The genomes of filamentous fungi contain up to ~90 biosynthetic gene clusters (BGCs), encoding diverse secondary metabolites, an enormous reservoir of untapped chemical potential. However, recalcitrant genetics, cryptic expression, and unculturability prevent the systematic exploitation of these gene clusters and harvesting of their products. With heterologous expression of fungal BGCs largely limited to expression of single or partial clusters, we established a scalable process for expression of large numbers of full-length gene clusters, called FAC-MS. Using Fungal Artificial Chromosomes (FACs) with Metabolomic Scoring (MS) we screened 56 secondary metabolite BGCs from diverse fungal species for expression in A. nidulans. Fifteen new metabolites were discovered and confidently assigned to their BGCs. A new macrolactone, valactamide A, and its hybrid PKS-NRPS gene cluster were characterized extensively using this integrated platform. Regularizing access to fungal secondary metabolites at an unprecedented scale stands to revitalize drug discovery platforms with renewable sources of natural products.

The family Gesneriaceae comprises ca. 150 genera and 3000 species, distributed in the tropics around the world. It is constituted of herbs, lianas, or shrubs, frequently with ornamental potential, due to the beauty of their flowers. Some species have been used in traditional medicine, mainly against fever, cough, colds, snakebite, pains, and infectious and inflammatory diseases. Although Gesneriaceae are a large family, only few species were chemically investigated, and this took place mainly in the last decade. In the present work, chemical and pharmacological studies on Gesneriaceae are reviewed based on original articles published. Altogether 300 compounds have been reported in Gesneriaceae species, including flavonoids, terpenes and steroids, phenolic glucosides, simple phenolics, quinones, lignans, xanthones, and compounds with unusual skeletons. Several species had been used in folk medicine, and some constituents have shown biological activities, such as antimicrobial, anti-inflamatory, antioxidant, and antitumor properties.

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We previously showed that plants from the genus Sinningia are a source of antiinflammatory and analgesic compounds with different mechanisms of action. The present study evaluated the antiinflammatory, antinociceptive, and antipyretic effects of a crude extract (CE) from Sinningia canescens, its fractions, and 6-methoxy-7-hydroxy-α-dunnione (MHD) in mice. These effects were evaluated using carrageenan (Cg)-induced paw edema, acetic acid- and formalin-induced nociception, mechanical hyperalgesia, lipopolysaccharide (LPS)-induced fever, and plasma cytokine levels. The CE and dichloromethane and hexane fractions reduced Cg-induced paw edema and hyperalgesia, LPS-induced fever, and plasma tumor necrosis factor-α (TNF-α) levels. The CE also reduced acetic acid-induced writhing and the second phase of formalin-induced nociception but did not alter thermal nociception or motor performance. Partition with solvents showed that the antiinflammatory, antihyperalgesic, and antipyretic activities were present in dichoromethane and hexane fractions, and the major compound isolated from these fractions was MHD. Oral and intraplantar MHD administration reduced paw edema. Oral MHD administration also reduced prostaglandin E-induced hyperalgesia but did not alter hyperalgesia that was induced by dopamine and dibutyryl cyclic adenosine monophosphate. Treatment with glibenclamide, a K channel blocker, did not alter the analgesic effect of MHD. Lipopolysaccharide-induced fever and TNF-α, interleukin-1β, and interleukin-6 levels were inhibited by MHD. Altogether, these data suggest that the CE has antiinflammatory, analgesic, and antipyretic activity, and these actions are at least partially related to MHD. These results also suggest that MHD acts by blocking cytokine synthesis and/or blocking prostaglandin activity.

Three new aromatic epsilon-lactones, aggregatins A (1), B (2), and C (3), a new naphthoquinone derivative, aggregatin D (4), and three known anthraquinones, 2-methylanthraquinone, 7-methoxy-2-methylanthraquinone, and 7-hydroxy-2-methylanthraquinone, were isolated from the tubers of Sinningia aggregata (Gesneriaceae). Compounds 1 and 4 and the anthraquinones showed marginal antimicrobial activity.

Chemical investigation of the extracts of the fruits fromCampomanesia xanthocarpa resulted in the isolation of six known compounds identified by NMR and comparison with literature data (2',4'-dihydroxy-5'methyl-6'-methoxychalcone (1), 2',4'-dihydroxy-3',5'-dimethyl-6'methoxychalcone (2), 2'-hydroxy-3'-methyl-4',6'-dimethoxychalcone (3), 2',6'dihydroxy-3'-methyl-4'-methoxychalcone (4), 5-hydroxy-7-methoxy-8methylflavanone (5) and 7-hydroxy-5-methoxy-6-methylflavanone ( 6)). The considerable antioxidant capacity of the extracts was demonstrated by ORAC-FL and DPPH tests. The antiproliferative assay of the extracts and 5 was done in vitro, against many different cancer cell lines besides a healthy one. The extracts presented low cytotoxicity and the substance demonstrated promising results against all of the cancer cell lines tested, with IC 50 values ranging from 4.75 to 45.81 µmol L -1 . The in vitro trypanocidal activity was evaluated against the epimastigote form of the Y strain of Trypanosoma cruzi and an improvement in

A new naphthoquinone, 6-methoxy-7-hydroxy--dunnione (1), along with four known compounds (2, 4, 10, and 11) were isolated from Sinningia canescens (Mart.) Wiehler tubers, while S. warmingii (Hiern.) Chautems furnished eight known compounds (3-10). The known compounds were identified as 7-hydroxy--dunnione (2), lapachenole (3), tectoquinone (4), 7-methoxytectoquinone (5), 1-hydroxytectoquinone (6), 7-hydroxytectoquinone (7), aggregatin C (8), aggregatin D (9), halleridone (10), and cedrol (11). In addition, S. canescens yielded a volatile fraction, which was analyzed by GC/FID and GC/MS. This fraction was constituted mainly by sesquiterpene hydrocarbons (82.6%). The major components were -santalene (14.6%), -cedrene (10.4%), and trans-cadina-1(6)-4-diene (10.0%).

Two new hydronaphthoquinones, aggregatins E and F (1 and 2, resp.) were isolated from the tubers of Sinningia aggregata (Ker-Gawl.) Wiehler (Gesneriaceae), along with twelve known compounds aggregatin D (3), tectoquinone (4), 1-hydroxy-2-methylanthraquinone (5), icosyl ferulate (6), pustuline (7), 1,6-dihydroxy-2-methylanthranquinone (8), 6-hydroxy-2-methylanthraquinone (9), 7-hydroxy-2-methylanthraquinone (10), tyrosol (11), halleridone (12), calceolarioside B (13), and cornoside (14). All compounds were identified by analysis of spectroscopic and spectrometric data. Compounds 3, 4, and 10 had already been reported in this species. Compounds 2 and 3 were evaluated against several tumor cell lines, but only 3 exhibited activities against UACC-62, 786-0 and OVCAR-3 cell lines, with IC50 values of 12.3, 12.8 and 0.3 μg/ml, respectively, without toxic effects on non-cancer cell line HaCat (human keratinocyte).