Histone deacetylase and microtubules as targets for the synthesis of releasable conjugate compounds.
Design and synthesis of an HDAC inhibitor and its merger with three tubulin binders to create releasable conjugate compounds is described. The biological evaluation includes: (a) in vitro reactivity with glutathione, (b) antiproliferative activity, (c) cell cycle analysis and (d) quantification of protein acetylation. The cellular pharmacology study indicated that the HDAC-inhibitor-drug conjugates retained antimitotic and proapoptotic activity with a reduced potency.
Passarella
Daniele
D
Dipartimento di Chimica Organica e Industriale, Università degli Studi di Milano, Via Venezian 21, Italy. Daniele.Passarella@unimi.it
Comi
Daniela
D
Vanossi
Andrea
A
Paganini
Gianfranco
G
Colombo
Francesco
F
Ferrante
Luca
L
Zuco
Valentina
V
Danieli
Bruno
B
Zunino
Franco
F
D000107:Acetylation / Q000187:drug effects; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D015195:Drug Design; D005978:Glutathione / Q000378:metabolism*; D006367:HeLa Cells; D056464:Histone Deacetylase 2 / Q000037:antagonists & inhibitors*; D006655:Histone Deacetylases / Q000737:chemistry; D006801:Humans; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D008870:Microtubules / Q000187:drug effects; D011499:Protein Processing, Post-Translational; D017434:Protein Structure, Tertiary; D013329:Structure-Activity Relationship; D014404:Tubulin / Q000737:chemistry* / Q000378:metabolism
D000970:Antineoplastic Agents; D008869:Microtubule-Associated Proteins; D014404:Tubulin; D056464:Histone Deacetylase 2; D006655:Histone Deacetylases; D005978:Glutathione