Long-Chain 2H-Azirines with Heterogeneous Terminal Halogenation from the Marine Sponge Dysidea fragilis

Abstract

Three new omega-halogenated long-chain 2H-azirines were isolated from the sponge Dysidea fragilis. Their structures revealed heterogeneity in both the composition of the terminal 1,1-dihalo-vinyl group and enantiomeric ratios at C2 of the azirine-2-carboxylate ester terminus. Azirine-2-carboxylate esters were shown to racemize spontaneously. A hypothesis is proposed for the biosynthesis of the azirinecarboxylate family of natural products that involves enzyme-catalyzed free radical halogenation followed by elimination of hydrohalic acid.

Synthesis and chain-dependent antifungal activity of long-chain 2H-azirine-carboxylate esters related to dysidazirine

“…Clearly terminal substitution or branching abrogates antifungal activity, consistent with the lack of activity for ω-halo-alkenyl antazirines ( 4 – 8 ) 3,7…”

“…with antibacterial activity against Staphylococcus aureus and MRSA 4. In our search5 for antifungal compounds from marine organisms with efficacy against Fluconazole-resistant strains of Candida and other pathogenic yeast,6 we found three new antazirines ( 6 – 8 ) along with 4 and 5 from a sample of Dysidea fragilis collected in Pohnpei, Micronesia that showed cytotoxicity in a crude screen 7. Compounds 4 – 8 were moderately cytotoxic (HCT-116 cells), but to our surprise they were completely inactive against a panel of fungal pathogens including Candida albicans (ATCC, UCD-FR1 and 96–489), less susceptible, non- albicans species such as C. glabrata and C. krusei , and two strains of Cryptococcus neoformans , var.…”

“…Natural dysidazirine and congeneric compounds have all been isolated as non-race mixtures of enantiomers. Neat, natural dysidazirine spontaneously epimerizes slowly in the dark ( t 1/2 ~12y, −20 °C),7 and the lack of racemization of 2 and 3 in the presence of light excludes a photocheal mechanism.…”

Aziridine alkaloids as potential therapeutic agents

“…have recently been isolated from the marine sponge D. fragilis, two of them containing a terminal (Z)-1-bromo-1-chlorovinyl group, the first such example from a marine invertebrate [67]. Cytotoxic activity of 17b and 18b, and new compounds (19a,b, and 20) is shown in Table 1.…”

“…These compounds inhibited the growth of a broad range of human cancer cell lines in vitro with low nM or sub-nM IC 50 . A series of 12a,13a-aziridinyl epothilone derivatives as anticancer agents (66)(67)(68)(69)(70), were synthesized in an efficient manner from epothilone A. The final semi-synthetic route involved a formal double-inversion of stereochemistry at both the C12 and C13 positions.…”