Monoenomycin: A Simplified Trienomycin A Analogue That Manifests Anticancer Activity

Abstract

Macrocyclic natural products are a powerful class of lead-like chemical entities. Despite commonly violating Lipinski’s “rule of 5”, these compounds often demonstrate superior drug-like physicochemical and pharmacokinetic attributes when compared to their acyclic counterparts. However, the elaborate structural architectures of such molecules require rigorous synthetic investigation that complicates analogue development and their application to drug discovery programs. To circumvent these limitations, a conformation-based approach using limited SAR and molecular modeling was implemented to design simplified analogues of trienomycin A, in which the corresponding analogues could be prepared in a succinct manner to rapidly identify essential structural components necessary for biological activity. Trienomycin A is a member of the ansamycin family of natural products that possesses potent anticancer activity. These studies revealed a novel trienomycin A analogue, monoenomycin, which manifests potent anticancer activity.

Conformation–activity relationships of polyketide natural products

“…66 After generating low-energy conformations of the semi-synthetic analogues with SYBYL, 67 Blagg and co-workers showed that while Funayama’s inactive derivatives exhibited significant conformational differences from trienomycin A, the active methyl ether analogue retained the parent geometry. The Blagg group hypothesized that mimicking the conformational preferences of 21 properly orients the critical phenol unit and N -acylated side chain within trienomycin’s binding pocket, thereby promoting tight binding.…”

COMU: scope and limitations of the latest innovation in peptide acyl transfer reagents

“…Successful Weinreb amidation of several Boc-amino acids (63-97% yield) and aliphatic acids has been recently achieved [15,33]. In addition, the use of COMU (16) in bioconjugation, anilide, and PNA-based construct formation has been described in numerous occasions [27,[34][35][36][37][38][39].…”

Tandem Mass Tag-Based Quantitative Proteomics and Virulence Phenotype of Hemolymph-Treated Bacillus thuringiensis kurstaki Cells Reveal New Insights on Bacterial Pathogenesis in Insects

“…Two upregulated DAPs identified as transketolase were enriched in the “biosynthesis of ansamycins” pathway, suggesting that these bacterial macrocyclic polyketides with demonstrated antimicrobial ( 62 ), anticancer ( 63 ), and antiviral ( 64 ) activities could be playing important roles in Btk’s survival in the hemolymph. The only known ansamycins of Bacillus origin are the antibiotic aurantinin and antivirals hydroxymycotrienins A and B ( 65 , 66 ).…”