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

• Published in: Bioorganic chemistry Vol. 143; p. 107094
• Main Authors: Iqbal, Sana, Firdous, Farhat, Furqan, Muhammad, Bilal, Aishah, Fozail, Salman, Pohl, Sebastian Öther-Gee, Doleschall, Nora Julia, Myant, Kevin B., Singh, Upendra, Emwas, Abdul-Hamid, Jaremko, Mariusz, Faisal, Amir, Saleem, Rahman Shah Zaib
• Format: Journal Article
• Language: English
• Published: SAN DIEGO Elsevier Inc 01.02.2024; Elsevier
• Subjects: Amides - pharmacology; Animals; Anticancer; Antineoplastic Agents - metabolism; Antineoplastic Agents - pharmacology; Apoptosis; Biochemistry & Molecular Biology; Bis-amide; Cell Line, Tumor; Cell Proliferation; Chemistry; Chemistry, Organic; Humans; Life Sciences & Biomedicine; Mice; Microtubule stabilizing agents; Microtubules - metabolism; Mitosis; Mouse organoid and human organoid models; Physical Sciences; Science & Technology; Tubulin - drug effects; Tubulin - metabolism; Tubulin Modulators - chemistry; Tubulin Modulators - pharmacology; Tubulin polymerization; Mouse organoid and human organoid models; Anticancer; Bis-amide; Microtubule stabilizing agents; Tubulin polymerization; TARGET; APOPTOSIS; POTENT; POLYMERIZATION; INHIBITOR; DISCOVERY
• ISSN: 0045-2068; 1090-2120
• DOI: 10.1016/j.bioorg.2023.107094

[Display omitted] •A library of 32 new α-aminoamides was synthesized and investigated for anticancer activity.•SSE1917 was the most potent compound with GI50 0.331 ± 0.01 µM in HCT116 and 0.48 ± 0.27 µM in BT-549 cancer cells.•SSE1917 was further characterized as microtubule-stabilizing agent with promising activity in organoid models. 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.