effective as sparsomycin.
Chemicals/CAS: sparsomycin, 1404-64-4; Antibiotics, Antineoplastic; octylsparsomycin, 88001-59-6; Sparsomycin, 1404-64-4
Chemicals/CAS: sparsomycin, 1404-64-4; Antibiotics, Antineoplastic; octylsparsomycin, 88001-59-6; Sparsomycin, 1404-64-4
Topics
new drugsparsomycinsparsomycin derivativeanimal cellblood and hemopoietic systemdose responsedrug analysisdrug comparisondrug cytotoxicitydrug identificationdrug responsedrug screeningdrug synthesisin vitro studyintoxicationleukemia l 1210mousenonhumannuclear magnetic resonanceoctylsparsomycinstructure activity relationAnimalAntibiotics, AntineoplasticColony-Forming Units AssayIsomerismLeukemia L1210Magnetic Resonance SpectroscopyMiceSparsomycinStructure-Activity RelationshipSupport, Non-U.S. Gov'tTumor Stem Cells
TNO Identifier
229697
ISSN
00222623
Source
Journal of Medicinal Chemistry, 27(3), pp. 301-306.
Pages
301-306
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