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Synthesis, cytotoxicity, topoisomerase I inhibition and molecular docking of novel phosphoramide mustard sophoridinic acid analogues
Author(s) -
Liu Kai,
Li DongDong,
Zhao XiuMei,
Dai LinLin,
Zhang Ting,
Tao ZunWei
Publication year - 2017
Publication title -
applied organometallic chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.53
H-Index - 71
eISSN - 1099-0739
pISSN - 0268-2605
DOI - 10.1002/aoc.3565
Subject(s) - chemistry , cytotoxicity , topoisomerase , docking (animal) , stereochemistry , dna , biochemistry , enzyme , molecular model , k562 cells , cell culture , enzyme inhibitor , cell , in vitro , biology , medicine , genetics , nursing
A series of novel phosphoramide mustard sophoridinic acid analogues, consisting of nitrogen mustard group and sophoridinic acid scaffold, have been designed, synthesized and evaluated for their topoisomerase inhibitory activity as well as cytotoxicity against six tumor cell lines (SMMC‐7721, LoVo, MCF‐7, K562, S180 and H22) and a normal cell line (L929). Among the compounds tested, five were found to be potent inhibitors and exhibited potent cytotoxicity against S180 and H22 cell lines with IC 50 values of 1–4 μM. Further mechanistic studies showed that this class of compounds acted as novel topoisomerase I (Topo I) catalytic inhibitors by preventing the binding of Topo I to DNA and inhibiting the cleavage of DNA, and molecular docking studies revealed that the binding energy for these compounds was comparable to that for classic Topo I inhibitors CPT and HCPT, indicating that the compounds have an interaction with DNA and Topo I.