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  3. Promising anti-proliferative indolic benzenesulfonamides alter mechanisms with sulfonamide nitrogen substituents

Promising anti-proliferative indolic benzenesulfonamides alter mechanisms with sulfonamide nitrogen substituents

  • Eur J Med Chem. 2024 Sep 5:275:116617. doi: 10.1016/j.ejmech.2024.116617.
Raúl Fuentes-Martín 1,  Pilar Ayuda-Durán 2,  Robert Hanes 3,  Laura Gallego-Yerga 1,  Lisanne Wolterinck 4,  Jorrit M Enserink 3,  Raquel Álvarez 1,  Rafael Peláez 5
Affiliations

Affiliations

  • 1 Laboratorio de Química Orgánica y Farmacéutica, Departamento de Ciencias Farmacéuticas, Universidad de Salamanca, Campus Miguel de Unamuno, E-37007, Salamanca, Spain; Instituto de Investigación Biomédica de Salamanca (IBSAL), Facultad de Farmacia, Universidad de Salamanca, Campus Miguel de Unamuno, E-37007, Salamanca, Spain; Centro de Investigación de Enfermedades Tropicales de la Universidad de Salamanca (CIETUS). Facultad de Farmacia, Universidad de Salamanca, Campus Miguel de Unamuno, E-37007, Salamanca, Spain.
  • 2 Department of Molecular Cell Biology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway; Centre for Cancer Cell Reprogramming, Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.
  • 3 Department of Molecular Cell Biology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway; Centre for Cancer Cell Reprogramming, Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway; Section for Biochemistry and Molecular Biology, Faculty of Mathematics and Natural Sciences, University of Oslo, Oslo, Norway.
  • 4 Department of Molecular Cell Biology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway; Centre for Cancer Cell Reprogramming, Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway; HAN University of Applied Sciences, Nijmegen, the Netherlands.
  • 5 Laboratorio de Química Orgánica y Farmacéutica, Departamento de Ciencias Farmacéuticas, Universidad de Salamanca, Campus Miguel de Unamuno, E-37007, Salamanca, Spain; Instituto de Investigación Biomédica de Salamanca (IBSAL), Facultad de Farmacia, Universidad de Salamanca, Campus Miguel de Unamuno, E-37007, Salamanca, Spain; Centro de Investigación de Enfermedades Tropicales de la Universidad de Salamanca (CIETUS). Facultad de Farmacia, Universidad de Salamanca, Campus Miguel de Unamuno, E-37007, Salamanca, Spain. Electronic address: pelaez@usal.es.
PMID: 38959729 DOI: 10.1016/j.ejmech.2024.116617
Abstract

Agents that cause apoptotic cell death by interfering with tubulin dynamics, such as vinblastine and paclitaxel, are an important class of chemotherapeutics. Unfortunately, these compounds are substrates for multidrug resistance (MDR) pumps, allowing Cancer cells to gain resistance to these chemotherapeutics. The indolesulfonamide family of tubulin inhibitors are not excluded by MDR pumps and have a promising activity profile, although their high lipophilicity is a pharmacokinetic limitation for their clinical use. Here we present a new family of N-indolyl-3,4,5-trimethoxybenzenesulfonamide derivatives with modifications on the indole system at positions 1 and 3 and on the sulfonamide nitrogen. We synthesized and screened against HeLa cells 34 novel indolic benzenesulfonamides. The most potent derivatives (1.7-109 nM) were tested against a broad panel of Cancer cell lines, which revealed that substituted benzenesulfonamides analogs had highest potency. Importantly, these compounds were only moderately toxic to non-tumorigenic cells, suggesting the presence of a therapeutic index. Consistent with known clinical anti-tubulin agents, these compounds arrested the cell cycle at G2/M phase. Mechanistically, they induced Apoptosis via Caspase 3/7 activation, which occurred during M arrest. The substituents on the sulfonamide nitrogen appeared to determine different mechanistic results and cell fates. These results suggest that the compounds act differently depending on the bridge substituents, thus making them very interesting as mechanistic probes as well as potential drugs for further development.

Keywords

Antitumor; Colchicine site; Indole; Mechanism; Resistance; SAR; Sulfonamides; Tubulin.

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