Abstract
Natural products are often the starting point for drug development and also the testing ground for synthetic methods. Herein we describe the total synthesis and antimicrobial evaluation of a marine natural product, pagoamide A, which is a macrocyclic depsipeptide with two backbone thiazole units and a dimethylated N-terminus. The two thiazole building blocks were synthesized from commercially available materials in four or fewer steps and employed directly in solid-phase peptide synthesis (SPPS) to afford pagoamide A. The use of SPPS ensured that the synthetic sequence is operationally straightforward and, if needed, permits modular substitution of building blocks to easily access diverse structural analogs. Our antimicrobial assays showed that pagoamide A has moderate activity against Bacillus subtilis.
Highlights
Microbial natural products have historically been a fruitful source of bioactive small molecules (Newman and Cragg, 2020)
Once a natural product demonstrated its potential as a drug candidate, the ability to access it with high efficiency through chemical synthesis from simple starting materials, i.e., total synthesis, is critically important and play an integral role as it progresses through the drug development pipeline
Pagoamide A (1) is a cyclic depsipeptide made of 11 amino acids, three of which are D-amino acids
Summary
Microbial natural products have historically been a fruitful source of bioactive small molecules (Newman and Cragg, 2020). Peptide natural products, including nonribosomal peptides (NRPs) (Fischbach and Walsh, 2006) and ribosomally-synthesized and post-translationally modified peptides (RiPPs) (Arnison et al, 2013), are highly represented in small molecule therapeutics in clinical use today, for the treatment of microbial infections. Both are very attractive classes of natural products that have inspired scientists as they look for starting points for the development of new drugs. SPPS has become the method of choice for the synthesis of linear peptides
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