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Total Synthesis and Biological Evaluation of 22-Hydroxyacuminatine and the Related Natural Products Norketoyobyrine and Naucleficine
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Total Synthesis and Biological Evaluation of 22-Hydroxyacuminatine and the Related Natural Products Norketoyobyrine and Naucleficine
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Journal Article
Total Synthesis and Biological Evaluation of 22-Hydroxyacuminatine and the Related Natural Products Norketoyobyrine and Naucleficine
2025
Overview
Aromathecin compounds—which contain the same indolizine core structure as camptothecin-like compounds—are expected to show anticancer activity. Among them, 22-hydroxyacuminatine—which has a substituent on the E-ring of the pentacyclic scaffold—exhibits topoisomerase 1 inhibitory activity; therefore, the development of efficient methods for its synthesis has been actively pursued. Herein, we report a versatile synthetic methodology for introducing various substituents on the E-ring, leading to the total synthesis of 22-hydroxyacuminatine as a model compound of the aromathecin family. The synthesis comprises the following key steps: the synthesis of an isoquinoline N-oxide via the thermal cyclization of 2-alkynylbenzaldehyde oxime, the subsequent Reissert–Henze-type reaction to yield an isoquinolone, and the construction of the indolizine moiety (CD-ring) through C–N bond formation via the Mitsunobu reaction. Consequently, a pentacyclic benz[6,7]indolizino[1,2-b]quinolin-11(13H)-one framework is obtained. Using this methodology, the total synthesis of the natural products norketoyobyrine and naucleficine and an intermediate of the latter, which are indoloquinolizidine-type alkaloids, was achieved, and their antiproliferative activity against HCT-116 human colon cancer cells and HepG2 human liver cancer cells was assessed. Naucleficine and its intermediate exhibited moderate antiproliferative activity against HCT-116 cells, with IC50 values of 55.58 and 41.40 μM, respectively.
Publisher
MDPI AG,MDPI
Subject
/ Alcohol
/ Antineoplastic Agents - chemical synthesis
/ Antineoplastic Agents - chemistry
/ Antineoplastic Agents - pharmacology
/ Biological Products - chemical synthesis
/ Biological Products - chemistry
/ Biological Products - pharmacology
/ Cancer
/ Cell Proliferation - drug effects
/ Humans
/ Indolizines - chemical synthesis
/ Isoquinolines - chemical synthesis
/ Isoquinolines - pharmacology
/ Structure-Activity Relationship
/ Topoisomerase I Inhibitors - chemical synthesis
/ Topoisomerase I Inhibitors - chemistry
