Discovery of pyrrole derivatives for the treatment of glioblastoma and chronic myeloid leukemia

Eur J Med Chem. 2021 Oct 5:221:113532. doi: 10.1016/j.ejmech.2021.113532.

Michela Puxeddu ¹, Hongliang Shen ², Ruoli Bai ³, Antonio Coluccia ¹, Marianna Bufano ¹, Marianna Nalli ¹, Jessica Sebastiani ¹, Diego Brancaccio ⁴, Eleonora Da Pozzo ⁵, Chiara Tremolanti ⁵, Claudia Martini ⁵, Viviana Orlando ⁶, Stefano Biagioni ⁶, Maria Stefania Sinicropi ⁷, Jessica Ceramella ⁷, Domenico Iacopetta ⁷, Addolorata Maria Luce Coluccia ⁸, Ernest Hamel ³, Te Liu ⁹, Romano Silvestri ¹⁰, Giuseppe La Regina ¹¹

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.
2 Department of Urology, Capital Medical University Beijing Friendship Hospital, Beijing, 100050, China.
3 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.
4 Department of Pharmacy, University of Naples"Federico II", Via Domenico Montesano 49, 80131, Naples, Italy.
5 Department of Pharmacy, University of Pisa, Via Bonanno Pisano 6, I-56126, Pisa, Italy.
6 Department of Biology and Biotechnologies "Charles Darwin", Sapienza University of Rome, Piazzale Aldo Moro 5, I-00185, Roma, Italy.
7 Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, I-87036, Rende, Cosenza, Italy.
8 Department of Biological and Environmental Sciences and Technologies, University of Salento, I-73100, Lecce, Italy.
9 Department of Biological and Environmental Sciences and Technologies, University of Salento, I-73100, Lecce, Italy; 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: 34052717 DOI: 10.1016/j.ejmech.2021.113532

Abstract

Long-term survivors of glioblastoma multiforme (GBM) are at high risk of developing second primary neoplasms, including leukemia. For these patients, the use of classic tyrosine kinase inhibitors (TKIs), such as imatinib mesylate, is strongly discouraged, since this treatment causes a tremendous increase of tumor and stem cell migration and invasion. We aimed to develop agents useful for the treatment of patients with GBM and chronic myeloid leukemia (CML) using an alternative mechanism of action from the TKIs, specifically based on the inhibition of tubulin polymerization. Compounds 7 and 25, as planned, not only inhibited tubulin polymerization, but also inhibited the proliferation of both GMB and CML cells, including those expressing the T315I mutation, at nanomolar concentrations. In in vivo experiments in BALB/cnu/nu mice injected subcutaneously with U87MG cells, in vivo, 7 significantly inhibited GBM Cancer cell proliferation, in vivo tumorigenesis, and tumor growth, tumorigenesis and angiogenesis. Compound 7 was found to block human Topoisomerase II (hTopoII) selectively and completely, at a concentration of 100 μM.

Keywords

Glioblastoma; Leukemia; Pyrrole; Synthesis; Tubulin.

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