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
| Autor: | Giuseppe La Regina, Addolorata Coluccia, Carmela Mazzoccoli, Ruoli Bai, Claudia Martini, Cristina Mazzoni, Eleonora Da Pozzo, Romano Silvestri, Marianna Nalli, Michela Puxeddu, Te Liu, Hongliang Shen, Ernest Hamel, Chiara Cavallini, Viviana Orlando, Stefano Biagioni, Antonio Coluccia |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
Injections
Subcutaneous Antineoplastic Agents Apoptosis 01 natural sciences 03 medical and health sciences Mice Structure-Activity Relationship In vivo pyrrole Drug Discovery medicine Tumor Cells Cultured Structure–activity relationship Animals Humans Pyrroles 030304 developmental biology Cell Proliferation Pharmacology 0303 health sciences Mice Inbred BALB C Dose-Response Relationship Drug Molecular Structure 010405 organic chemistry Cell growth Chemistry Brain Neoplasms Organic Chemistry Optical Imaging leukemia General Medicine In vitro 0104 chemical sciences inhibitor Nilotinib tubulin Cell culture solid tumor Hematologic Neoplasms Clear cell carcinoma Cancer research Female Drug Screening Assays Antitumor Glioblastoma Injections Intraperitoneal medicine.drug |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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