2. Academic Validation
  3. Total Synthesis of Verlamelin A and (5 R)-Verlamelin A with Antifungal Activity

Total Synthesis of Verlamelin A and (5 R)-Verlamelin A with Antifungal Activity

  • J Org Chem. 2025 Sep 5;90(35):12425-12434. doi: 10.1021/acs.joc.5c01629.
Xin Sun 1 2,  Youhong Li 1 2,  Wenshen Lin 1 2,  Yuyue Li 3 4,  Huayan Xu 5,  Ziqiang Yan 5,  Bin Yang 3 4,  Yonghong Liu 3 4,  Bin Wang 1 2,  Shengrong Liao 3 4
Affiliations

Affiliations

  • 1 Shenzhen Clinical College of Integrated Chinese and Western Medicine, Guangzhou University of Chinese Medicine, Shenzhen 518104, China.
  • 2 Shenzhen Hospital of Integrated Traditional Chinese and Western Medicine, Shenzhen 518104, China.
  • 3 Research Center for Marine Microbes, Laboratory of Tropical Marine Bio-Resources and Ecology, Guangdong Key Laboratory of Marine Materia Medica, South China Sea Institute of Oceanology, Chinese Academy of Sciences, Guangzhou 510301, China.
  • 4 University of Chinese Academy of Sciences, Beijing 100049, China.
  • 5 Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang 110016, China.
PMID: 40855721 DOI: 10.1021/acs.joc.5c01629
Abstract

Verlamelin A is a naturally occurring macrocyclic depsipeptide exhibiting high and broad-spectrum Antifungal activity. The first unified total synthesis of verlamelin A and its (5R)-verlamelin A (C5-epimer) is reported. This strategy involved homogeneous solution-phase synthesis of Fmoc-l-Val-O-(5S/5R)-tetradecanoic acid, solid-phase peptide synthesis of pentapeptide NH2-d-allo-Thr-d-Ala-l-Pro-l-Gln-d-Tyr-OH, on-resin coupling of these two fragments to form a linear precursor 17, and off-resin cyclization followed by global deprotection to generate the final verlamelin A and (5R)-verlamelin A in 6.8 and 7.8% overall yields, respectively. 1H/13C{1H} NMR, HRMS, and analytic HPLC were performed to confirm our successful total synthesis of verlamelin A. Antimicrobial evaluation revealed that both compounds exhibited potent Antifungal activity against Alternaria alternate, Alternaria solani, and Rhizoctonia solani with MIC values ranging from 4 to 16 μg/mL. (5R)-verlamelin A showed superior efficacy against A. alternate (MIC = 4 μg/mL) compared with verlamelin A (MIC = 8 μg/mL), suggesting its potential as a lead Antifungal candidate for further development against this pathogen.

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