Quinazoline Based HSP90 Inhibitors: Synthesis,Modeling Study and ADME Calculations Towards Breast Cancer Targeting |
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| Institution: | 1. Department of Chemistry and Biochemistry, University of Notre Dame, IN, USA;2. Department of Chemistry, University of South Florida, Tampa, FL 33620, USA;1. Department of Pharmacology, School of Pharmacy, Fujian Medical University (FMU), Fuzhou, PR China;2. Institute of Materia Medica, Fujian Medical University (FMU), Fuzhou, PR China;3. Fujian Key Laboratory of Natural Medicine Pharmacology, Fujian Medical University (FMU), Fuzhou, PR China;4. Department of Public Technology Service Center, Fujian Medical University (FMU), Fuzhou, PR China;5. Department of Pharmacochemistry, School of Pharmacy, Fujian Medical University (FMU), Fuzhou, PR China;1. School of Pharmacy, Bengbu Medical College, 2600 Donghai Road, Bengbu 233030, Anhui, China;2. School of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai 200433, China;3. Anticancer Agent Research Center, KRIBB, Cheongju 28116, Republic of Korea;1. Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura, 35516, Egypt;2. Le Mans Université, IMMM-UMR 6283 CNRS, MSO Team, Faculté des Sciences, 72085, Le Mans, Cedex 9, France;1. Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt;2. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Horus University, New Dammeitta, Egypt;1. Research Laboratories, Ildong Pharmaceutical Co., Hwaseong-si, Gyeonggi-do 18449, South Korea;2. AIMS BioScience Co., 2, Baumoe-ro 27-gil, Seocho-gu, Seoul 06752, South Korea;3. Laboratory of Medicinal Chemistry, College of Pharmacy, Seoul National University, Seoul 08826, South Korea |
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| Abstract: | A new 2-thioquinazolinones series was designed and synthesized as HSP90 inhibitors based on the structure of hit compound VII obtained by virtual screening approach. Their in vitro anti-proliferative activity was evaluated against three human cancer cell lines rich in HSP90 namely; colorectal carcinoma (HCT-116), and cervical carcinoma (Hela), breast carcinoma (MCF-7). Compounds 5a, 5d, 5e and 9h showed a significant broad spectrum anti-proliferative activity against all tested cell lines. They were characterized by potent effect against breast cancer in particular with IC50 of 11.73, 8.56, 7.35 and 9.48 μM, respectively against Doxorubicin (IC50 4.17 μM). HSP90 ATPase activity inhibition assay were conducted where compound 5d exhibited the best IC50 with 1.58 μM compared to Tanespimycin (IC50 = 2.17 μM). Compounds 5a and 9h showed higher IC50 values of 3.21 and 3.41 μM, respectively. The effects of 5a, 5d and 9h on Her2 (a client proteins of HSP90) and HSP70 were evaluated in MCF-7 cells. All tested compounds were found to reduce Her2 protein expression levels and induce Hsp70 protein expression levels significantly, emphasizing that antibreast cancer effect is a consequence of HSP90 chaperone inhibition. Cell cycle analysis of MCF-7 cells treated with 5d showed cell cycle arrest at G2/M phase 38.89% and pro-apoptotic activity as indicated by annexin V-FITC staining by 22.42%. Molecular docking studies suggested mode of interaction to HSP90 via hydrogen bonding. ADME properties prediction of the active compounds suggested that they could be used as orally absorbed anticancer drug candidates. |
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| Keywords: | 2-Thioquinazolin-4-one Anticancer activity Breast cancer HSP90 Her2 HSP70 Molecular modeling |
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