Total Synthesis of a TNBC-Selective Cytotoxic Bromo Nor-eremophilane, PC-A, and Its Preliminary Structure-Activity Relationships

  • J Nat Prod. 2024 Mar 4. doi: 10.1021/acs.jnatprod.3c01075.
Sayaka Maeda  1 ,  Wakana Nakayama  1 ,  Yohei Saito  1 ,  Momoko Sagano  1 ,  Masuo Goto  2 ,  Kyoko Nakagawa-Goto  1  2
Affiliations
  • 1. School of Pharmaceutical Sciences, College of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, 920-1192, Japan.
  • 2. Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina 27599-7568, United States.
PMID: 38438305 DOI: 10.1021/acs.jnatprod.3c01075
Abstract

PC-A (1), a bromo nor-eremophilane, showed selective antiproliferative activity against a triple-negative breast Cancer (TNBC) cell line. This unique activity prompted us to establish a total synthesis to facilitate a structure-activity relationship (SAR) study and selectivity optimization. An enantioselective first total synthesis of 1 was achieved starting from (R)-carvone through a side chain extension with a Mukaiyama aldol reaction and decalin construction. The synthesized decalin derivatives and debromo PC-A (2) were evaluated for antiproliferative activity against five human tumor cell lines, including TNBC, to assess preliminary SAR correlations.

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