Design and synthesis of novel 3,4-disubstituted pyrazoles for nanomedicine applications against malignant gliomas.
A series of novel 3,4-disubstituted pyrazoles were synthesized. The cytotoxicity against U87MG glioma cell line have been investigated in vitro and three of these compounds showed promising inhibitory activity on cell growth with an IC50 lower than 90 microM. AutoDock molecular docking into type I TGF-beta receptor (TGF-beta-RI; PDB: 1py5) has been done for lead optimization of the mentioned compounds as potential TGF-beta-RI1 inhibitors. In particular, 3-aryl-4-amido pyrazole containing long omega-amino-aliphatic chain emerged as a good candidate for further optimization. Entrapment into targetable PEG-based micelles improved growth inhibition IC50 values up to 100 nM and this could lead to a novel drug delivery strategy for treating glioblastoma.
Dipartimento di Chimica Organica, Università di Bologna, and Dipartmento Clinico Scienze Radiologiche ed Istocitopatologiche, Ospedale Bellaria, Viale Risorgimento 4, Bologna 40136, Italy. mauro.comesfranchini@unibo.it
Mauro
M
Comes Franchini
Bianca Flavia
BF
Bonini
Carlo Maurizio
CM
Camaggi
Denis
D
Gentili
Annalisa
A
Pession
Monica
M
Rani
Elena
E
Strocchi
D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D005910:Glioma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008823:Micelles; D008956:Models, Chemical; D015394:Molecular Structure; D050997:Nanomedicine; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D018125:Receptors, Transforming Growth Factor beta / Q000037:antagonists & inhibitors / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; D008823:Micelles; D011720:Pyrazoles; D018125:Receptors, Transforming Growth Factor beta