TY - JOUR
T1 - Structure-based design
T2 - Synthesis, X-ray crystallography, and biological evaluation of N-substituted-4-hydroxy-2-quinolone-3-carboxamides as potential cytotoxic agents
AU - Sabbah, Dima A.
AU - Hishmah, Bayan
AU - Sweidan, Kamal
AU - Bardaweel, Sanaa
AU - AlDamen, Murad
AU - Zhong, Haizhen A.
AU - Khalaf, Reema Abu
AU - Hasan Ibrahim, Ameerah
AU - Al-Qirim, Tariq
AU - Abu Sheikha, Ghassan
AU - Mubarak, Mohammad S.
N1 - Funding Information:
This work was financially supported by the Deanship of Scientific Research and Graduate Studies at Al-Zaytoonah University of Jordan; this support is highly acknowledged. Authors acknowledge the Chemistry Department, The University of Jordan for the use of crystallographic, NMR, and elemental analysis facilities. We are grateful to the College of Pharmacy, The University of Jordan for use of cell culture laboratory and equipment. The authors thank Dr. Kamal Sweidan for his collaboration to make this work successful. This work was performed during Dr. Kamal's sabbatical leave at Al-Zaytoonah University of Jordan.
Publisher Copyright:
© 2018 Bentham Science Publishers.
PY - 2018
Y1 - 2018
N2 - 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.
AB - 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.
KW - Apoptosis
KW - Cytotoxicity
KW - Docking
KW - HCT-116
KW - LDH
KW - Quinolone-3-carboxamide
UR - http://www.scopus.com/inward/record.url?scp=85047643540&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85047643540&partnerID=8YFLogxK
U2 - 10.2174/1871520617666170911171152
DO - 10.2174/1871520617666170911171152
M3 - Article
C2 - 28901259
AN - SCOPUS:85047643540
VL - 18
SP - 263
EP - 276
JO - Anti-Cancer Agents in Medicinal Chemistry
JF - Anti-Cancer Agents in Medicinal Chemistry
SN - 1871-5206
IS - 2
ER -