Molecular modeling based approach, synthesis, and cytotoxic activity of novel benzoin derivatives targeting phosphoinostide 3-kinase (PI3Kα)

Dima A Sabbah; Musaab Saada; Reema Abu Khalaf; Sanaa Bardaweel; Kamal Sweidan; Tariq Al-Qirim; Amani Al-Zughier; Heba Abdel Halim; Ghassan Abu Sheikha

doi:10.1016/j.bmcl.2015.06.011

Molecular modeling based approach, synthesis, and cytotoxic activity of novel benzoin derivatives targeting phosphoinostide 3-kinase (PI3Kα)

Bioorg Med Chem Lett. 2015 Aug 15;25(16):3120-4. doi: 10.1016/j.bmcl.2015.06.011. Epub 2015 Jun 11.

Authors

Dima A Sabbah¹, Musaab Saada², Reema Abu Khalaf², Sanaa Bardaweel³, Kamal Sweidan⁴, Tariq Al-Qirim², Amani Al-Zughier², Heba Abdel Halim⁵, Ghassan Abu Sheikha²

Affiliations

¹ Department of Pharmacy, Faculty of Pharmacy, Al-Zaytoonah University of Jordan, P.O. Box 130, Amman 11733, Jordan. Electronic address: dima_sabbah@yahoo.com.
² Department of Pharmacy, Faculty of Pharmacy, Al-Zaytoonah University of Jordan, P.O. Box 130, Amman 11733, Jordan.
³ Department of Pharmaceutical Sciences, Faculty of Pharmacy, The University of Jordan, Amman 11942, Jordan.
⁴ Department of Chemistry, The University of Jordan, Amman 11942, Jordan.
⁵ Faculty of Pharmacy and Medical Sciences, University of Petra, P.O. Box 961343, Amman, Jordan.

PMID: 26099539
DOI: 10.1016/j.bmcl.2015.06.011

Abstract

The oncogenic potential of phosphatidylinositol 3-kinase (PI3Kα) has made it an attractive target for anticancer drug design. In this work, we describe our efforts to optimize the lead PI3Kα inhibitor 2-hydroxy-1,2-diphenylethanone (benzoin). A series of 2-oxo-1,2-diphenylethyl benzoate analogs were identified as potential PI3Kα inhibitors. Docking studies confirmed that the aromatic interaction is mediating ligand/protein complex formation and identified Lys802 and Val851 as H-bonding key residues. Our biological data in human colon carcinoma HCT116 showed that the structure analogs inhibited cell proliferation and induced apoptosis.

Keywords: Benzoin; Cancer; Docking; HCT116; PI3Kα.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antineoplastic Agents / chemical synthesis*
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology
Apoptosis / drug effects
Benzoin / analogs & derivatives*
Benzoin / chemical synthesis
Benzoin / pharmacology
Binding Sites
Cell Proliferation / drug effects
Drug Design
HCT116 Cells
Humans
Molecular Docking Simulation
Phosphatidylinositol 3-Kinases / metabolism
Phosphoinositide-3 Kinase Inhibitors*
Protein Kinase Inhibitors / chemical synthesis*
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology
Protein Structure, Tertiary

Substances

Antineoplastic Agents
Phosphoinositide-3 Kinase Inhibitors
Protein Kinase Inhibitors
Benzoin