Synthesis and characterization of bis-amide SSE1917 as a microtubule-stabilizing anticancer agent

Sana Iqbal; Farhat Firdous; Muhammad Furqan; Aishah Bilal; Salman Fozail; Sebastian Öther-Gee Pohl; Nora Julia Doleschall; Kevin B Myant; Upendra Singh; Abdul-Hamid Emwas; Mariusz Jaremko; Amir Faisal; Rahman Shah Zaib Saleem

doi:10.1016/j.bioorg.2023.107094

Synthesis and characterization of bis-amide SSE1917 as a microtubule-stabilizing anticancer agent

Bioorg Chem. 2024 Feb:143:107094. doi: 10.1016/j.bioorg.2023.107094. Epub 2024 Jan 5.

Authors

Affiliations

¹ Department of Chemistry and Chemical Engineering, Syed Babar Ali School of Science and Engineering, Lahore University of Management Sciences, Lahore 54792, Pakistan.
² Department of Chemistry and Chemical Engineering, Syed Babar Ali School of Science and Engineering, Lahore University of Management Sciences, Lahore 54792, Pakistan; Department of Life Sciences, Syed Babar Ali School of Science and Engineering, Lahore University of Management Sciences, Lahore 54792, Pakistan.
³ Department of Life Sciences, Syed Babar Ali School of Science and Engineering, Lahore University of Management Sciences, Lahore 54792, Pakistan.
⁴ Institute of Genetics and Cancer, The University of Edinburgh, Western General Hospital Campus, Crewe Road, Edinburgh EH4 2XU, Scotland, United Kingdom.
⁵ Division of Biological and Environmental Sciences and Engineering, King Abdullah University of Science and Technology, Thuwal 23955-6900, Saudi Arabia.
⁶ KAUST Core Labs, King Abdullah University of Science and Technology, Thuwal 23955-6900, Saudi Arabia.
⁷ Department of Life Sciences, Syed Babar Ali School of Science and Engineering, Lahore University of Management Sciences, Lahore 54792, Pakistan. Electronic address: amir.faisal@lums.edu.pk.
⁸ Department of Chemistry and Chemical Engineering, Syed Babar Ali School of Science and Engineering, Lahore University of Management Sciences, Lahore 54792, Pakistan. Electronic address: rahman.saleem@lums.edu.pk.

PMID: 38199139
DOI: 10.1016/j.bioorg.2023.107094

Abstract

Microtubule dynamics are critical for spindle assembly and chromosome segregation during cell division. Pharmacological inhibition of microtubule dynamics in cells causes prolonged mitotic arrest, resulting in apoptosis, an approach extensively employed in treating different types of cancers. The present study reports the synthesis of thirty-two novel bis-amides (SSE1901-SSE1932) and the evaluation of their antiproliferative activities. N-(1-oxo-3-phenyl-1-(phenylamino)propan-2-yl)benzamide (SSE1917) exhibited the most potent activity with GI₅₀ values of 0.331 ± 0.01 µM in HCT116 colorectal and 0.48 ± 0.27 µM in BT-549 breast cancer cells. SSE1917 stabilized microtubules in biochemical and cellular assays, bound to taxol site in docking studies, and caused aberrant mitosis and G₂/M arrest in cells. Prolonged treatment of cells with the compound increased p53 expression and triggered apoptotic cell death. Furthermore, SSE1917 suppressed the growth of both mouse and patient-derived human colon cancer organoids, highlighting its potential therapeutic value as an anticancer agent.

Keywords: Anticancer; Bis-amide; Microtubule stabilizing agents; Mouse organoid and human organoid models; Tubulin polymerization.

MeSH terms

Amides / pharmacology
Animals
Antineoplastic Agents* / metabolism
Antineoplastic Agents* / pharmacology
Apoptosis
Cell Line, Tumor
Cell Proliferation
Humans
Mice
Microtubules / metabolism
Mitosis
Tubulin Modulators* / chemistry
Tubulin Modulators* / pharmacology
Tubulin* / drug effects
Tubulin* / metabolism

Substances

Amides
Antineoplastic Agents
Tubulin
Tubulin Modulators