Structure-activity relationship of pyrazolo pyrimidine derivatives as inhibitors of mitotic kinesin Eg5 and anticancer agents |
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| Affiliation: | 1. Department of Industrial Chemistry, Alagappa University, Karaikudi 630006, India;2. Department of Biotechnology, School of Chemical & Biotechnology, SASTRA Deemed University, Thanjavur 613401, India;1. Research and Development Centre, Bharathiar University, Coimbatore 641046, India;2. Department of Biotechnology, School of Bio-Sciences and Technology, VIT University, Vellore 632014, India;3. PG & Research Department of Chemistry, Government Arts College, Coimbatore 641018, Tamil Nadu, India;1. Department of Chemistry, St Berchmans College (Autonomous), Changanassery, Kerala, India;2. Department of Physics, Fatima Mata National College (Autonomous), Kollam, Kerala, India;3. Department of Chemistry, Mangalore University, Mangalagangothri, Karnataka, India;4. Department of Industrial Chemistry, Mangalore University, Mangalagangothri, Karnataka, India;5. Department of Chemistry, Arinagar Anna Government Arts College, Musiri PO, Thiruchirapalli, Tamil Nadu, India;6. Department of Chemistry, University of Antwerp, Groenenborgerlaan 171, B-2020, Antwerp, Belgium;1. Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, Jinan 250012, PR China;2. Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA;3. Shandong Qidu Pharmaceutical Co., Ltd., 28 Renmin East Road, Zibo 255400, PR China;1. Department of Pharmaceutical Chemistry, Faculty of Pharmacy (girls), Al-Azhar University, Nasr City, Cairo, Egypt;2. Department of Organic Chemistry, Faculty of Science, Ain Shams University, Abbassia, 11566 Cairo, Egypt;1. Al-Azhar University, Faculty of Pharmacy, Pharmaceutical Organic Chemistry Department, Assiut 71524, Egypt;2. Cairo University, Faculty of Pharmacy, Pharmaceutical Organic Chemistry Department, Cairo 11562, Egypt;3. South Dakota State University, Faculty of Science, Chemistry Department, Brookings, SD 57007, USA;1. National Organization for Drug Control & Research, P.O. Box: 29, Cairo, Egypt;2. Pharmaceutical Chemistry Department, Faculty of Pharmaceutical Sciences and Pharmaceutical Industries, Future University in Egypt, Cairo 12311, Egypt |
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| Abstract: | Human kinesin Eg5 is a potential inhibiting site for cancer chemotherapy. Blocking metaphase by binding foreign inhibitors with Eg5 eventually leads to apoptotic cell death. Here, we report the pyrazolopyrimidine derivates as potent inhibitors of Eg5 that prevents mitotic kinesin progression. IC50 values were evaluated against the motor domain of Eg5 using steady-state ATPase assay. To better understanding, we have performed molecular docking simulation. It reveals that the interactions of the proposed inhibitors with both the allosteric sites (helices α2, α3 and loopL5, and helices α4 & α6). Out of fifteen pyrazolopyrimidine derivates, three compounds (12, 25, and 27) have shown significant inhibition of Eg5. The synthesized compounds (12, 25, and 27) were tested for their in-vitro anticancer activity against cervical cancer cell line (HeLa). |
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| Keywords: | Pyrazaole Thienopyridines Kinesin spindle protein Anticancer agents |
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