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

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 enant...

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Bibliographic Details
Published in:Journal of natural products (Washington, D.C.) D.C.), 2024-04, Vol.87 (4), p.861-868
Main Authors: Maeda, Sayaka, Nakayama, Wakana, Saito, Yohei, Sagano, Momoko, Goto, Masuo, Nakagawa-Goto, Kyoko
Format: Article
Language:English
Subjects:
Antineoplastic Agents - chemical synthesis
Antineoplastic Agents - chemistry
Antineoplastic Agents - pharmacology
Cell Line, Tumor
Cyclohexane Monoterpenes - chemistry
Cyclohexane Monoterpenes - pharmacology
Drug Screening Assays, Antitumor
Female
Humans
Molecular Structure
Monoterpenes - chemical synthesis
Monoterpenes - chemistry
Monoterpenes - pharmacology
Polycyclic Sesquiterpenes - chemical synthesis
Polycyclic Sesquiterpenes - chemistry
Polycyclic Sesquiterpenes - pharmacology
Sesquiterpenes - chemical synthesis
Sesquiterpenes - chemistry
Sesquiterpenes - pharmacology
Stereoisomerism
Structure-Activity Relationship
Triple Negative Breast Neoplasms - drug therapy
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Summary: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.
ISSN:0163-3864
1520-6025
1520-6025
DOI:10.1021/acs.jnatprod.3c01075