Synthesis and biological characterization of the histone deacetylase inhibitor largazole and C7- modified analogues.
Largazole 4a and analogues with modifications at the C7 position, as well as 2,4'-bithiazole 5a, have been synthesized using an acyclic cross-metathesis of the corresponding depsipeptide structures assembled by N-C6(O) or C15(O)-N lactam formation. Similar to the parent system 4a, the series of largazole depsipeptides 4b-d, but not 2,4'-bithiazole 5a, showed a marked inhibition of recombinant HDAC1 and selectivity over HDAC4, as well as strong pro-apoptotic effects on the NB4 leukemia cell line, but they failed to induce differentiation to mature granulocytes. Functional assays of the analogues correlated with the in vitro activities, as shown by increased H3 and alpha-tubulin acetylation levels and p21(WAF1/CIP1) up-regulation in NB4 cells. The activity of the natural product HDACi largazole 4a is not significantly altered by the presence of groups of different size (H, Et, Ph) at C7 on the dihydrothiazole ring.
Souto
José A
JA
Departamento de Quimica Organica, Universidade de Vigo, Lagoas-Marcosende, 36310 Vigo, Spain.
Vaz
Esther
E
Lepore
Ilaria
I
Pöppler
Ann-Christin
AC
Franci
Gianluigi
G
Alvarez
Rosana
R
Altucci
Lucia
L
de Lera
Angel R
AR
D000107:Acetylation; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D039521:CD11c Antigen / Q000378:metabolism; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000096:biosynthesis; D047630:Depsipeptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor; D006098:Granulocytes / Q000166:cytology / Q000187:drug effects; D056284:Histone Deacetylase 1 / Q000037:antagonists & inhibitors; D056572:Histone Deacetylase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006655:Histone Deacetylases; D006801:Humans; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors; D012097:Repressor Proteins / Q000037:antagonists & inhibitors; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014404:Tubulin / Q000378:metabolism
D000970:Antineoplastic Agents; D039521:CD11c Antigen; D050759:Cyclin-Dependent Kinase Inhibitor p21; D047630:Depsipeptides; D056572:Histone Deacetylase Inhibitors; D011994:Recombinant Proteins; D012097:Repressor Proteins; D013844:Thiazoles; D014404:Tubulin; C527895:largazole; C400300:HDAC4 protein, human; D056284:Histone Deacetylase 1; D006655:Histone Deacetylases