Design and Synthesis of (2- oxo-1,2-Dihydroquinolin-4-yl)-1,2,3-triazole Derivatives via Click Reaction: Potential Apoptotic Antiproliferative Agents

Essmat M El-Sheref; Mohammed A I Elbastawesy; Alan B Brown; Ahmed M Shawky; Hesham A M Gomaa; Stefan Bräse; Bahaa G M Youssif

doi:10.3390/molecules26226798

Design and Synthesis of (2- oxo-1,2-Dihydroquinolin-4-yl)-1,2,3-triazole Derivatives via Click Reaction: Potential Apoptotic Antiproliferative Agents

Molecules. 2021 Nov 10;26(22):6798. doi: 10.3390/molecules26226798.

Authors

Essmat M El-Sheref¹, Mohammed A I Elbastawesy², Alan B Brown³, Ahmed M Shawky⁴, Hesham A M Gomaa⁵, Stefan Bräse^{6

7}, Bahaa G M Youssif⁸

Affiliations

¹ Chemistry Department, Faculty of Science, Minia University, El-Minia 61519, Egypt.
² Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Al-Azhar University, Assiut 71524, Egypt.
³ Program in Chemistry, Florida Institute of Technology, 150 W University Blvd, Melbourne, FL 32901, USA.
⁴ Science and Technology Unit (STU), Umm Al-Qura University, Makkah 21955, Saudi Arabia.
⁵ Pharmacology Department, College of Pharmacy, Jouf University, Sakaka 72314, Saudi Arabia.
⁶ Institute of Organic Chemistry, Karlsruhe Institute of Technology, 76131 Karlsruhe, Germany.
⁷ Institute of Biological and Chemical Systems (IBCS-FMS), Karlsruhe Institute of Technology, 76344 Eggenstein-Leopoldshafen, Germany.
⁸ Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Assiut University, Assiut 71526, Egypt.

Abstract

A mild and versatile method based on Cu-catalyzed [2+3] cycloaddition (Huisgen-Meldal-Sharpless reaction) was developed to tether 3,3'-((4-(prop-2-yn-1-yloxy)phenyl)methylene)bis(4-hydroxyquinolin-2(1H)-ones) with 4-azido-2-quinolones in good yields. This methodology allowed attaching three quinolone molecules via a triazole linker with the proposed mechanism. The products are interesting precursors for their anti-proliferative activity. Compound 8g was the most active one, achieving IC₅₀ = 1.2 ± 0.2 µM and 1.4 ± 0.2 µM against MCF-7 and Panc-1 cell lines, respectively. Moreover, cell cycle analysis of cells MCF-7 treated with 8g showed cell cycle arrest at the G2/M phase (supported by Caspase-3,8,9, Cytochrome C, BAX, and Bcl-2 studies). Additionally, significant pro-apoptotic activity is indicated by annexin V-FITC staining.

Keywords: anti-proliferative; apoptosis; azido; click; quinolones; triazole.

MeSH terms

Antineoplastic Agents / pharmacology
Apoptosis / drug effects
Cell Cycle Checkpoints / drug effects
Cell Line, Tumor
Cell Proliferation / drug effects
Click Chemistry / methods*
Copper / chemistry
Drug Screening Assays, Antitumor / methods
Humans
MCF-7 Cells
Molecular Structure
Quinolones / chemical synthesis
Quinolones / chemistry*
Structure-Activity Relationship
Triazoles / chemical synthesis
Triazoles / chemistry*

Substances

Antineoplastic Agents
Quinolones
Triazoles
Copper