2. Academic Validation
  3. Design and Synthesis of Bendamustine-Carbonic Anhydrase Inhibitors with Antiproliferative Effects in Clear Cell Renal Cell Carcinoma

Design and Synthesis of Bendamustine-Carbonic Anhydrase Inhibitors with Antiproliferative Effects in Clear Cell Renal Cell Carcinoma

  • J Med Chem. 2026 Jun 24. doi: 10.1021/acs.jmedchem.6c01549.
Gioele Renzi 1,  Alessandro Tubita 2,  Lorenzo Antonuzzo 2,  Serena Pillozzi 2,  Marta Ferraroni 3,  Andrea Angeli 1,  Claudiu T Supuran 1
Affiliations

Affiliations

  • 1 Neurofarba Department, Sezione di Scienze Farmaceutiche, University of Florence, Via Ugo Schiff 6, Sesto Fiorentino, Florence 50019, Italy.
  • 2 Department of Experimental and Clinical Biomedical Sciences "Mario Serio", University of Florence, Viale Morgagni, 50, Florence 50134, Italy.
  • 3 Department of Chemistry "Ugo Schiff", University of Florence, Via della Lastruccia 3-13, Sesto Fiorentino 50019, Italy.
PMID: 42339601 DOI: 10.1021/acs.jmedchem.6c01549
Abstract

Human Carbonic Anhydrase IX (hCA IX) is markedly overexpressed in clear cell renal cell carcinoma and plays a key role in establishing an acidic tumor microenvironment associated with intrinsic chemoresistance. Extracellular acidification limits the uptake and efficacy of several cytotoxic agents, including bendamustine, a bifunctional alkylating agent whose activity depends on intracellular accumulation and DNA cross-link formation. Herein, we report the design and synthesis of novel bendamustine-carbonic anhydrase inhibitor (CAI) hybrids aimed at combining CA IX targeting with DNA-damaging activity. Structural modification of the bendamustine butyric acid side chain enabled the introduction of CAI warheads while preserving the alkylating moiety. The resulting compounds were evaluated against hCA I, II, IX, and XII, displaying preferential inhibition of the tumor-associated isoforms. Selected derivatives (13a and 14c) showed antiproliferative activity in 786-O and CAKI-1 cells, inducing cell-cycle arrest and reducing long-term proliferative capacity more effectively than the reference CA IX Inhibitor SLC-0111.

Keywords

Bendamustine; carbonic anhydrase; clear cell renal cell carcinoma; kidney cancer; metalloenzyme.

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