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Nonenzymatic reactions sometimes construct complex structures observed in natural products, showing us unique chemical reactions. In our exploration of natural products, we identified a novel type of isochromene-derived polyketide dimer 7 with a 6/6/6/6/6 five-ring system from Chaetomium indicum along with several new related polyketides. We demonstrated that isochromene 6 and its oxidized derivative 8 undergo nonenzymatic dimerization under acidic conditions to give 7 . Furthermore, density functional theory (DFT) calculations revealed the dimerization pathways, suggesting that the acidity (reaction condition) and O -prenylation are key factors in determining reaction mode.

Using CRISPR-Cas9 technology and a microhomology-mediated end-joining repair system, we substituted genes of the gliotoxin pathway in Aspergillus fumigatus with genes responsible for chetomin biosynthesis from Chaetomium cochliodes , leading to the production of three new epipolythiodioxopiperazines (ETPs). This work represents the first successful endeavor to produce ETPs in a non-native host. Additionally, the simultaneous disruption of five genes in a single transformation marks the most extensive gene knockout event in filamentous fungi to date.

Four novel rearranged cytochalasans ( 1 - 4 ) were isolated from an endophytic fungus Chaetomium globosum P2-2-2. Pchaeglobolactone A ( 1 ) possessed an unprecedented 13-aza-21-oxa-tetracyclo-[10.6.1.2 17,19 .0 15,19 ]henicosane core. Spiropchaeglobosin A ( 2 ) was the first example of cytochalasans featuring a novel spiro[5.10]hexadecane unit. Pchaeglobosals A ( 3 ) and B ( 4 ) featured a unique 5/5/13 fused tricyclic ring system. Compounds 1 - 4 were tested for their antiproliferative, apoptosis, cell cycle arrest, and TRAIL-resistance-overcoming activities on cancer cell lines.

Cytochathiazines A-C (1-3), which represent a new type of merocytochalasan, were isolated from coculture of Chaetomium globosum and Aspergillus flavipes. Compounds 1-3 are the first natural products featuring an unprecedented 2 H-1,4-thiazine functionality. Plausible biosynthetic pathways for 1-3 with a chaetoglobosin and a dipeptide as the main constitutional units were proposed. Compound 2 induced apoptosis in leukemia cells through the activation of caspase-3 and the degradation of poly ADP-ribose polymerase.

Chaetoviridins constitute a large family of structurally related secondary metabolites isolated from Chaetomium fungi. To elucidate the biosynthesis pathway and understand how the chemical diversity of chaetoviridins is generated, gene deletion and in vitro characterization of the four post-PKS modifications enzymes were undertaken. CazL and CazP were identified to have substrate promiscuity that facilitates the formation of nonchlorinated analogues. In addition, enzymatic oxidation and reduction combined with spontaneous dehydration and lactonization of the intermediates further expand the chemical diversity.

Armochaeglobines A (1) and B (2), two indole-based cytochalasan alkaloids with new carbon skeletons, were obtained from the fungus Chaetomium globosum TW1-1, which was first isolated from the arthropod Armadillidium vulgare. Their structures were elucidated by extensive spectroscopic analyses, ECD calculation, and single-crystal X-ray diffraction analysis. Interestingly, compound 1 featured a unique tetracyclic 5/6/7/5 fused ring system and 2 possessed a rare 12-membered carbon scaffold.

Spiroindicumides A (1) and B (2), novel spirolactone polyketides, were isolated from a filamentous fungus, Chaetomium indicum, cultivated in the presence of a histone deacetylase inhibitor. Their structures including relative configurations were determined by spectroscopic analyses. Their absolute configurations were unambiguously assigned by the vibrational circular dichroism (VCD) exciton chirality method using only ca. 0.3 mg of each sample. This study presents the first application of the VCD exciton approach to novel natural products. A possible biosynthetic pathway of the new compounds was also proposed.

Epigenetic manipulation of gene expression in Chaetomium indicum using a HDAC inhibitor led to the isolation of structurally diverse chaetophenols, and 3, 4 and 5 bear unprecedented polycyclic skeletons. The expression of two silent genes (pksCH-1 and pksCH-2) for nonreducing PKSs involved in chaetophenol biosynthesis was associated with an increase of histone acetylation level. The heterologous gene expression study in Aspergillus oryzae revealed pksCH-2 to be the NR-PKS gene for 8.

Chaetoconvosins A and B (1 and 2), two novel cytochalasan alkaloids with a new 6/6/5/5/7 pentacyclic ring system, were isolated from the solid-state fermented medium of the wheat rhizospheric fungus Chaetomium convolutum cib-100. Their structures were elucidated on the basis of spectroscopic data. The structure of chaetoconvosin A (1) was confirmed by X-ray crystallographic analysis. Chaetoconvosin B (2), the major metabolite, showed remarkable inhibitory ability on root elongation and moderate cytotoxicity against several cancer cell lines.

Cultivation of Chaetomium mollipilium with nicotinamide, a NAD(+)-dependent HDAC inhibitor, stimulated its secondary metabolism, leading to the isolation of structurally diverse new C(13)-polyketides, mollipilin A-E (1-5) as well as two known compounds (6 and 7). Spectroscopic methods, X-ray single crystal diffraction analysis, and VCD elucidated the absolute configurations of structures 1-6, and plausible biosynthetic pathways for 1-7 were proposed based on structural relationships. Mollipilins A (1) and B (2) exhibited moderate growth inhibitory effects on HCT-116 cells.

Chaetominine (1), an alkaloidal metabolite with a new framework, was characterized from the solid-substrate culture of Chaetomium sp. IFB-E015, an endophytic fungus on the apparently healthy Adenophora axilliflora leaves. Its structure was determined by a combination of its spectral data and single-crystal X-ray diffraction analysis, with its absolute configuration elucidated by Marfey's method. Chaetominine was more cytotoxic than 5-fluorouracil against the human leukemia K562 and colon cancer SW1116 cell lines. [structure: see text]

[structure: see text] Chaetoindicins A-C (1-3), three isoquinolines with novel skeletons, were isolated from the solid-state fermented culture of Chaetomiumindicum. Their structures were elucidated on the basis of spectral data. X-ray crystallographic analysis confirmed the structure of 2.