Design,synthesis and biological evaluation of novel thieno[3,2-d]pyrimidine and quinazoline derivatives as potent antitumor agents |
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| Institution: | 1. Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia;2. Department of Medicinal Chemistry, Faculty of Pharmacy, University of Mansoura, Mansoura 35516, Egypt;3. Department of Pharmaceutical Chemistry, College of Pharmacy, Salman Bin Abdulaziz University, Alkharj, Saudi Arabia;4. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Al-Azhar University, Cairo 11884, Egypt;5. Department of Organic Chemistry, Faculty of Pharmacy, Al-Azhar University, Cairo 11884, Egypt;1. College of Life Science and Bioengineering & Beijing Key Laboratory of Environmental and Oncology, Beijing University of Technology, Beijing 100124, China;2. Beijing Scitech-MQ Pharmaceuticals Limited, Beijing 101320, China;3. Guangxi Key Laboratory Cultivation Base for Polysaccharide Materials and Modifications, School of Marine Science and Biotechnology, Guangxi University for Nationalities, Nanning 530008, China;1. Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, 44 West Wenhua Road, Jinan 250012, China;2. Health and Biomedical Innovation, Clinical and Health Sciences, University of South Australia, Adelaide, SA 5000, Australia;3. School of Pharmacy, Liaocheng University, Liaocheng, China |
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| Abstract: | Four series of novel thieno3,2-d]pyrimidine and quinazoline derivatives containing N-acylhydrazone or semicarbazone were designed, synthesized, and evaluated for their biological activity. Of which compound 14 showed the most potent antitumor activities with IC50 values of 1.78 μM, 1.02 μM, 1.98 μM, 0.41 μM and 0.22 μM against HT-29, MDA-MB-231, U87MG, PC-3 and HCT-116 cell lines respectively. Inhibition of enzymatic assays showed that PI3Kα was very likely to be one of the drug targets of 14 with the IC50 value of 0.20 μM. According to the results of antitumor activity, the SARs were summarized, which indicated that thieno3,2-d]pyrimidine and semicarbazone are optimal fragments. In addition, compounds with hydroxyl group at the 4-position on the terminal phenyl ring were more active. Annexin-V and propidium iodide (PI) double staining confirmed that the most active cytotoxic compound 14 can induce cell apoptosis in HCT-116 cells. Moreover, the influence of 14 on the cell cycle distribution was assessed on the HCT-116 cell line, exhibiting a cell cycle arrest at the G2/M phase. Furthermore, molecular docking analysis was also performed to determine possible binding modes between PI3Kα and the target compound. These results will guide us to further refine the structure of the thieno3,2-d]pyrimidine and quinazoline derivatives to achieve optimal antitumor activity. |
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| Keywords: | Quinazoline Synthesis Antitumor activity |
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