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Spirooxindol‐1,3‐oxazine Alkaloids: Highly Potent and Selective Antitumor Agents Evolved from Iterative Structure Optimization
Author(s) -
Eichhorst Annika,
Gallhof Malte,
Voss Alice,
Sekora Anett,
Eggers Leon,
Huyen Le Thi,
Junghanss Christian,
Murua Escobar Hugo,
Brasholz Malte
Publication year - 2022
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.202200162
Subject(s) - chemistry , alkaloid , combinatorial chemistry , ic50 , photooxygenation , stereochemistry , in vitro , biochemistry , organic chemistry , singlet oxygen , oxygen
Spirooxindole‐1,3‐oxazines are a small and structurally unique class of spirooxindole alkaloids. To date, only four of these compounds have been isolated from natural sources, and their biological properties remained unknown thus far. Dioxyreserpine is a synthetic spirooxindole‐1,3‐oxazine, that can readily be prepared from the Rauvolfia alkaloid (–)‐reserpine by catalytic photooxygenation. While dioxyreserpine itself was now identified as a moderately effective antitumoral agent, structurally modified analogs of it emerged as a new class of highly potent and selective growth inhibitors of various human cancers, including pancreatic cancers. Systematic structural optimization ultimately led to an inhibitor displaying low‐micromolar IC 50 ‐values against six cancer cell lines as well as selective apoptosis induction in vitro .