Bispyridinium dienes: histone deacetylase inhibitors with selective activities.
A novel synthetic route to the cyclostellettamines 1 using as the key step a microwave-mediated macrocyclic ring-closing metathesis of precursors bispyridinium dienes 10 followed by catalytic hydrogenation has been developed. The open-chain bispyridinium dienes 10 showed uniformly higher histone deacetylase (HDAC) inhibitory potency than the natural products. Diene 10b inhibited HDAC1 and was inactive on HDAC4, whereas 10a showed a weak inhibition of HDAC1 and a higher activity on HDAC4. Neither 10b nor 10a inhibited isoforms HDAC2 and HDAC3. Cell cycle analysis, cell differentiation, and apoptosis as well as evaluation of the acetylation status of H3 lysine tails, up-regulation of p21WAF1/CIP1, and alpha-tubulin acetylation induced by the dienes 10 and cyclostellettamines 1 were also carried out on the human leukemia U937 cell line. These enzymatic and functional assays suggest that 10b is a HDAC1-selective inhibitor and 10a is a HDAC subclass IIa-selective inhibitor.
Pérez-Balado
Carlos
C
Departamento de Química Orgánica, Universidade de Vigo, Lagoas-Marcosende, 36310 Vigo, Spain.
Nebbioso
Angela
A
Rodríguez-Graña
Paula
P
Minichiello
Annunziata
A
Miceli
Marco
M
Altucci
Lucia
L
de Lera
Angel R
AR
D000107:Acetylation; D000466:Alkadienes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000096:biosynthesis; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D047028:Macrocyclic Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011726:Pyridinium Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014404:Tubulin / Q000737:chemistry
D000466:Alkadienes; D000970:Antineoplastic Agents; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D056572:Histone Deacetylase Inhibitors; D047028:Macrocyclic Compounds; D011726:Pyridinium Compounds; D014404:Tubulin