1-Hydroxy-4-methoxy-2-naphthoic acid

Karamomycins A-C (2-4), the first natural 2-naphthalen-2-yl-thiazole derivatives, were isolated along with a plausible precursor molecule, 1-hydroxy-4-methoxy-2-naphthoic acid (1), uracil, 1-acetyl-β-carboline, and actinomycin C2 from the culture broth of the terrestrial actinomycete strain GW58/450, identified as Nonomuraea endophytica. These compounds were characterized by analysis of their NMR and mass spectrometry (MS) data; the absolute configurations of 2 and 4 were determined by comparison of 13C NMR, NOESY, and circular dichroism (CD) spectra with density functional theory (DFT)-calculated data. In karamomycin C (4), the thiazole of 2 is connected to an unusual iminothiazolo[4,3- c][1,4]thiazepinone, for which we proposed a biosynthetic origin from two cysteine residues. It is closely related to ulbactin F; however, the heterocycle is enantiomeric to the latter and connected to phenol instead of 4-methoxy-1-naphthol. Karamomycins A (2) and C (4) were cytotoxic.

The strain SCSIO 03039 was isolated from a sediment sample in the Indian Ocean and was characterized as a Nocardiopsis alba species on the basis of its 16S rRNA gene sequence. Seven diketopiperazines (DKPs), including two new DKPs nocazines D (2a) and E (2b), and five known DKPs (1, 3-6), were isolated from N. alba SCSIO 03039, along with two known compounds 2-methoxy-1,4-naphthoquinone (7) and 1-hydroxy-4-methoxy-2-naphthoic acid (8). Their structures were elucidated by mass and NMR spectroscopic analyses. The structure of methoxyneihumicin (1), previously proposed in a conference poster lacking publicly available experimental data, was validated for the first time by detailed NMR analyses and X-ray diffraction study. The two enantiomers nocazines D (2a) and E (2b) were isolated as a mixture. Compounds 3 and 4 were only known as synthetic compounds before. Methoxyneihumicin (1) exhibited in vitro cytotoxicities against MCF-7 and SF-268 with IC₅₀ values of 4.6 and 12.7 μM, respectively, better than those of 6 (22.0 and 20.6 μM). The other compounds showed less pronounced cytotoxities against three tested human cancer cell lines and no compounds displayed antibacterial activities toward four indicator strains.

Microbial natural products have been a cornerstone of the pharmaceutical industry, but the supply of novel bioactive secondary metabolites has diminished due to extensive exploration of the most easily accessible sources, namely terrestrial Streptomyces species. The Persian Gulf is a unique habitat for marine sponges, which contain diverse communities of microorganisms including marine Actinobacteria. These exotic ecosystems may cradle rare actinomycetes with high potential to produce novel secondary metabolites. In this study, we harvested 12 different species of sponges from two locations in the Persian Gulf and isolated 45 symbiotic actinomycetes to assess their biodiversity and sponge-microbe relationships. The isolates were classified into Nocardiopsis (24 isolates), Streptomyces (17 isolates) and rare genera (4 isolates) by 16S rRNA sequencing. Antibiotic activity tests revealed that culture extracts from half of the isolates displayed growth inhibitory effects against seven pathogenic bacteria. Next, we identified five strains with the genetic potential to produce aromatic polyketides by genotyping ketosynthase genes responsible for synthesis of carbon scaffolds. The combined data led us to focus on Streptomonospora sp. PA3, since the genus has rarely been examined for its capacity to produce secondary metabolites. Analysis of culture extracts led to the discovery of a new bioactive aromatic polyketide denoted persiamycin A and 1-hydroxy-4-methoxy-2-naphthoic acid. The genome harbored seven gene clusters involved in secondary metabolism, including a tetracenomycin-type polyketide synthase pathway likely involved in persiamycin formation. The work demonstrates the use of multivariate data and underexplored ecological niches to guide the drug discovery process for antibiotics and anticancer agents.