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 pp60$\sp{{\rm v}-src}$ and HIV p17$\sp{gag}$, 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-(NH$\sb2$) (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 (K$\sb{\rm i}$ = 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.
Degree
Ph.D.
Advisors
Chang, Purdue University.
Subject Area
Pharmaceuticals|Organic chemistry|Pharmacology|Oncology
Off-Campus Purdue Users:
To access this dissertation, please log in to our
proxy server.