2. Academic Validation
  3. Structure-activity relationship studies and in vitro and in vivo anticancer activity of novel 3-aroyl-1,4-diarylpyrroles against solid tumors and hematological malignancies

Structure-activity relationship studies and in vitro and in vivo anticancer activity of novel 3-aroyl-1,4-diarylpyrroles against solid tumors and hematological malignancies

  • Eur J Med Chem. 2020 Jan 1;185:111828. doi: 10.1016/j.ejmech.2019.111828.
Michela Puxeddu 1,  Hongliang Shen 2,  Ruoli Bai 3,  Antonio Coluccia 4,  Marianna Nalli 4,  Carmela Mazzoccoli 5,  Eleonora Da Pozzo 6,  Chiara Cavallini 6,  Claudia Martini 6,  Viviana Orlando 7,  Stefano Biagioni 7,  Cristina Mazzoni 7,  Addolorata Maria Luce Coluccia 8,  Ernest Hamel 3,  Te Liu 9,  Romano Silvestri 10,  Giuseppe La Regina 11
Affiliations

Affiliations

  • 1 Laboratory Affiliated with the Institute Pasteur Italy - Cenci Bolognetti Foundation, Department of Drug Chemistry and Technologies, Sapienza University of Rome, Piazzale Aldo Moro 5, I-00185, Roma, Italy. Electronic address: michela.puxeddu@uniroma1.it.
  • 2 Department of Urology, Capital Medical University Beijing Friendship Hospital, Beijing, 100050, China. Electronic address: 1051486940@qq.com.
  • 3 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, MD, 21702, United States.
  • 4 Laboratory Affiliated with the Institute Pasteur Italy - Cenci Bolognetti Foundation, Department of Drug Chemistry and Technologies, Sapienza University of Rome, Piazzale Aldo Moro 5, I-00185, Roma, Italy.
  • 5 Laboratorio di Ricerca Pre-Clinica e Traslazionale, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Centro di Riferimento Oncologico della Basilicata, Via Padre Pio 1, I-85028, Rionero in Vulture, Italy.
  • 6 Department of Pharmacy, University of Pisa, Via Bonanno Pisano 6, I-56126, Pisa, Italy.
  • 7 Department of Biology and Biotechnologies "Charles Darwin", Sapienza University of Rome, Piazzale Aldo Moro 5, I-00185, Roma, Italy.
  • 8 Department of Biological and Environmental Sciences and Technologies, University of Salento, I-73100, Lecce, Italy.
  • 9 Shanghai Geriatric Institute of Chinese Medicine, Shanghai University of Traditional Chinese Medicine, 365 South Xiangyang Road, Shanghai, 200031, China. Electronic address: 0721160004@mail.tongji.edu.cn.
  • 10 Laboratory Affiliated with the Institute Pasteur Italy - Cenci Bolognetti Foundation, Department of Drug Chemistry and Technologies, Sapienza University of Rome, Piazzale Aldo Moro 5, I-00185, Roma, Italy. Electronic address: romano.silvestri@uniroma1.it.
  • 11 Laboratory Affiliated with the Institute Pasteur Italy - Cenci Bolognetti Foundation, Department of Drug Chemistry and Technologies, Sapienza University of Rome, Piazzale Aldo Moro 5, I-00185, Roma, Italy. Electronic address: giuseppe.laregina@uniroma1.it.
PMID: 31727471 DOI: 10.1016/j.ejmech.2019.111828
Abstract

Novel 3-aroyl-1,4-diarylpyrrole derivatives were synthesized to explore structure-activity relationships at the phenyls at positions 1 and 4 of the pyrrole. The presence of amino phenyl rings at positions 1 and 4 of the pyrrole ring were found to be a crucial requirement for potent antitumor activity. Several compounds strongly inhibited tubulin assembly through binding to the colchicine site. Compounds 42, 44, 48, 62 and 69 showed antitumor activity with low nanomolar IC50 values in several Cancer cell lines. Compound 48 was generally more effective as an inhibitor of glioblastoma, colorectal and urinary bladder Cancer cell lines; 69 consistently inhibited CML cell lines and demonstrated superiority in nilotinib and imatinib resistant LAMA84-R and KBM5-T315I cells. In animal models, compound 48 exhibited significant inhibition of the growth of T24 bladder carcinoma and ES-2 ovarian clear cell carcinoma tumors. Compounds 48 and 69 represent robust lead compounds for the design of new broad-spectrum Anticancer agents active in different types of solid and hematological tumors.

Keywords

Inhibitor; Leukemia; Pyrrole; Solid tumor; Tubulin.

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