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Synthesis and In Vitro Antiproliferative Activity of Amido and Amino Analogues of the Marine Alkaloid Isogranulatimide
Author(s) -
Lavrard Hubert,
Salvetti Béatrice,
Mathieu Véronique,
Rodriguez Frédéric,
Kiss Robert,
Delfourne Evelyne
Publication year - 2015
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.201500025
Subject(s) - in vitro , alkaloid , chemistry , melanoma , cell culture , mechanism of action , biochemistry , natural product , cancer , cancer cell , stereochemistry , cancer research , pharmacology , biology , genetics
Marine organisms have proven to be a promising source of new compounds with activity against tumor cell lines. Granulatimide and isogranulatimide are marine alkaloids that have been shown to inhibit checkpoint kinase 1 (Chk1), a key protein in the DNA damage response and an emerging target for anticancer therapeutics. Here, we describe the synthesis and preliminary evaluation of amido and amino analogues of isogranulatimide. The new derivatives were prepared in three steps from 2‐imidazol‐1‐yl‐ 1H ‐indol‐5‐ylamine. Two of the compounds synthesized exhibited more potent in vitro antiproliferative activity (single‐digit micromolar concentration range), by at least one log of magnitude, than the natural product isogranulatimide when evaluated in six human tumor cell lines: non‐small‐cell lung cancer (A549), colon cancer (LoVo), breast cancer (MCF7), oligodendroglioma (Hs683), glioblastoma (U373), and melanoma (SKMEL28). The mechanism of action of these derivatives remains to be elucidated, given that they did not significantly inhibit Chk1, however these compounds are easily synthesized and exhibit potent anticancer activity and are thus worthy of further study.