Structure-based design: Synthesis, X-ray crystallography, and biological evaluation of N-substituted-4-hydroxy-2-quinolone-3-carboxamides as potential cytotoxic agents

Dima A. Sabbah, Bayan Hishmah, Kamal Sweidan, Sanaa Bardaweel, Murad AlDamen, Haizhen Andrew Zhong, Reema Abu Khalaf, Ameerah Hasan Ibrahim, Tariq Al-Qirim, Ghassan Abu Sheikha, Mohammad S. Mubarak

Research output: Contribution to journalArticle

6 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)263-276
Number of pages14
JournalAnti-Cancer Agents in Medicinal Chemistry
Volume18
Issue number2
DOIs
StatePublished - Jan 1 2018

Fingerprint

Phosphatidylinositol 3-Kinase
X Ray Crystallography
Cytotoxins
Caspase 3
HCT116 Cells
Colon
Carcinoma
Cell Line
Crystallography
Drug Design
Inhibitory Concentration 50
carbostyril
Catalytic Domain
Phosphotransferases
Cell Proliferation
Apoptosis
DNA

Keywords

  • Apoptosis
  • Cytotoxicity
  • Docking
  • HCT-116
  • LDH
  • Quinolone-3-carboxamide

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology
  • Cancer Research

Cite this

Structure-based design : Synthesis, X-ray crystallography, and biological evaluation of N-substituted-4-hydroxy-2-quinolone-3-carboxamides as potential cytotoxic agents. / Sabbah, Dima A.; Hishmah, Bayan; Sweidan, Kamal; Bardaweel, Sanaa; AlDamen, Murad; Zhong, Haizhen Andrew; Khalaf, Reema Abu; Hasan Ibrahim, Ameerah; Al-Qirim, Tariq; Abu Sheikha, Ghassan; Mubarak, Mohammad S.

In: Anti-Cancer Agents in Medicinal Chemistry, Vol. 18, No. 2, 01.01.2018, p. 263-276.

Research output: Contribution to journalArticle

Sabbah, Dima A. ; Hishmah, Bayan ; Sweidan, Kamal ; Bardaweel, Sanaa ; AlDamen, Murad ; Zhong, Haizhen Andrew ; Khalaf, Reema Abu ; Hasan Ibrahim, Ameerah ; Al-Qirim, Tariq ; Abu Sheikha, Ghassan ; Mubarak, Mohammad S. / Structure-based design : Synthesis, X-ray crystallography, and biological evaluation of N-substituted-4-hydroxy-2-quinolone-3-carboxamides as potential cytotoxic agents. In: Anti-Cancer Agents in Medicinal Chemistry. 2018 ; Vol. 18, No. 2. pp. 263-276.
@article{1ca51ff6a4ac4ffeb56a2bc0c8d4a173,
title = "Structure-based design: Synthesis, X-ray crystallography, and biological evaluation of N-substituted-4-hydroxy-2-quinolone-3-carboxamides as potential cytotoxic agents",
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.",
keywords = "Apoptosis, Cytotoxicity, Docking, HCT-116, LDH, Quinolone-3-carboxamide",
author = "Sabbah, {Dima A.} and Bayan Hishmah and Kamal Sweidan and Sanaa Bardaweel and Murad AlDamen and Zhong, {Haizhen Andrew} and Khalaf, {Reema Abu} and {Hasan Ibrahim}, Ameerah and Tariq Al-Qirim and {Abu Sheikha}, Ghassan and Mubarak, {Mohammad S.}",
year = "2018",
month = "1",
day = "1",
doi = "10.2174/1871520617666170911171152",
language = "English (US)",
volume = "18",
pages = "263--276",
journal = "Anti-Cancer Agents in Medicinal Chemistry",
issn = "1871-5206",
publisher = "Bentham Science Publishers B.V.",
number = "2",

}

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 Andrew

AU - Khalaf, Reema Abu

AU - Hasan Ibrahim, Ameerah

AU - Al-Qirim, Tariq

AU - Abu Sheikha, Ghassan

AU - Mubarak, Mohammad S.

PY - 2018/1/1

Y1 - 2018/1/1

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 -