Abstract
Dysidazirine carboxylic acid (1) was isolated from the lipophilic extract of a collection of the benthic marine cyanobacterium Caldora sp. from reefs near Fort Lauderdale, Florida. The planar structure of this new compound was determined by spectroscopic methods and comparisons between HRMS and NMR data with its reported methyl ester. The absolute configuration of the single chiral center was determined by the conversion of 1 to the methyl ester and the comparison of its specific rotation data with the two known methyl ester isomers, 2 and 3. Molecular sequencing with 16S rDNA indicated that this cyanobacterium differs from Caldora penicillata (Oscillatoriales) and represents a previously undocumented and novel Caldora species. Dysidazirine (2) showed weak cytotoxicity against HCT116 colorectal cancer cells (IC50 9.1 µM), while dysidazirine carboxylic acid (1) was non-cytotoxic. Similar cell viability patterns were observed in RAW264.7 cells with dysidazirine only (2), displaying cytotoxicity at the highest concentration tested (50 µM). The non-cytotoxic dysidazirine carboxylic acid (1) demonstrated anti-inflammatory activity in RAW264.7 cells stimulated with LPS. After 24 h, 1 inhibited the production of NO by almost 50% at 50 µM, without inducing cytotoxicity. Compound 1 rapidly decreased gene expression of the pro-inflammatory gene iNOS after 3 h post-LPS treatment and in a dose-dependent manner (IC50 ~1 µM); the downregulation of iNOS persisted at least until 12 h.
Highlights
Azirine natural products are rare in nature
Azirinomycin is the first example of a natural product containing an unstable strained azirine ring
Molinski and Ireland reported the isolation of cytotoxic dysidazirine (2), an azacyclopropene methyl ester, from the marine sponge Dysidea fragilis collected in Fiji, and this was the first example of a strained 2H-azirine from a marine source [3]
Summary
Azirine natural products are rare in nature. Azirinomycin is the first example of a natural product containing an unstable strained azirine ring. Dereplication using the molecular formula of the methyl ester 2 in the marine natural product database, together with the 1H and 13C NMR spectral data analysis, identified the prepared methyl ester 2 of the isolate as one of the three previously reported dysidazirines (2–4) [3,4]. This information, together with the 1H-1H COSY, HMBC, and HSQC NMR data analysis, the coupling constant of J = 15.1 Hz for 4-H and 5-H of the free acid (1) and the methyl ester (2), eliminated the (Z) geometric isomer (4).
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