2. Academic Validation
  3. Ferroptosis Induction by a New Pyrrole Derivative in Triple Negative Breast Cancer and Colorectal Cancer

Ferroptosis Induction by a New Pyrrole Derivative in Triple Negative Breast Cancer and Colorectal Cancer

  • J Med Chem. 2025 Aug 28;68(16):17840-17858. doi: 10.1021/acs.jmedchem.5c01561.
Domiziana Masci 1 2,  Lele Ling 3,  Lian Yang 4,  Michela Puxeddu 5,  Claudia Colla 5,  Antonio Coluccia 5,  Martina Santelli 1,  Pietro Sciò 5,  Petra Cuřínová 6,  Mohammad Salik Zeya Ansari 1 7,  Chiara Naro 1 7,  Claudio Sette 1 7,  Lucia Jimenez 8,  Wolfgang Link 8,  Chiara Bigogno 9,  Giulio Dondio 9,  Ernest Hamel 10,  Te Liu 4,  Romano Silvestri 5,  Giuseppe La Regina 5
Affiliations

Affiliations

  • 1 Department of Basic Biotechnological Sciences, Intensivological and Perioperative Clinics, Catholic University of the Sacred Heart, Largo Francesco Vito 1, 00168 Rome, Italy.
  • 2 Policlinico Universitario A. Gemelli Foundation-IRCCS, 00168 Rome, Italy.
  • 3 Department of Acupuncture and Moxibustion, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200086, China.
  • 4 Shanghai Geriatric Institute of Chinese Medicine, Shanghai University of Traditional Chinese Medicine, 365 South Xiangyang Road, Shanghai 200031, China.
  • 5 Laboratory Affiliated with the Institute Pasteur Italy-Cenci Bolognetti Foundation, Department of Drug Chemistry and Technologies, Sapienza University of Rome, Piazzale Aldo Moro 5, 00185 Rome, Italy.
  • 6 Department of Organic Chemistry, University of Chemistry and Technology Prague, Technická 5, Prague 6 16628, Czech Republic.
  • 7 GSTeP-Organoids Research Core Facility, Fondazione Policlinico Universitario A. Gemelli, IRCCS, 00168 Rome, Italy.
  • 8 Sols-Morreale Biomedical Research Institute (IIBM), Spanish National Research Council (CSIC), Universidad Autónoma de Madrid (UAM), 28029 Madrid, Spain.
  • 9 Aphad SrL, Via della Resistenza 65, 20090 Buccinasco, Italy.
  • 10 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, Maryland 21702, United States.
PMID: 40789158 DOI: 10.1021/acs.jmedchem.5c01561
Abstract

Ferroptosis-inducing agents are an emerging class of nonapoptotic, iron-dependent compounds for Anticancer chemotherapy. We describe the synthesis of new aroyl diheterocyclyl pyrrole derivatives 2-21. Compound 12 exhibited the most potent in vitro Anticancer activity against breast Cancer (BC), triple-negative breast Cancer (TNBC), and colorectal Cancer (CRC) cell lines, as well as significant efficacy in an HCT116 CRC xenograft model. Compound 12 showed typical hallmarks of Ferroptosis in HCT116 cells from tumor tissues both in immunofluorescence and a qPCR gene assay and in the expression of Ferroptosis inhibited proteins. Compound 12 significantly lowered GSH, NADP+, and NADPH levels. Furthermore, lactoperoxidase, malondialdehyde, and Fe(II) levels significantly increased in 12-treated tissues, whereas superoxide dismutase concentrations decreased. Taken together, these results indicate that the antitumor activity of compound 12 was caused by the strong induction of Ferroptosis. Given its high activity, compound 12 represents a promising therapeutic candidate for TNBC and CRC.

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