Bipolaquinones A-J, Immunosuppressive Meroterpenoids from a Soil-Derived Bipolaris zeicola.

Ten new meroterpenoids, bipolaquinones A-J (1-10), and one known congener, isocochlioquinone F (11), were isolated and identified from the fermented rice cultures of a soil-derived fungus, Bipolaris zeicola. The planar structures of 1-10 were elucidated based on extensive spectroscopic analyses (including HRESIMS and 1D and 2D NMR data), and their absolute configurations were determined by single-crystal X-ray diffraction analyses, comparison of experimental electronic circular dichroism (ECD) data, ECD calculations, and hydrolysis reaction. The immunosuppressive activity assay revealed that compounds 2, 3, and 7-10 showed significant inhibitory activity against concanavalin A (ConA)-induced T lymphocyte proliferation with IC50 values ranging from 4.1 to 9.4 µM, which furnished potential lead molecules for the design and development of new immunosuppressants for treating autoimmune-associated diseases.

Investigation of biological activity of soil fungal extracts and LC/MS-QTOF based metabolite profiling.

Soil is considered an extensively explored ecological niche for microorganisms that produce useful biologically active natural products suitable for pharmaceutical applications. The current study aimed at investigating biological activities and metabolic profiles of three fungal strains identified from different desert sites in Saudi Arabia. Soil fungal isolates were collected from AlQasab, Tabuk, and Almuzahimiyah in Saudi Arabia and identified. Furthermore, their antibacterial activity was investigated against Staphylococcus aureus, Enterococcus faecalis, Klebsiella pneumonia, and Escherichia coli in blood, nutrient, and Sabouraud dextrose agars. Moreover, fungal extracts were evaluated on cell viability/proliferation against human breast carcinoma and colorectal adenocarcinoma cells. To identify the biomolecules of the fungal extracts, High-performance liquid chromatography HPLC-DAD coupled to analytical LC-QTOF-MS method was employed for fungal ethyl acetate crude extract. Identified fungal isolates, Chaetomium sp. Bipolaris sp. and Fusarium venenatum showed varied inhibitory activity against tested microbes in relation to crude extract, microbial strain tested, and growth media. F. venenatum showed higher anticancer activity compared to Chaetomium sp. and Bipolaris sp. extracts against four of the tested cancer cell lines. Screening by HPLC and LC/MS-QTOF identified nine compounds from Chaetomium sp. and three from Bipolaris sp. however, for F. venenatum extracts compounds were not fully identified. In light of the present findings, some biological activities of fungal extracts were approved in vitro, suggesting that such extracts could be a useful starting point to find compounds that possess promising agents for medical applications. Further investigations to identify exact biomolecules from F. venenatum extracts are needed.

Evolution of a Synthetic Strategy for Complex Polypyrrole Alkaloids: Total Syntheses of Curvulamine and Curindolizine.

Structurally unprecedented antibacterial alkaloids containing multiple electron-rich pyrrole units have recently been isolated from Curvularia sp. and Bipolaris maydis fungi. This article documents the evolution of a synthetic program aimed at accessing the flagship metabolites curvulamine and curindolizine which are presumably a dimer and trimer of a C10N biosynthetic building block, respectively. Starting with curvulamine, we detail several strategies to merge two simple, bioinspired fragments, which while ultimately unsuccessful, led us toward a pyrroloazepinone building block-based strategy and an improved synthesis of this 10π-aromatic heterocycle. A two-step annulation process was then designed to forge a conserved tetracyclic bis-pyrrole architecture and advanced into a variety of late-stage intermediates; unfortunately, however, a failed decarboxylation thwarted the total synthesis of curvulamine. By tailoring our annulation precursors, success was ultimately found through the use of a cyanohydrin nucleophile which enabled a 10-step total synthesis of curvulamine. Attempts were then made to realize a biomimetic coupling of curvulamine with an additional C10N fragment to arrive at curindolizine, the most complex family member. Although unproductive, we developed a 14-step total synthesis of this alkaloid through an abiotic coupling approach. Throughout this work, effort was made to harness and exploit the innate reactivity of the pyrrole nucleus, an objective which has uncovered many interesting findings in the chemistry of this reactive heterocycle.

New secondary metabolites with immunosuppressive activity from the phytopathogenic fungus Bipolaris maydis.

Three previously undescribed compounds, including a meroterpenoid, guignardone T (1), and two ophiobolin-type sesterterpenoids, maydispenoids A and B (2 and 3), along with four known compounds (4-7), were isolated from the phytopathogenic fungus Bipolaris maydis collected from Anoectochilus roxburghii (Wall.) Lindl leaves. The structures of all undescribed compounds were elucidated by spectroscopic analysis, electronic circular dichroism (ECD) calculations and single-crystal X-ray diffraction. Structurally, maydispenoids A was characterized by a fascinating decahydro-3-oxacycloocta[cd]pentalene fragment. It is notable that the compounds 2 and 3 exhibited potential inhibitory activity in anti-CD3/anti-CD28 monoclonal antibodies (mAbs) stimulated murine splenocytes proliferation, with IC50 values of 5.28 and 9.38 µM, respectively, and also suppress the murine splenocytes proliferation activated by lipopolysaccharide (LPS), with IC50 values of 7.25 and 16.82 µM, respectively. This is the first report of ophiobolin-type sesterterpenoids as immunosuppressor, and may provide new chemical templates for the development of new immunosuppressive drugs for autoimmune disease treatment.

Genome-based mining of new antimicrobial meroterpenoids from the phytopathogenic fungus Bipolaris sorokiniana strain 11134.

Polyketide-terpenoid hybrid compounds are one of the largest families of meroterpenoids, with great potential for drug development for resistant pathogens. Genome sequence analysis of secondary metabolite gene clusters of a phytopathogenic fungus, Bipolaris sorokiniana 11134, revealed a type I polyketide gene cluster, consisting of highly reducing polyketide synthase, non-reducing polyketide synthase, and adjacent prenyltransferase. MS- and UV-guided isolations led to the isolation of ten meroterpenoids, including two new compounds: 19-dehydroxyl-3-epi-arthripenoid A (1) and 12-keto-cochlioquinone A (2). The structures of 1-10 were elucidated by the analysis of NMR and high-resolution electrospray ionization mass spectroscopy data. Compounds 5-8 and 10 showed moderate activity against common Staphylococcus aureus and methicillin-resistant S. aureus, with minimum inhibitory concentration (MIC) values of 12.5-100 µg/mL. Compound 5 also exhibited activity against four clinical resistant S. aureus strains and synergistic antifungal activity against Candida albicans with MIC values of 12.5-25 µg/mL. The biosynthetic gene cluster of the isolated compounds and their putative biosynthetic pathway are also proposed. KEY POINTS: • Ten meroterpenoids were identified from B. sorokiniana, including two new compounds. • Cochlioquinone B (5) showed activity against MRSA and synergistic activity against C. albicans. • The biosynthetic gene cluster and biosynthetic pathway of meroterpenoids are proposed. • Genome mining provided a new direction to uncover the diversity of meroterpenoids.