Nitropyrrolins A−E, Cytotoxic Farnesyl-α-nitropyrroles from a Marine-Derived Bacterium within the Actinomycete Family Streptomycetaceae

Abstract

Five new farnesyl-α-nitropyrroles, nitropyrrolins A-E (1-5), were isolated from the saline culture of the marine actinomycete strain CNQ-509. This strain belongs to the "MAR4" group of marine actinomycetes, which have been demonstrated to be a rich source of hybrid isoprenoid secondary metabolites. The structures of the nitropyrrolins are composed of α-nitropyrroles with functionalized farnesyl groups at the C-4 position. These compounds are the first examples of naturally-occurring terpenyl-α-nitropyrroles. Chemical modifications, including one-step acetonide formation from an epoxide, and application of the modified Mosher method, provided the full stereostructures and absolute configurations of these compounds. Several of the nitropyrrolins, nitropyrrolin D in particular, are cytotoxic toward HCT-116 human colon carcinoma cells, but show weak to little antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA).As part as our continuing interest in the chemistry and biomedical potential of sedimentderived marine actinomycetes, we have isolated a variety of new actinomycete taxa, which show the capacity to produce unique secondary metabolites.1 These taxa include the chemically prolific genera Salinispora2 and "Marinispora",3 members of which produce new structural classes of secondary metabolites including salinosporamide A,4 a potent proteasome inhibitor that recently completed phase I clinical trial for the treatment of cancer.5 Another group of marine-derived actinomycetes, designated as MAR 4, is proving to be of significant chemical interest.1 To date, at least 15 strains belonging to this group have been isolated from diverse marine sediments. Previous chemical studies of cultured MAR4 strains led to the discovery of a broad range of polyketide-terpenoid secondary metabolites including marinone,6 compounds in the napyradiomycin series7 and azamerone. 8 Further chemical analysis of the cultured MAR4 strain CNQ-509, isolated from a marine sediment sample collected off La Jolla, CA, has led to the discovery of a new set of hybrid * To whom Correspondence should be addressed. Tel: + 1 858 534 2133. Fax: +1 858 558 3702. wfenical@ucsd.edu. ‡ Scripps Institution of Oceanography. † Korea Institute of Science and Technology, Gangneung, Korea § Contributed equally to this work.Supporting Information Available: Spectroscopic data sets (1D and 2D NMR, ESI MS, UV/VIS, HRMS, etc) for 1-5, 1 H NMR spectra for 6 and (S)-Mosher ester of 11, 1 H NMR and 1 H-1 H COSY spectra for 9a, 9b, 12a, 12b, 13a, 13b, 14a and 14b, 1 H NMR and 2D NOESY spectra for 10 and 11, and 1 H and 13 C NMR spectra for 7 and 8. This material is available free of charge via the Internet at http://pubs.acs.org polyketide-terpenoid metabolites composed of sesquiterpenoid and α-nitropyrrole components. These compounds, nitropyrrolins A-E (1-5), are unusual examples illustrating rare pyrrole nitration in the α position with linear sesquiterpenoid substitution. The structures of these new compounds, including their absolu...

Salinamide F, new depsipeptide antibiotic and inhibitor of bacterial RNA polymerase from a marine-derived Streptomyces sp.

“…To confirm this, the acetonide derivative 4 was prepared and its relative configuration evaluated by ROESY NMR experiments using methods alrerady applied in similar systems. 16 Strong NOE correlations were observed between the H 2 -40 (δ H 3.64, m), and both H-66 methylene protons [δ H 3.29, dd, J = 15.0, 10.0), 3.62, dd, J = 15.0, 5.0] and an acetonide methyl (δ H 1.26, s), as well as NOE correlation between H-8 (δ H 4.61,m) and H-66 (δ H 3.62, dd, J = 15.0, 5.0). Slight differences in the bond angles of derivative 4, apparently derived by formation of the semi-planar ketal ring decreases the spatial distance between the H 2 -40 protons and the benzyl protons at C-66, thus confirming the spatial proximity of these protons.…”

Total synthesis and complete stereochemical assignment of heronapyrroles A and B

“…14 After Boc protection of the pyrrole nitrogen, treatment of the epoxide with boron trifluoride etherate in acetone gave acetonide 13, the stereochemistry of which was confirmed by NOEs indicated in 13, in a diastereoselective manner with inversion of configuration upon regioselective epoxide-opening at C8. 3 Deprotection of the Boc group and reductive cleavage of the bromo ether with metallic sodium regenerated C11-C12 trisubstituted double bond in a ratio of E/Z = 2:1. After TBS protection of 15-hydroxy group in the olefinic mixture 4, nitration of the pyrrole nucleus with nitric acid in acetic anhydride was carried out to provide a mixture of C2/C5 = 1:1.5 nitro compounds.…”

“…After TBS protection of 15-hydroxy group in the olefinic mixture 4, nitration of the pyrrole nucleus with nitric acid in acetic anhydride was carried out to provide a mixture of C2/C5 = 1:1.5 nitro compounds. 3,17 Finally, removal of protective groups in 14 afforded the target compound 1 after chromatographic separation. The spectral data ( 1 H and 13 C NMR) and the optical rotation of synthetic 1, [a] D 23 +18.0 (c 0.05, methanol), were identical to those reported for the natural product, lit., 1 [a] D +16.9 (c 0.05, methanol).…”

“…1,2 Heronapyrroles A-C exhibit activity against the Gram-positive bacteria Staphylococcus aureus ATCC 9144 (IC 50 0.6-1.1 lM) and Bacillus subtilis ATCC 6633 (IC 50 1.1-6.5 lM), while they display no cytotoxicity toward mammalian cell lines and are inactive against the Gram-negative bacteria. The rare structures as naturally occurring members, 4-farnesylated-2-nitropyrroles which have ever been limited to cytotoxic nitropyrrolins A-E reported by Fenical and co-workers, 3 were revealed on the basis of spectroscopic analysis. The absolute configurations at C7 and C15 in heronapyrrole A were determined to be 7S and 15R by the modified Mosher method.…”

Farnesides A and B, Sesquiterpenoid Nucleoside Ethers from a Marine-Derived Streptomyces sp., strain CNT-372 from Fiji

“…This is also supported by the 13 C chemical shifts of C-15 and C-4 as observed in related terpenoids (δ C 16.9 and 36.2 ppm). 6 …”