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. 2024 Feb 12:696:149483.
doi: 10.1016/j.bbrc.2024.149483. Epub 2024 Jan 9.

Biological evaluation of 9-thioansamitocin P3

Natalya I Vasilevich  1 , Huangyu Jiang  2 , Haihua Xiao  2 , Kunxian Feng  2 , Chengfang Jian  2 , Changfeng Chen  2 , Min Li  2 , Zhenhua Chen  2 , Li Pang  2 , Xiang Li  2 , Alexander V Chestkov  2 , Andre H Sun  3 , Wang Xu  3 , Joseph A Fuselier  4 , David H Coy  4 , Lichun Sun  5
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Biological evaluation of 9-thioansamitocin P3

Natalya I Vasilevich et al. Biochem Biophys Res Commun. .

Abstract

Highly cytotoxic maytansine derivatives are widely used in targeted tumor delivery. Structure-activity studies published earlier suggested the C9 carbinol to be a key element necessary to retain the potency. However, in 1984 a patent was published by Takeda in which the synthesis of 9-thioansamitocyn (AP3SH) was described and its activity in xenograft models was shown. In this article we summarize the results of an extended study of the anti-tumor properties of AP3SH. Like other maytansinoids, it induces apoptosis and arrests the cell cycle in the G2/M phase. It is metabolized in liver microsomes predominately by C3A4 isoform and doesn't inhibit any CYP isoforms except CYP3A4 (midazolam, IC50 7.84 μM). No hERG inhibition, CYP induction or mutagenicity in Ames tests were observed. AP3SH demonstrates high antiproliferative activity against 25 tumor cell lines and tumor growth inhibition in U937 xenograft model. Application of AP3SH as a cytotoxic payload in drug delivery system was demonstrated by us earlier.

Keywords: 9-thioansamitocin; AP3OH; AP3SH; Ansamitocin-P3; Maytansine; Maytansinoid.

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Conflict of interest statement

Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Sun L. reports financial support was provided by Shenzhen Science and Technology Program. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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