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Ligand-Based Drug Design: Synthesis and Biological Evaluation of Substituted Benzoin Derivatives as Potential Antitumor Agents

Author(s):

Dima A. Sabbah*, Ameerah Hasan Ibrahim, Wamidh H. Talib, Khalid M. Alqaisi, Kamal Sweidan, Sanaa K. Bardaweel, Ghassan Abu Sheikha, Haizhen A. Zhong, Eveen Al-Shalabi, Reema Abu Khalaf and Mohammad S. Mubarak   Pages 1 - 13 ( 13 )

Abstract:


Background: Phosphoinositide 3-kinase α (PI3Kα) has emerged as a promising target for anticancer drug design. Objectives: Target compounds were designed to investigate the effect of the p-OCH3 motifs on ligand/PI3Kα complex interaction and antiproliferative activity. Methods: Synthesis of the proposed compounds, biological examination tests against human colon adenocarcinoma (HCT-116), breast adenocarcinoma (MCF-7), and breast carcinoma (T47D) cell lines, along with Glide docking studies. Results: A series of 1,2-bis(4-methoxyphenyl)-2-oxoethyl benzoates was synthesized and characterized by means of FT-IR, 1H and 13C NMR, and by elemental analysis. Biological investigation demonstrated that the newly synthesized compounds exhibit antiproliferative activity in human colon adenocarcinoma (HCT-116), breast adenocarcinoma (MCF-7), and breast carcinoma (T47D) cell lines possibly via inhibition of PI3Kα and estrogen receptor alpha (ERα). Additionally, results revealed that these compounds exert selective inhibitory activity, induce apoptosis, and suppress VEGF production. Compound 3c exhibited promising antiproliferative activity in HCT-116 interrogating that hydrogen bond-acceptor mediates ligand/PI3Kα complex formation on m- position. Compounds 3e and 3i displayed high inhibitory activity in MCF-7 and T47D implying a wide cleft discloses the o-attachment. Furthermore, compound 3g exerted selective inhibitory activity against T47D. Glide docking studies against PI3Kα and ERα demonstrated that the series accommodate binding to PI3Kα and/or ERα. Conclusion: The series exhibited a potential antitumor activity in human carcinoma cell lines encoding PI3Kα and/or ERα.

Keywords:

PI3K?, Caspase-3, AKT, Angiogenesis, Glide docking, p-anisoin, HCT-116, MCF-7, T47D

Affiliation:

Department of Pharmacy, Faculty of Pharmacy, Al-Zaytoonah University of Jordan, P.O. Box 130 Amman 11733, Department of Pharmacy, Faculty of Pharmacy, Al-Zaytoonah University of Jordan, P.O. Box 130 Amman 11733, Department of Clinical Pharmacy and Therapeutics, Applied Science Private University, Amman, Department of Allied Medical Sciences, Zarqa University College, Al-Balqa Applied University, P.O. Box 132222, Zarqa 13132, Department of Chemistry, The University of Jordan, Amman 11942, Department of Pharmaceutical Sciences, Faculty of Pharmacy, The University of Jordan, Amman 11942, Department of Pharmacy, Faculty of Pharmacy, Al-Zaytoonah University of Jordan, P.O. Box 130 Amman 11733, DSC 362, Department of Chemistry, The University of Nebraska at Omaha, 6001 Dodge Street, Omaha, Nebraska 68182, Department of Pharmacy, Faculty of Pharmacy, Al-Zaytoonah University of Jordan, P.O. Box 130 Amman 11733, Department of Pharmacy, Faculty of Pharmacy, Al-Zaytoonah University of Jordan, P.O. Box 130 Amman 11733, Department of Chemistry, The University of Jordan, Amman 11942



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