Design,synthesis and biological study of hybrid drug candidates of nitric oxide releasing cucurbitacin-inspired estrone analogs for treatment of hepatocellular carcinoma |
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| Affiliation: | 1. Al-Azhar University, Faculty of Pharmacy, Pharmaceutical Organic Chemistry, Assiut 71524, Egypt;2. Cairo University, Faculty of Pharmacy, Pharmaceutical Organic Chemistry, Cairo 11562, Egypt;3. University of Sadat City, Faculty of Pharmacy, Organic and Medicinal Chemistry, Menoufia 32958, Egypt;4. South Dakota State University, Chemistry & Biochemistry, Box 2202, Brookings, SD 57007, USA;1. National Engineering Research Center of Chiral Drugs, Chengdu Institute of Organic Chemistry, Chinese Academy of Sciences, Chengdu 610041, China;2. University of Chinese Academy of Sciences, Beijing 100049, China;1. University of Southern California, Los Angeles, CA, United States;2. The Ohio State University, Columbus, OH, United States;3. Zunyi Medical College, Zunyi, China;4. Leidos Biomedical Research Inc, Frederick, MD, United States;1. Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Cairo University, 11562, Egypt;2. Organic & Medicinal Chemistry Department, Faculty of Pharmacy, University of Sadat City, Sadat City, Menoufia, 32958, Egypt;3. Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy (Boys), Al-Azahar University, Cairo 11884, Egypt;4. Pharmaceutical Chemistry Department, Faculty of Pharmacy, Misr International University, Cairo 11431, Egypt;5. Department of Pharmacology, Faculty of Medicine, Al-Azher University, 71524 Assiut, Egypt;6. Biochemistry Department, Faculty of Pharmacy, Al-Azher University, 71524 Assiut, Egypt;7. Biochemistry Department, Faculty of Pharmacy, Nahda University, Benisuif, Egypt;1. Biodesign Center for BioEnergetics, Arizona State University, Tempe, AZ 85287, USA;2. Department of Central Laboratory, Taizhou Central Hospital (Taizhou University Hospital), Taizhou, Zhejiang, PR China;3. School of Medcine, Taizhou University, Taizhou, Zhejiang, PR China |
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| Abstract: | Development of hybrid drug candidates is well known strategy for designing antitumor agents. Herein, a novel class of nitric oxide donating cucurbitacin inspired estrone analogs (NO-CIEAs) were designed and synthesized as multitarget agents. Synthesized analogs were initially evaluated for their anti-hepatocellular carcinoma activities. Among the tested analogs, NO-CIEAs 17 and 20a exhibited more potent activity against HepG2 cells (IC50 = 4.69 and 12.5 µM, respectively) than the reference drug Erlotinib (IC50 = 25 µM). Interestingly, NO-CIEA 17 exerted also a high potent activity against Erlotinib-resistant HepG2 cell line (HepG2-R) (IC50 = 8.21 µM) giving insight about its importance in drug resistance therapy. Intracellular measurements of NO revealed that NO-CIEAs 17 and 20a showed a significant increase in NO production in tumor cells after 1 h of incubation comparable to the reference prodrug JS-K. Flow cytometric analysis showed that both NO-CIEAs 17 and 20a mainly arrested the HepG2 cells in the G0/G1 phase. Also, In-Cell Based ELISA screening showed that NO-CIEA 17 resulted in a potential inhibitory activity towards the EGFR and MAPK (25% and 29% inhibition compared to untreated control cells, respectively). This data suggests the binding ability of NO-CIEA 17 to the EGFR and ERK to be well correlated along with the docking and cellular studies. Also, treatment of HepG2-R cells with NO-CIEA 17 showed a potential reduction of MRP2 expression in a dose dependent manner providing a significant impact on the chemotherapeutic resistance. Overall, the current study provides a potential new approach for the discovery of a novel antitumor agent against HCC. |
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| Keywords: | Nitric oxide HCC EGFR DAF-FM DA MRP2 MAPK NO-CIEAs |
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