Design, synthesis and anti-tumor activities of cyclic phosphoramidate mustard-quinazoline conjugates

doi:10.5246/jcps.2017.10.082

Abstract

Abstract:

A series of new cyclic phosphoramidate mustard-quinazolineconjugates were designed and synthesized based on the drug candidate EMB-3, a multi-target-directed ligand against tumor cells, and their anti-tumor activities were evaluated on breast cancer and lung cancer cells. Compound 6d exhibited the best anti-tumor performance with IC₅₀ = 0.6 μM(8-fold of EMB-3) on BT474breast tumor cells. Compound 6d inhibited epidermal growth factor receptor (EGFR, biomarker for NSCLC) and human epidermal growth factor 2 (HER2, biomarker for breast cancer) with IC₅₀ of 18 nM and 78 nM, respectively. The preliminary pharmacokinetic study revealed that 6d was more stable than EMB-3 during the in vivo metabolism. A single dose per os (PO) administration of 6d in rat model (10 mg/kg) resulted in a moderate t_1/2of 1.7 h. These results indicated that compound 6d was a potential lead compound for the treatment of breast cancer.

Key words: Phosphoramidate mustard conjugate, Anti-tumor, Breast cancer, EGFR/HER2

CLC Number:

R916

Supporting:

Jiabei Chen, Yufen Zheng, Weiqi Kong, Xin Li, Laichun Luo, Yanjun Han, Songwen Lin, Qi Sun, Zemei Ge, Runtao Li. Design, synthesis and anti-tumor activities of cyclic phosphoramidate mustard-quinazoline conjugates[J]. Journal of Chinese Pharmaceutical Sciences, 2017, 26(10): 727-736.

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