ABSTRACT
Chetocochliodin M (5) containing a rare cage-ring and chetocochliodin N (6) featuring an unusual piperazine-2,3-dione ring system together with known analogues chetomin (1), chetoseminudin C (2), chetocochliodin I (3), and oidioperazine E (4) were targeted for purification from the fungus Chaetomium cochliodes using a UPLC-Q-TOF-MS/MS approach. The structures of the new compounds were elucidated using HR-ESI-MS, NMR, and ECD spectra. Compounds 1, 3, and 6 exhibited strong cytotoxic activities against A549 and HeLa cancer cell lines.
Subject(s)
Chaetomium , Tandem Mass Spectrometry , Chaetomium/chemistry , Humans , Molecular Structure , Tandem Mass Spectrometry/methods , HeLa Cells , Chromatography, High Pressure Liquid/methods , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemistry , Antineoplastic Agents/isolation & purification , Drug Screening Assays, Antitumor , A549 Cells , Piperazines/pharmacology , Piperazines/chemistry , Piperazines/isolation & purificationABSTRACT
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.
Subject(s)
Aspergillus fumigatus , Gliotoxin , Piperazines , Aspergillus fumigatus/metabolism , Aspergillus fumigatus/genetics , Piperazines/chemistry , Piperazines/metabolism , Gliotoxin/biosynthesis , Gliotoxin/chemistry , Molecular Structure , Chaetomium/metabolism , Chaetomium/chemistry , CRISPR-Cas SystemsABSTRACT
This review provides a critical analysis of shielding effects induced by an aromatic (indole) ring of small molecules mainly including three members of naturally occurring secondary metabolites asterric acid analogs, diketopiperazines (DKPs) possessing an aromatic or an indole ring, and rubrolides. Empirical rules about the shielding effects induced by an aromatic (indole) ring are classified, based on which some 1H NMR chemical shift values in the A-ring and structures of asterric acid analogs are revised, and the relative configurations of some DKPs possessing an indole ring are also assigned or revised. The empirical rules could provide an efficient and convenient method for NMR data analysis and configuration determination for the three members of small molecules mentioned above.
