Unveiling the anti-cancer potentiality of phthalimide-based Analogues targeting tubulin polymerization in MCF-7 cancerous Cells: Rational design, chemical Synthesis, and Biological-coupled Computational investigation

Ateyatallah Aljuhani; Mohamed S Nafie; Nader R Albujuq; Wafa Hourani; Fawzia F Albelwi; Khaled M Darwish; Aya Samir Ayed; Mohamed Reda Aouad; Nadjet Rezki

doi:10.1016/j.bioorg.2024.107827

Unveiling the anti-cancer potentiality of phthalimide-based Analogues targeting tubulin polymerization in MCF-7 cancerous Cells: Rational design, chemical Synthesis, and Biological-coupled Computational investigation

Bioorg Chem. 2024 Dec:153:107827. doi: 10.1016/j.bioorg.2024.107827. Epub 2024 Sep 18.

Authors

Ateyatallah Aljuhani¹, Mohamed S Nafie², Nader R Albujuq³, Wafa Hourani⁴, Fawzia F Albelwi⁵, Khaled M Darwish⁶, Aya Samir Ayed⁷, Mohamed Reda Aouad⁸, Nadjet Rezki⁹

Affiliations

¹ Department of Chemistry, Faculty of Science, Taibah University, Al-Madinah Al-Munawarah 41477, Saudi Arabia. Electronic address: [email protected].
² Department of Chemistry, College of Sciences, University of Sharjah, Sharjah P.O. 27272, United Arab Emirates (UAE); Chemistry Department, Faculty of Science, Suez Canal University, Ismailia, P.O. 41522, Egypt. Electronic address: [email protected].
³ Department of Chemistry, School of Science, The University of Jordan, Amman 11942, Jordan. Electronic address: [email protected].
⁴ Department of Pharmaceutical Sciences, Faculty of Pharmacy, Philadelphia University, Amman 19392, Jordan. Electronic address: [email protected].
⁵ Department of Chemistry, Faculty of Science, Taibah University, Al-Madinah Al-Munawarah 41477, Saudi Arabia. Electronic address: [email protected].
⁶ Department of Medicinal Chemistry, Faculty of Pharmacy, Suez Canal University, Ismailia 41522, Egypt; Department of Medicinal Chemistry, Faculty of Pharmacy, Galala University, New Galala 43713, Egypt. Electronic address: [email protected].
⁷ Zoology Department, Faculty of Science, Suez Canal University, Ismailia, P.O. 41522, Egypt. Electronic address: [email protected].
⁸ Department of Chemistry, Faculty of Science, Taibah University, Al-Madinah Al-Munawarah 41477, Saudi Arabia. Electronic address: [email protected].
⁹ Department of Chemistry, Faculty of Science, Taibah University, Al-Madinah Al-Munawarah 41477, Saudi Arabia. Electronic address: [email protected].

PMID: 39321715
DOI: 10.1016/j.bioorg.2024.107827

Abstract

The present study deals with an anti-cancer investigation of an array of phthalimide-1,2,3-triazole molecular conjugates with various sulfonamide fragments against human breast MCF-7 and prostate PC3 cancer cell lines. The targeted 1,2,3-triazole derivatives 4a-l and 6a-c were synthesized from focused phthalimide-based alkyne precursors using a facile click synthesis approach and were thoroughly characterized using several spectroscopic techniques (IR, ¹H, ¹³C NMR, and elemental analysis). The hybrid click adducts 4b, 4 h, and 6c displayed cytotoxic potency (IC₅₀ values of 1.49, 1.07, and 0.56 μM, respectively) against MCF-7 cells. On the contrary, none of the synthesized compounds showed apparent cytotoxic efficacy for PC3 cells (IC₅₀ ranging from 9.87- >100 μM). As a part of the mechanism analysis, compound 6c demonstrated a potent inhibitory effect (78.3 % inhibition) of tubulin polymerization in vitro with an IC₅₀ value of 6.53 µM. In addition, biological assays showed that compound 6c could prompt apoptotic cell death and induce G2/M cell cycle arrest in MCF-7 cells. Accordingly, compound 6c can be further developed as an anti-breast cancer agent through apoptosis-induction.

Keywords: 1,2,3-Triazoles; Apoptosis activity; Phthalimides; Sulfonamides; Tubulin inhibitor.

MeSH terms

Antineoplastic Agents* / chemical synthesis
Antineoplastic Agents* / chemistry
Antineoplastic Agents* / pharmacology
Apoptosis / drug effects
Cell Proliferation* / drug effects
Dose-Response Relationship, Drug*
Drug Design*
Drug Screening Assays, Antitumor*
Humans
MCF-7 Cells
Molecular Docking Simulation
Molecular Structure
Phthalimides* / chemical synthesis
Phthalimides* / chemistry
Phthalimides* / pharmacology
Polymerization* / drug effects
Structure-Activity Relationship
Tubulin Modulators* / chemical synthesis
Tubulin Modulators* / chemistry
Tubulin Modulators* / pharmacology
Tubulin* / metabolism

Substances

Antineoplastic Agents
Phthalimides
Tubulin
Tubulin Modulators
phthalimide