Antileukemic compounds derived from the chemical modification of macrocyclic trichothecenes. 1. Derivatives of verrucarin A

Abstract

Verrucarin A (2) was epoxidized to give the beta-9,10-epoxide 7 (major product) and alpha-9,10-epoxide 9 (minor product). The beta-epoxide 7 and its acetate 8 exhibit high in vivo antileukemic activity against P-388 mouse leukemia, whereas 2 and 9 are inactive. Epoxidation of verrucarin B (3) and roridin A (1) to their respective beta-9,10-epoxides (11 and 12, respectively) also yields compounds with substantially increased activity. Allylic alcohols derived from 2, alpha-C8 (20), beta-C8 (14), and C16 (15), were synthesized and tested; only 15 exhibited substantial in vivo activity.

Structures and Cytotoxic Properties of Trichoverroids and Their Macrolide Analogues Produced by Saltwater Culture of Myrothecium verrucaria

“…Highlights of this SAR appear in Chart S2 and reflect substantial in vivo data collected in the early 1980s from the P388 leukemia mouse model on 61 anguidoid (I′) 33 analogues and on 37 type III and IV macrocycles. 21 The positive in vivo activity in the mouse for anguidin (17) 34 prompted, in the late 1970s, five distinct series of Phase II studies that involved a total of 484 patients. 35 Unfortunately each of the studies, where anguidin was used as a single agent, was discontinued because of varied toxicity effects and the lack of substantive antitumor activity.…”

“…19 Alternatively, there are few examples of 12,13-deoxytrichothecenes. 20 Interest in the trichothecenes continues because of their biological activity, 21 the challenge associated with their total synthesis, 22 curiosity about their biosynthesis, 23 and the possibility for the re-engineering of their biosynthetic pathways. 24 Myrothecium verrucaria cultured in this study was a source of three new trichothecenes (1a, 2, and 3), together with nine related known compoundssroridin L (1b), 25 roridin M (4), 25 verrucarin M (5), 25 verrucarin A (6), 26 roridin A (7a), 26 isororidin A (7b), 27 epiroridin E (8), 15a trichoverrin A (9a), 28 and trichoverrin B (9b).…”

Potential inhibitors against Sclerotinia sclerotiorum, produced by the fungus Myrothecium sp. associated with the marine sponge Axinella sp.

“…(Sudakin 2003), and from some higher plants such as Bacchairis artemisioides and Baccharis coridifolia (Habermehl et al 1985;Rizzo et al 1997), Ficus fistulosa and Rhaphidophora decursiva (Zhang et al 2002). Biologically, macrocyclic trichothecenes were reported to be antileukemic (Jarvis et al 1980(Jarvis et al , 1984, antimalarial (Isaka et al 1999;Zhang et al 2002), antimicrobial (Liu et al 2006;Wagenaar and Clardy 2001), antiviral (Tani et al 1995), phytotoxic and cytotoxic (Abbas et al 2002;Masuda et al 2007), and some were reported to possess animal toxicity (Hughes et al 1989). In the present study, the two trichothecenes (compounds 1 and 2), obtained from the EtOAc extract of the fungus JS9 isolated from the marine sponge Axinella sp., were ascertained to be antifungal compounds with the MICs comparable with those of fluconazole.…”

3D QSAR study of the toxicity of trichothecene mycotoxins

“…Jarvis et al concluded that epoxidation at carbons 9 and 10 would lead to an increase in activity [15,16]. The CoMFA contour map shows that this effect is electrostatic in nature.…”

“…An ideal data set should be large enough to provide 4-5 compounds per PLS component and enable a separation into a learning (L) set and a test (T) set. Jarvis et al measured the ability of macrolide mycotoxins to extend the life span of mice inoculated with P-388 mouse leukemia and their data presumably reflect the effect of the toxins on the leukemia cells [15,16]. Their quantitative measure of activity is R, 100 times the ratio of the days test animals lived over the days control animals lived.…”