title: Synthesis, characterization, and optimization for in vivo delivery of a nonselective isopeptidase inhibitor as new antineoplastic agent.
abstract: Bis-arylidenecycloalkanones structurally related to the nonselective isopeptidase inhibitor G5 were synthesized and tested for cytotoxic activity against glioblastoma cells. Cytotoxicities correlate well with Hammett σ constants for substituted arylidene groups, confirming the proposed inhibition mechanism. A new inhibitor (2c) based on the 4-hydroxycyclohexanone scaffold, which favors apoptosis over necrosis, was selected for further development. 2c inhibited representative deubiquitinases with micromolar IC50, and its proapoptotic activity was studied on several cancer cell lines. Inhibitor 2c was conjugated to PEG via dicarbamate and diester linkers. While the dicarbamate was inactive, the diester (2cPE) behaves like a prodrug and is converted into the active species 2c by secreted esterase activities. Finally, 2cPE was also tested in vivo on A549 lung carcinoma xenografts generated in mice. Intravenous treatment with 2cPE led to a significant reduction in primary tumor growth, without appreciable toxicity to mice.
authors: Dipartimento di Scienze Chimiche e Farmaceutiche, Università degli Studi di Trieste , Via Giorgieri 1, 34127 Trieste, Italy.
authors: Ulma
authors: U
authors: Cersosimo
authors: Andrea
authors: A
authors: Sgorbissa
authors: Carmen
authors: C
authors: Foti
authors: Sara
authors: S
authors: Drioli
authors: Rosario
authors: R
authors: Angelica
authors: Andrea
authors: A
authors: Tomasella
authors: Raffaella
authors: R
authors: Picco
authors: Marta Stefania
authors: MS
authors: Semrau
authors: Paola
authors: P
authors: Storici
authors: Fabio
authors: F
authors: Benedetti
authors: Federico
authors: F
authors: Berti
authors: Claudio
authors: C
authors: Brancolini
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D019759:Carbon-Nitrogen Lyases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D016503:Drug Delivery Systems; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D005260:Female; D019073:HT29 Cells; D006801:Humans; D007659:Ketones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008958:Models, Molecular; D015394:Molecular Structure; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000473:pathology; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D007659:Ketones; D019759:Carbon-Nitrogen Lyases; C034300:isopeptidase