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  3. Development of [1,2]oxazoloisoindoles tubulin polymerization inhibitors: Further chemical modifications and potential therapeutic effects against lymphomas

Development of [1,2]oxazoloisoindoles tubulin polymerization inhibitors: Further chemical modifications and potential therapeutic effects against lymphomas

  • Eur J Med Chem. 2022 Dec 5:243:114744. doi: 10.1016/j.ejmech.2022.114744.
Marilia Barreca 1,  Virginia Spanò 2,  Roberta Rocca 3,  Roberta Bivacqua 1,  Anne-Catherine Abel 4,  Annalisa Maruca 5,  Alessandra Montalbano 1,  Maria Valeria Raimondi 1,  Chiara Tarantelli 6,  Eugenio Gaudio 6,  Luciano Cascione 6,  Andrea Rinaldi 6,  Ruoli Bai 7,  Michel O Steinmetz 4,  Andrea E Prota 8,  Stefano Alcaro 9,  Ernest Hamel 7,  Francesco Bertoni 10,  Paola Barraja 1
Affiliations

Affiliations

  • 1 Department of Biological, Chemical and Pharmaceutical Sciences and Technologies (STEBICEF), University of Palermo, Via Archirafi 32, 90123, Palermo, Italy.
  • 2 Department of Biological, Chemical and Pharmaceutical Sciences and Technologies (STEBICEF), University of Palermo, Via Archirafi 32, 90123, Palermo, Italy. Electronic address: virginia.spano@unipa.it.
  • 3 Net4Science srl, Academic spinoff, Università Magna Græcia di Catanzaro, Viale Europa, 88100, Italy; Dipartimento di Medicina Sperimentale e Clinica, Università Magna Græcia di Catanzaro, Viale Europa, 88100, Italy.
  • 4 Laboratory of Biomolecular Research, Division of Biology and Chemistry, Paul Scherrer Institut, Forschungsstrasse 111, 5232, Villigen, PSI, Switzerland; University of Basel, Biozentrum, CH - 4056, Basel, Switzerland.
  • 5 Net4Science srl, Academic spinoff, Università Magna Græcia di Catanzaro, Viale Europa, 88100, Italy.
  • 6 Institute of Oncology Research, Faculty of Biomedical Sciences, USI, Via Francesco Chiesa 5, 6500, Bellinzona, Switzerland.
  • 7 Molecular Pharmacology Branch, Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, Frederick National Laboratory for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD, 21702, United States.
  • 8 Laboratory of Biomolecular Research, Division of Biology and Chemistry, Paul Scherrer Institut, Forschungsstrasse 111, 5232, Villigen, PSI, Switzerland.
  • 9 Net4Science srl, Academic spinoff, Università Magna Græcia di Catanzaro, Viale Europa, 88100, Italy; Dipartimento di Scienze della Salute, Università Magna Græcia di Catanzaro, Viale Europa, 88100, Italy.
  • 10 Institute of Oncology Research, Faculty of Biomedical Sciences, USI, Via Francesco Chiesa 5, 6500, Bellinzona, Switzerland; Oncology Institute of Southern Switzerland, Ente Ospedaliero Cantonale, 6500, Bellinzona, Switzerland.
PMID: 36242921 DOI: 10.1016/j.ejmech.2022.114744
Abstract

Lymphomas are among the ten most common cancers, and, although progress has been achieved in increasing survival, there is still an unmet need for more effective therapeutic approaches, including better options for patients with refractory tumors that initially respond but then relapse. The lack of effective alternative treatment options highlights the need to develop new therapeutic strategies capable of improving survival prospects for lymphoma patients. Herein, we describe the identification and exploration of the SAR of a series of [1,2]oxazolo[5,4-e]isoindoles as potent small molecules that bind to the colchicine site of tubulin and that have promise for the treatment of refractory lymphomas. Exploration of the chemical space of this class of compounds at the pyrrole moiety and at the [1,2]oxazole ring highlighted two compounds bearing a 3,5-dimethoxybenzyl and a 3,4,5-trimethoxybenzyl group as potent candidates and showed that structural modifications at the isoxazole moiety are generally not favorable for activity. The two best candidates showed efficacy against different lymphoma histotypes and displayed 88 and 80% inhibition of colchicine binding fitting well into the colchicine pocket, as demonstrated by X-ray crystallography T2R-TTL-complexes, docking and thermodynamic analysis of the tubulin-colchicine complex structure. These results were confirmed by transcriptome data, thus indicating [1,2]oxazolo[5,4-e]isoindoles are promising candidates as antitubulin agents for the treatment of refractory lymphomas.

Keywords

Antitubulin agents; Colchicine site; Lymphoma; T(2)R-TTL–Complexes; X-ray crystallography; [1,2]oxazolo[5,4-e]isoindoles.

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