A series of new cyclic phosphoramidate mustard-quinazoline conjugates were designed and synthesized based on the drug candidate EMB-3, a multi-target-directed ligand against tumor cells, and their anti-tumor activitie...A series of new cyclic phosphoramidate mustard-quinazoline conjugates 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 IC5o = 0.6 pM （8-fold of EMB-3） on BT474 breast tumor cells. Compound 6d inhibited epidermal growth factor receptor （EGFIL 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 tl/2 of 1.7 h. These results indicated that compound 6d was a potential lead compound for the treatment of breast cancer.展开更多
基金Ministry of Science and Technology of China(Grant No.2012ZX09103101-042)
文摘A series of new cyclic phosphoramidate mustard-quinazoline conjugates 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 IC5o = 0.6 pM （8-fold of EMB-3） on BT474 breast tumor cells. Compound 6d inhibited epidermal growth factor receptor （EGFIL 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 tl/2 of 1.7 h. These results indicated that compound 6d was a potential lead compound for the treatment of breast cancer.
