ABSTRACT
Bahamaolides A and B (1 and 2), two new 36-membered macrocyclic lactones, were isolated from the culture of the marine actinomycete Streptomyces sp. derived from a sediment sample collected at North Cat Cay in the Bahamas. The planar structures of 1 and 2, bearing a hexaenone and nine consecutive skipped hydroxy groups, were determined by 1D and 2D NMR, mass, IR, and UV spectra. The absolute configurations of the bahamaolides were established by combined multistep chemical reactions and spectroscopic analysis. Bahamaolide A displayed significant inhibitory activity against Candida albicans isocitrate lyase and antifungal activity against various pathogenic fungi.
Subject(s)
Antifungal Agents/isolation & purification , Antifungal Agents/pharmacology , Lactones/isolation & purification , Lactones/pharmacology , Macrolides/isolation & purification , Macrolides/pharmacology , Polyenes/isolation & purification , Polyenes/pharmacology , Streptomyces/chemistry , Antifungal Agents/chemistry , Bahamas , Candida albicans/enzymology , Fungi/drug effects , Isocitrate Lyase/drug effects , Isocitrate Lyase/metabolism , Lactones/chemistry , Macrolides/chemistry , Molecular Structure , Nuclear Magnetic Resonance, Biomolecular , Polyenes/chemistryABSTRACT
Brazilin (7,11b-dihydrobenz[b]indeno[1,2-d]pyran-3,6a,9,10 (6H)-tetrol) isolated from Caesalpinia sappan has been known as a natural red pigment. Many studies suggest that inducible isoform of nitric oxide synthase (NOS) plays an important role in inflammation and carcinogenesis. On this line, we evaluated the inhibitory effect of brazilin on nitric oxide (NO) production and investigated its mechanism of action. As a result, brazilin exhibited the inhibitory effect on lipopolysaccharide (LPS)-stimulated NO production in a dose-dependent manner (IC50=24.3 microM). In addition, brazilin suppressed LPS-induced iNOS protein and mRNA expression in RAW 264.7 macrophage cells, indicating that the inhibitory activity of brazilin possibly involved in the regulation of iNOS expression. To further investigate the mechanism responsible for the suppression of iNOS gene expression by brazilin, the effect of brazilin on LPS-induced transcription factors nuclear factor-kappaB (NF-kappaB) and activator protein-1 (AP-1) activation was examined. The DNA binding activity of NF-kappaB and AP-1 stimulated LPS was inhibited by treatment of brazilin in a dose-dependent manner, suggesting that brazilin-mediated inhibition of NO production might be associated with the regulation of transcription factors NF-kappaB and AP-1. Taken together, these findings suggest that the suppressive effect of iNOS gene expression by brazilin might provide one possible mechanism for its anti-inflammatory and cancer chemopreventive activity.