OF4949 IV

The crystal structure of the chloride salt of H3N(+)-cyclo-(Phe(4-O)-Phe-Phe(3-O)-OMe, cyclo-phenylalanyl-phenylalanyl-phenylalaninium chloride methyl esther, C28H30N3O5+.Cl(-), is described. It is oxidatively linked through a biaryl ether linkage formed from the hydroxyl of 4-hydroxyphenylalanine and the meta position of the distal phenylalanine residue. This is the first reported crystal-structure determination of a cyclic 17-membered biphenyl ether tripeptide, a class which includes the natural products K-13 and OF4949 I-IV. An unusual C-H...O hydrogen bond is formed between the methine H atom of the N-terminal C alpha and a carbonyl-O atom of a neighboring molecule [C...O = 2.995 (4) A].

OF4949-I and II inhibited aminopeptidase B from Ehrlich ascites carcinoma in a competitive way and the Ki value for both against L-arginine-beta-naphthylamide was 8 X 10(-9) M. Inhibition by I and II of various exopeptidases and endopeptidases was examined. OF4949-I and II both strongly inhibited leucine aminopeptidase and enkephalin-degrading aminopeptidase; I also inhibited enkephalinase B. The inhibitory effects of various derivatives of I and II on aminopeptidase B activity, showed that the terminal amino and carboxamide groups are essential for activity.

The polar extract of the Vanuatu sponge Reniera n. sp., which showed immunomodulating activity in preliminary tests, was found to contain a cyclic tripeptide, which we named renieramide (1). This metabolite is identical to a synthetic derivative mentioned in a patent concerning the preparation of cyclic peptides of the OF4949 family of anticancer agents. We describe here the first isolation of this metabolite from natural sources and its complete characterization by spectroscopic and chemical approaches. Renieramide (1) possesses a 17-membered cyclic side-chain-linked biphenyl ether skeleton, typical of the class that includes the natural products OF4949 I-IV, K13, and eurypamides. A tridimensional model of 1, obtained by NMR restrained molecular mechanics and dynamics, is also presented.