2. Academic Validation
  3. Pyrrolo[2',3':3,4]cyclohepta[1,2- d][1,2]oxazoles, a New Class of Antimitotic Agents Active against Multiple Malignant Cell Types

Pyrrolo[2',3':3,4]cyclohepta[1,2- d][1,2]oxazoles, a New Class of Antimitotic Agents Active against Multiple Malignant Cell Types

  • J Med Chem. 2020 Oct 22;63(20):12023-12042. doi: 10.1021/acs.jmedchem.0c01315.
Virginia Spanò 1,  Roberta Rocca 2 3,  Marilia Barreca 1 4,  Daniele Giallombardo 1,  Alessandra Montalbano 1,  Anna Carbone 1,  Maria Valeria Raimondi 1,  Eugenio Gaudio 4,  Roberta Bortolozzi 5,  Ruoli Bai 6,  Pierfrancesco Tassone 3,  Stefano Alcaro 7 2,  Ernest Hamel 6,  Giampietro Viola 5 8,  Francesco Bertoni 4 9,  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 Net4Science srl, Academic Spinoff, Università Magna Græcia di Catanzaro, Viale Europa, 88100 Catanzaro, Italy.
  • 3 Dipartimento di Medicina Sperimentale e Clinica, Università Magna Græcia di Catanzaro, Viale Europa, 88100 Catanzaro, Italy.
  • 4 Institute of Oncology Research, Faculty of Biomedical Sciences, Università della Svizzera Italiana, Via Vincenzo Vela 6, 6500 Bellinzona, Switzerland.
  • 5 Istituto di Ricerca Pediatrica IRP, Fondazione Città della Speranza, Corso Stati Uniti 4, 35127 Padova, Italy.
  • 6 Screening Technologies Branch, Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, Frederick National Laboratory for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, Maryland 21702, United States.
  • 7 Dipartimento di Scienze della Salute, Università Magna Græcia di Catanzaro, Viale Europa, 88100 Catanzaro, Italy.
  • 8 Dipartimento di Salute della Donna e del Bambino, Laboratorio di Oncoematologia, Università di Padova, Via Giustiniani 2, 35131 Padova, Italy.
  • 9 Oncology Institute of Southern Switzerland, Via Ospedale, 6500 Bellinzona, Switzerland.
PMID: 32986419 DOI: 10.1021/acs.jmedchem.0c01315
Abstract

A new class of pyrrolo[2',3':3,4]cyclohepta[1,2-d][1,2]oxazoles was synthesized for the treatment of hyperproliferative pathologies, including neoplasms. The new compounds were screened in the 60 human Cancer cell lines of the NCI drug screen and showed potent activity with GI50 values reaching the nanomolar level, with mean graph midpoints of 0.08-0.41 μM. All compounds were further tested on six lymphoma cell lines, and eight showed potent growth inhibitory effects with IC50 values lower than 500 nM. Mechanism of action studies showed the ability of the new [1,2]oxazoles to arrest cells in the G2/M phase in a concentration dependent manner and to induce Apoptosis through the mitochondrial pathway. The most active compounds inhibited tubulin polymerization, with IC50 values of 1.9-8.2 μM, and appeared to bind to the colchicine site. The G2/M arrest was accompanied by Apoptosis, mitochondrial depolarization, generation of Reactive Oxygen Species, and PARP cleavage.

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