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

Michela Puxeddu; Hongliang Shen; Ruoli Bai; Antonio Coluccia; Marianna Nalli; Carmela Mazzoccoli; Eleonora Da Pozzo; Chiara Cavallini; Claudia Martini; Viviana Orlando; Stefano Biagioni; Cristina Mazzoni; Addolorata Maria Luce Coluccia; Ernest Hamel; Te Liu; Romano Silvestri; Giuseppe La Regina

doi:10.1016/j.ejmech.2019.111828

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. Epub 2019 Nov 2.

Authors

Michela Puxeddu¹, Hongliang Shen², Ruoli Bai³, Antonio Coluccia⁴, Marianna Nalli⁴, Carmela Mazzoccoli⁵, Eleonora Da Pozzo⁶, Chiara Cavallini⁶, Claudia Martini⁶, Viviana Orlando⁷, Stefano Biagioni⁷, Cristina Mazzoni⁷, Addolorata Maria Luce Coluccia⁸, Ernest Hamel³, Te Liu⁹, Romano Silvestri¹⁰, Giuseppe La Regina¹¹

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: [email protected].
² Department of Urology, Capital Medical University Beijing Friendship Hospital, Beijing, 100050, China. Electronic address: [email protected].
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: [email protected].
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: [email protected].
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: [email protected].

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.

MeSH terms

Animals
Antineoplastic Agents / administration & dosage
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Apoptosis / drug effects
Brain Neoplasms / drug therapy*
Brain Neoplasms / pathology
Cell Proliferation / drug effects
Dose-Response Relationship, Drug
Drug Screening Assays, Antitumor
Female
Glioblastoma / drug therapy*
Glioblastoma / pathology
Hematologic Neoplasms / drug therapy*
Hematologic Neoplasms / pathology
Humans
Injections, Intraperitoneal
Injections, Subcutaneous
Mice
Mice, Inbred BALB C
Molecular Structure
Optical Imaging
Pyrroles / administration & dosage
Pyrroles / chemistry
Pyrroles / pharmacology*
Structure-Activity Relationship
Tumor Cells, Cultured

Substances

Antineoplastic Agents
Pyrroles