Molecular Pharmacology, Vol 20, 211-217, Copyright © 1981 by the American Society for Pharmacology and Experimental Therapeutics

Inhibition of Histone H1 Phosphorylation by Sangivamycin and other Pyrrolopyrimidine Analogues

¹ Applied Pharmacology Section, Laboratory of Medicinal Chemistry and Biology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20205

We have examined the ability of the pyrrolopyrimidine antibiotic, sangivamycin [4-amino-5-carboxamide-7(-D-ribofuranosyl)pyrrolo[2,3-d]pyrimidine], to inhibit the phosphorylation of the 2% trichloroacetic acid-soluble nuclear proteins from Ehrlich ascites cells in vitro. In whole cells, sangivamycin inhibited histone H1 phosphorylation, with 50% inhibition observed at a drug concentration of 100 µM, but phosphorylation of the high-mobility group (HMG) proteins, HMG 14 and 17, was unaffected. At all concentrations, histone H1 phosphorylation was inhibited to a greater degree than nRNA synthesis. The pyrrolopyrimidine analogues toyocamycin, sangivamycin-amidine, and sangivamycin-amidoxime did not differ substantially from sangivamycin in their inhibitory effects on histone H1 phosphorylation and nRNA synthesis in whole cells, whereas thiosangivamycin was approximately 50-fold more potent. Cell-free assays with partially purified nuclear protein kinase activities, PK-I and PK-II, revealed that sangivamycin was a competitive inhibitor versus ATP with either histone H1 or casein as substrate. The 50% inhibitory concentration of thiosangivamycin for PK-I activity was 40-fold less than sangivamycin and closely paralleled their relative inhibitory activities for inhibiting histone H1 phosphorylation in intact cells in vitro. This relationship was not apparent for sangivamycin-amidine, sangivamycin-amidoxime, and toyocamycin.

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