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Design, synthesis and biological evaluation of quinazoline-phosphoramidate mustard conjugates as anticancer drugs.

Abstract：

:A series of novel compounds with phosphoramide mustard functionality incorporated into the quinazoline scaffold of EGFR/HER2 inhibitors were designed and synthesized as multi-target-directed ligands against tumor cells. In vitro assays showed that tumor cell lines with high HER2 level were more sensitive to the compounds than tumor cells with low HER2 level. Compound 10d (EMB-3) was one of the most potent inhibitors with IC50 of 7.4 nM and 82 nM against EGFR and HER2, respectively. The mechanism studies were also supported by the effect of 10d-induced DNA damage in MDA-MB-468 cells. In vivo efficacy study showed that 10d could significantly inhibit H522 tumor xenograft model with a TGI of 68% at dose of 100 mg/kg (QDx28, p.o.) and no significant body weight loss was observed. MTD study indicated that compound 10d had no acute toxicity to mice at doses up to 900 mg/kg (single dose).

journal_name

Eur J Med Chem

journal_title

European journal of medicinal chemistry

authors

Lin S,Li Y,Zheng Y,Luo L,Sun Q,Ge Z,Cheng T,Li R

doi

10.1016/j.ejmech.2016.12.055

subject

Has Abstract

pub_date

2017-02-15 00:00:00

pages

442-458

eissn

0223-5234

issn

1768-3254

pii

S0223-5234(16)31061-3

journal_volume

127

pub_type

杂志文章

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