An investigative study of antitumor properties of a novel thiazolo[4,5-d]pyrimidine small molecule revealing superior antitumor activity with CDK1 selectivity and potent pro-apoptotic properties |
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| Affiliation: | 1. Department of Biochemistry, Faculty of Pharmacy, Egyptian Russian University, Badr 11829, Cairo, Egypt;2. Pharmaceutical Chemistry Department, Faculty of Pharmacy, Helwan University, Ain Helwan 11795, Cairo, Egypt;3. Biochemistry and Molecular Biology Department, Faculty of Pharmacy, Helwan University, Ain Helwan 11795, Helwan, Cairo, Egypt;4. Basic and Applied Sciences Institute, Egypt-Japan University of Science and Technology (E-JUST), New Borg El-Arab City, 21934 Alexandria, Egypt;5. Pharmaceutical Chemistry Department, Faculty of Pharmacy, Ain Shams University, Abbassia 11566, Cairo, Egypt;6. Department of Organic and Medicinal Chemistry, Faculty of Pharmacy, University of Sadat City, Sadat City, Egypt;1. Small Molecule Drug Research Laboratories, R&D Division, Kyowa Kirin Co., Ltd., 1188 Shimotogari, Nagaizumi-cho, Sunto-gun, Shizuoka 411-8731, Japan;2. Immunology & Allergy Research Laboratories, R&D Division, Kyowa Kirin Co., Ltd., 1188 Shimotogari, Nagaizumi-cho, Sunto-gun, Shizuoka 411-8731, Japan;3. Pharmacokinetics Research Laboratories, R&D Division, Kyowa Kirin Co., Ltd., 1188 Shimotogari, Nagaizumi-cho, Sunto-gun, Shizuoka 411-8731, Japan;1. Department of Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor, MI 48105, USA;2. Department of Medicinal Chemistry, University of Michigan, Ann Arbor, MI 48109, USA;3. Vahlteich Medicinal Chemistry Core, University of Michigan, Ann Arbor, MI 48109, USA;4. Department of Pharmaceutical Sciences, University of Michigan, Ann Arbor, MI 48109, USA;5. Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI 48109, USA;1. School of Pharmacy, Jinan University, Guangzhou 510632, China;2. YZ Health-tech Inc., Hengqin District, Zhuhai 519000, China;3. School of Biology and Biological Engineering, South China University of Technology, Guangzhou 510006, China;4. Institute of Biomedical and Pharmaceutical Sciences, Guangdong University of Technology, Guangzhou 510006, China;5. Jeffrey Cheah School of Medicine and Health Sciences, Monash University Malaysia, Bandar Sunway 47500, Selangor Darul Ehsan, Malaysia;1. KU Leuven, Rega Institute for Medical Research, Laboratory of Medicinal Chemistry, Herestraat 49, 3000 Leuven, Belgium;2. Department of Medicine, Division of Infectious Diseases and Geographic Medicine, and Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA 94305, USA;3. KU Leuven, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, Laboratory of Virology and Chemotherapy, Herestraat 49, 3000 Leuven, Belgium |
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| Abstract: | New thiazolo[4,5-d]pyrimidine analogues were synthesized and biologically assessed in-vitro for their antineoplastic activity. The growth inhibitory effects of these compounds were assessed through the National Cancer Institute-United States of America (NCI-USA) anticancer screening program. Compound 5 (7-Chloro-3-(2,4-dimethoxyphenyl)-5-methylthiazolo[4,5-d]pyrimidine-2(3H)-thione) was found to have a potent and broad-spectrum cytotoxic action against NCI panel with GI50 (50% growth inhibition concentration) mean graph midpoint (MG-MID) = 2.88 µM. MTT assay was used to determine IC50 values of the most potent agent against HCT-116 colorectal carcinoma and WI-38 human lung fibroblast cell lines; 5.33 µM ± 0.69 and 21.69 µM ± 1.04, respectively. Flow cytometric analysis revealed that compound 5 triggered apoptosis and G2/M cell cycle arrest. The ability of compound 5 to inhibit CDK1 (Cyclin-Dependent Kinase 1)/Cyclin B complex was evaluated, and its IC50 value was 97 nM ± 2.33. Moreover, according to the gene expression analysis, compound 5 up-regulated p53, BAX, cytochrome c, caspases-3,-8 and-9 besides down-regulated Bcl-2. In conclusion, compound 5 exerted a potent pro-apoptotic activity through the activation of the intrinsic apoptotic pathway and arrested the cell cycle at the G2/M phase. |
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| Keywords: | Anticancer activity Apoptosis Cell cycle arrest |
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