Important note: Information in this article was accurate in 1992. The state of the art may have changed since the publication date.
PART 1. CYTOTOXIC AGENTS FROM THE MOSSES POLYTRICHUM OHIOENSE AND POLYTRICHUM PALLIDISETUM. PART 2. DESIGN AND SYNTHESIS OF INHIBITORS OF MYRISTOYL COA:PROTEIN N-MYRISTOYLTRANSFERASE AS POTENTIAL ANTICANCER DRUGS
Abstract:
The National Cancer Institute has conducted an extensive screening program to isolate and characterize novel anticancer agents from plants. As part of the program, two moss species of the genus Polytrichum (Polytrichaceae) were subjected to investigation. Ohioensin A (1), B (2), C (3), D (4), and E (5), novel benzonaphthoxanthenones consisting of an oxygenated bibenzyl nucleus and a pyran-fused benzene, were isolated from P. ohioense following bioassay-directed fractionation. Another species, P. pallidisetum, was also subjected to extraction and fractionation guided by cytotoxicity. Three novel benzonaphthoxanthenones, named 1-O-methylohioensin B (6), 1-O-methyldihydroohioensin B (7) and 1,14-di-O-methyldihydroohioensin B (8), and two novel cinnamoyl bibenzyls, named pallidisetin A (9) and B (10), were isolated from the ethanol extract of P. pallidisetum. The structures and relative configurations of ohioensins and pallidisetins were established unequivocally on the basis of interpretation of spectral data (UV, FT-IR, MS, 2D NMR and CD), single crystal X-ray analysis, and chemical correlation. These compounds showed cytotoxicity against 9PS and several human tumor cell lines. A biogenetic pathway to ohioensins and pallidisetins is proposed. Certain oncogene products and viral structural proteins, such as protein-tyrosine kinase pp60v-src and HIV p17gag, require cotranslational myristoylation in order to function in malignant transformation and virus particle assembly. Myristoyl CoA:protein N-myristoyltransferase (NMT) catalyzes the transfer of myristate from myristoyl CoA to the N-terminal glycine of a polypeptide chain during biosynthesis of several cellular and viral proteins and thus is a novel target for design of potential antitumor and antiviral agents. To develop inhibitors of the enzyme NMT, a series of myristoyl coenzyme A analogs and myristoyl peptides were synthesized, including S-(2-oxopentadecyl)-CoA (11), S-(2-hydroxypentadecyl)-CoA (12), S-(2-oxopentadecyl)-pantetheine (13), 2-fluoromyristoyl CoA (14), 2-bromomyristoyl CoA (15), 2-hydroxymyristoyl CoA (16), Myr-N-Gly-(L)-Phe (17), Myr-N-Gly-(L)-Tyr (18), and Myr-N-Gly-(L)-Asn-Ala-Ala-Ala-Ser-Ala-Arg-(NH2) (19). Biological evaluation of these compounds in an in vitro NMT assay revealed that nonhydrolyzable acyl CoA analog 11 was the most potent competitive inhibitor of NMT (Ki = 24 nM). Of 2-substituted myristoyl CoA esters 14-16, only compound 16 exhibited potent inhibitory activity. The myristoylated dipeptides 17 and 18 were poor inhibitors of NMT and the heptapeptide 19 was inactive. (Full text available from University Microfilms International, Ann Arbor, MI, as Order No. AAD91-16495).
Keywords: Acyltransferases/*ANTAGONISTS & INHIB Antineoplastic Agents/*CHEMICAL SYNTHESIS/PHARMACOLOGY Antineoplastic Agents, Phytogenic/*ISOLATION & PURIF/PHARMACOLOGY Human *Protein Processing, Post-Translational Tumor Cells, Cultured/DRUG EFFECTS THESIS 920228
M9220886
AEGiS presents published material, reprinted with permission and neither endorses nor opposes any material. All information contained on this website, including information relating to health conditions, products, and treatments, is for informational purposes only. It is often presented in summary or aggregate form. It is not meant to be a substitute for the advice provided by your own physician or other medical professionals. Always discuss treatment options with a doctor who specializes in treating HIV.
Important note: Information in this article was accurate in 1992. The state of the art may have changed since the publication date.
