Studies on the biosynthesis of chetomin: enantiospecific synthesis of a putative, late-stage biosynthetic intermediate

Abstract

The enantiospecific synthesis of desthiochetomin, a putative biosynthetic intermediate of the epidithiodioxopiperazine natural product chetomin, is described. A diastereoselective N-alkylation was employed to form the key C3-N1’ bond of the heterodimeric indoline core, followed by peptide coupling and dioxopiperazine cyclization with the requisite N-methyl amino acids. A related sarcosine–derived dioxopiperazine was prepared in the same manner. The first proposed biosynthesis of chetomin is also detailed in the text.

Double the Chemistry, Double the Fun: Structural Diversity and Biological Activity of Marine-Derived Diketopiperazine Dimers

“…While the biosynthetic origin of the C3-N1’ linkage is not well understood, Welch and Williams [175] proposed a route to the biosynthesis of chetomin ( 52 ) through the convergent and enantioselective synthesis of an intermediate.…”

Epidithiodioxopiperazines. occurrence, synthesis and biogenesis

“…From a biosynthetic viewpoint, the more interesting discoveries are chetoseminudins B-D ( 75-77 ), monomeric bisdethiodi(methylthio) structures that potentially provide insight as to the biosynthetic sequence that produces chetomin, the chaetocochins, and other related epipolythiodioxopiperazines derived from tryptophan and serine. 76 …”

“…From a biosynthetic viewpoint, the more interesting discoveries are chetoseminudins B-D (75-77), monomeric bisdethiodi(methylthio) structures that potentially provide insight as to the biosynthetic sequence that produces chetomin, the chaetocochins, and other related epipolythiodioxopiperazines derived from tryptophan and serine. 76 Chetomin ( 12) has an unprecedented mechanism of action as a cancer chemotherapeutic agent. Solid tumors must adapt to oxygen deprivation through induction of the heterodimeric transcription factor hypoxia-inducible factor 1 (HIF-1) in order to survive.…”

Cytotoxic and antimicrobial indole alkaloids from an endophytic fungusChaetomiumsp. SYP-F7950 ofPanax notoginseng

“…3. For compounds 1-5, all of them began with the condensation of serine and tryptophan by a nonribosomal peptide synthetase, 31 followed by C-hydroxylation, 32 water elimination, 33 sulfurization 33 and O-or S-methylation 34 to afford compounds 1-5. For compounds 6 and 9-13, they were derived from tryptophan-derived heterodimer via a radical dimerization, 35 followed by the peptide coupling reactions with serine and subsequent dioxopiperazine cyclization by a nonribosomal peptide synthetase, Nmethylation, water elimination, sulfurization, S-methylation and di or polythiol-oxidation to afford compounds 6 and 9-13 which has been reported previously.…”

“…For compounds 6 and 9-13, they were derived from tryptophan-derived heterodimer via a radical dimerization, 35 followed by the peptide coupling reactions with serine and subsequent dioxopiperazine cyclization by a nonribosomal peptide synthetase, Nmethylation, water elimination, sulfurization, S-methylation and di or polythiol-oxidation to afford compounds 6 and 9-13 which has been reported previously. 31 Seven test bacteria (Staphylococcus aureus, Bacillus subtilis, Escherichia coli, Enterococcus faecium, Proteus mirabilis, Acinetobacter baumannii and Achromobacter marplatensis) and one fungus (Candida albicans) were selected for antibacterial and antifungal assays (Table 3). In antimicrobial assay, compounds 1 and 2 showed weak inhibitory activity against A. marplatensis and C. albicans with MICs values of 117.7, 76.7, 103.3 and 124.1 mg mL À1 (vancomycin, MIC ¼ 50 mg mL À1 and geneticin, MIC ¼ 6.0 mg mL À1 ), respectively.…”