title: Synthesis and evaluation of new Hsp90 inhibitors based on a 1,4,5-trisubstituted 1,2,3-triazole scaffold.
abstract: Ruthenium catalyzed 1,3-cycloaddition (click chemistry) of an azido moiety installed on dihydroxycumene scaffold with differently substituted aryl propiolates gave a new family of 1,4,5-trisubstituted triazole carboxylic acid derivatives that showed high affinity toward Hsp90 associated with cell proliferation inhibition, both in nanomolar range. The 1,5 arrangement of the resorcinol, the aryl moieties, and the presence of an alkyl (secondary) amide in position 4 of the triazole ring were essential to get high activity. Docking simulations suggested that the triazoles penetrate the Hsp90 ATP binding site. Some 1,4,5-trisubstituted triazole carboxamides induced dramatic depletion of the examined client proteins and a very strong increase in the expression levels of the chaperone Hsp70. In vitro metabolic stability and in vivo preliminary studies on selected compounds have shown promising results comparable to the potent Hsp90 inhibitor NVP-AUY922. One of them, (compound 18, SST0287CL1) was selected for further investigation as the most promising drug candidate.
authors.affiliation: Dipartimento di Biotecnologie, Chimica e Farmacia, Università degli Studi di Siena , Via A. Moro 2, I-53100 Siena, Italy.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Taddei
authors.forename: Serena
authors.initials: S
authors.lastname: Ferrini
authors.forename: Luca
authors.initials: L
authors.lastname: Giannotti
authors.forename: Massimo
authors.initials: M
authors.lastname: Corsi
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Manetti
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Giannini
authors.forename: Loredana
authors.initials: L
authors.lastname: Vesci
authors.forename: Ferdinando M
authors.initials: FM
authors.lastname: Milazzo
authors.forename: Domenico
authors.initials: D
authors.lastname: Alloatti
authors.forename: Mario B
authors.initials: MB
authors.lastname: Guglielmi
authors.forename: Massimo
authors.initials: M
authors.lastname: Castorina
authors.forename: Maria L
authors.initials: ML
authors.lastname: Cervoni
authors.forename: Marcella
authors.initials: M
authors.lastname: Barbarino
authors.forename: Rosanna
authors.initials: R
authors.lastname: Foderà
authors.forename: Valeria
authors.initials: V
authors.lastname: Carollo
authors.forename: Claudio
authors.initials: C
authors.lastname: Pisano
authors.forename: Silvia
authors.initials: S
authors.lastname: Armaroli
authors.forename: Walter
authors.initials: W
authors.lastname: Cabri
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology*; D015153:Blotting, Western; D002384:Catalysis; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D019295:Computational Biology; D005434:Flow Cytometry; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D007202:Indicators and Reagents; D007555:Isoxazoles / Q000138:chemical synthesis / Q000494:pharmacology; D051379:Mice; D008958:Models, Molecular; D011485:Protein Binding; D012118:Resorcinols / Q000138:chemical synthesis / Q000494:pharmacology; D012428:Ruthenium; D013050:Spectrometry, Fluorescence; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000138:chemical synthesis* / Q000494:pharmacology*; D014961:X-Ray Diffraction; D023041:Xenograft Model Antitumor Assays
chemical_list: C528044:5-(2,4-dihydroxy-5-isopropylphenyl)-4-(4-morpholin-4-ylmethylphenyl)isoxazole-3-carboxylic acid ethylamide; D000970:Antineoplastic Agents; D018841:HSP90 Heat-Shock Proteins; D007202:Indicators and Reagents; D007555:Isoxazoles; D012118:Resorcinols; D014230:Triazoles; D012428:Ruthenium