Title:Structure-Based Design: Synthesis, X-ray Crystallography, and Biological Evaluation of N-Substituted-4-Hydroxy-2-Quinolone-3-Carboxamides as Potential Cytotoxic Agents
VOLUME: 18 ISSUE: 2
Author(s):Dima A. Sabbah*, Bayan Hishmah, Kamal Sweidan, Sanaa Bardaweel, Murad AlDamen, Haizhen A. Zhong, Reema Abu Khalaf, Ameerah (Hasan Ibrahim), Tariq Al-Qirim, Ghassan Abu Sheikha and Mohammad S. Mubarak
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 Pharmacy, Faculty of Pharmacy, Al-Zaytoonah University of Jordan, P.O. Box 130 Amman 11733, Department of Pharmaceutical Sciences, Faculty of Pharmacy, The University of Jordan, Amman 11942, Department of Chemistry, The University of Jordan, Amman 11942, 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 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
Keywords:Cytotoxicity, HCT-116, apoptosis, LDH, docking, quinolone-3-carboxamide.
Abstract:Background: Oncogenic potential of phosphatidylinositol 3-kinase (PI3Kα) has been highlighted as a
therapeutic target for anticancer drug design.
Objective: Target compounds were designed to address the effect of different substitution patterns at the N atom
of the carboxamide moiety on the bioactivity of this series.
Methods: Synthesis of the targeted compounds, crystallography, biological evaluation tests against human colon
carcinoma (HCT-116), and Glide docking studies.
Results: A new series of N-substituted- 4-hydroxy-2-quinolone-3-carboxamides was prepared and characterized
by means of FT-IR, 1H and 13C NMR, and elemental analysis. In addition, the identity of the core nucleus 5 was
successfully characterized with the aid of X-ray crystallography. Biological activity of prepared compounds was
investigated in vitro against human colon carcinoma (HCT-116) cell line. Results revealed that these compounds
inhibit cell proliferation and induce apoptosis through an increase in caspase-3 activity and a decrease in DNA
cellular content. Compounds 7, 14, and 17 which have H-bond acceptor moiety on p-position displayed promising
PI3Kα inhibitory activity. On the other hand, derivatives tailored with bulky and hydrophobic motifs (16 and
18) on o- and m-positions exhibited moderate activity. Molecular docking studies against PI3Kα and caspase-3
showed an agreement between the predicted binding affinity (ΔGobsd) and IC50 values of the derivatives for the
caspase-3 model. Furthermore, Glide docking studies against PI3Kα demonstrated that the newly synthesized
compounds accommodate PI3Kα kinase catalytic domain and form H-bonding with key binding residues.
Conclusion: The series exhibited a potential PI3Kα inhibitory activity in HCT-116 cell line.
