Synthesis and Biological Activity of Analogs of Fecapentaene-12

Abstract

Analogs of the potent fecal mutagen fecapentaene-12 have been prepared and tested both for mutagenicity and for their ability to serve as biological precursors of 1. It was found that mutagenicity in three different Salmonella tester strains TA96, TA100, and TA104, decreased rapidly as the number of conjugated double bonds was reduced. The aldehyde 8, analogous to the hydrolysis product of 1, showed only low mutagenicity, even in the aldehyde-sensitive strain TA104. None of the polyenes prepared was able to function as a direct biological precursor of 1 under the conditions employed.

Decomposition and quality control considerations in biological work with fecapentaene preparations

“…We have been engaged in characterizing their chronic genotoxic effects in mammals by repetitively administering large doses of synthetic fecapentaene 12 (FP-12)1 to rodents for extended periods of time (16). In planning these experiments we noted previous reports of fecapentaene instability (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15) and, therefore, needed to know the following: (a) to what extent the composition of an FP-12 sample actually changes during a typical bioassay application; (b) the extent to which any changes observed make a difference in the biological properties of the sample (rather than simply transforming it into a mixture of isomers or other derivatives of equivalent activity); and (c) what steps should be taken to ensure the chemical and toxicological integrity of the test substance throughout the dosing procedure.…”

On the Stereochemistry of Fecapentaene-12

“…It, thus, appears that the significant structural feature for biological activity is the presence of a pentaenyl enol ether unit with stereochemical factors playing at most a minor role (13). EXPERIMENTAL General experimental procedures.-Synthetic methods and analytical techniques were as described previously (13). Pure 1-E and 1-Zfecapentaene-12 [3 and 5] were prepared as previously described (11), and a mixture of 5-E-and 5-Z-fecapentaene-12 [3, 4} was prepared by the method of Nicolaou etal.…”

My 60-Year Love Affair with Natural Products

“…Unsurprisingly, mutagenic activity decreased with decreasing numbers of double bonds, and the tetraene 25 was 20−30-fold less mutagenic than fecapentaene-12. 56 We also isolated and determined the structures of the biological precursors of the fecapentaenes, the plasmalopentaenes (26). Although the fecapentaenes are microbial products, with production enhanced by incubation with several species of the common intestinal anaerobes of the Bacterioides genus, 57 the plasmalopentaenes can be isolated from germ-free pigs and are thus not microbial products.…”

“…In later studies we and others − synthesized fecapentaene-12, and we also prepared compounds 22 – 25 with varying numbers of double bonds. Unsurprisingly, mutagenic activity decreased with decreasing numbers of double bonds, and the tetraene 25 was 20–30-fold less mutagenic than fecapentaene-12 …”