title: 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 IC50of 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).
authors.affiliation: State Key Lab of Natural and Mimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, PR China.
authors.forename: Songwen
authors.initials: S
authors.lastname: Lin
authors.affiliation: State Key Lab of Natural and Mimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, PR China.
authors.forename: Yingbo
authors.initials: Y
authors.lastname: Li
authors.affiliation: State Key Lab of Natural and Mimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, PR China.
authors.forename: Yufen
authors.initials: Y
authors.lastname: Zheng
authors.affiliation: State Key Lab of Natural and Mimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, PR China.
authors.forename: Laichun
authors.initials: L
authors.lastname: Luo
authors.affiliation: State Key Lab of Natural and Mimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, PR China. Electronic address: sunqi@bjmu.edu.cn.
authors.forename: Qi
authors.initials: Q
authors.lastname: Sun
authors.affiliation: State Key Lab of Natural and Mimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, PR China.
authors.forename: Zemei
authors.initials: Z
authors.lastname: Ge
authors.affiliation: State Key Lab of Natural and Mimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, PR China.
authors.forename: Tieming
authors.initials: T
authors.lastname: Cheng
authors.affiliation: State Key Lab of Natural and Mimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, PR China. Electronic address: lirt@bjmu.edu.cn.
authors.forename: Runtao
authors.initials: R
authors.lastname: Li
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D045744:Cell Line, Tumor; D060326:Chemistry Techniques, Synthetic; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D006801:Humans; D008297:Male; D051379:Mice; D010752:Phosphoramide Mustards / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D011799:Quinazolines / Q000737:chemistry*; D051381:Rats; D013329:Structure-Activity Relationship; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D010752:Phosphoramide Mustards; D011799:Quinazolines; C030090:phosphoramide mustard
keywords: Anticancer drugs; DNA alkylating agents; EGFR/HER2 inhibitors; Multi-target-directed ligands; Phosphoramide mustard