Total syntheses of the histone deacetylase inhibitors largazole and 2-epi-largazole: application of N-heterocyclic carbene mediated acylations in complex molecule synthesis.
Details of the evolution of strategies toward convergent assembly of the histone deacetylase inhibiting natural product largazole exploiting γ,δ-unsaturated-α,β-epoxy-aldehydes and a thiazole-thiazoline containing ω-amino-acid are described. The initial N-heterocyclic carbene mediated redox amidation exploying these two types of building blocks representing largazole's structural domains of distinct biosynthetic origin directly afforded the seco-acid of largazole. This was accomplished without any protecting groups resident upon either thioester bearing epoxy-aldehyde or the tetrapeptide. However, the ineffective production of largazole via the final macrolactonization led to an alternative intramolecular esterification/macrolactamization strategy employing the established two building blocks. This provided largazole along with its C2-epimer via an unexpected inversion of the α-stereocenter at the valine residue. The biological evaluation demonstrated that both largazole and 2-epi-largazole led to dose-dependent increases of acetylation of histone H3, indicating their potencies as class I histone deacetylase selective inhibitiors. Enhanced p21 expression was also induced by largazole and its C2 epimer. In addition, 2-epi-largazole displayed more potent activity than largazole in cell viability assays against PC-3 and LNCaP prostate cancer cell lines.
Department of Chemistry, The Ohio State University, 100 W. 18th St., Columbus, Ohio 43210, USA.
Bo
B
Wang
Po-Hsien
PH
Huang
Ching-Shih
CS
Chen
Craig J
CJ
Forsyth
D000215:Acylation; D001688:Biological Products / Q000737:chemistry*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects*; D047630:Depsipeptides / Q000138:chemical synthesis* / Q000737:chemistry; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D006571:Heterocyclic Compounds / Q000138:chemical synthesis* / Q000737:chemistry*; D056572:Histone Deacetylase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry; D006801:Humans; D008297:Male; D008697:Methane / Q000031:analogs & derivatives* / Q000737:chemistry; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*
D001688:Biological Products; D047630:Depsipeptides; D004791:Enzyme Inhibitors; D006571:Heterocyclic Compounds; D056572:Histone Deacetylase Inhibitors; D013844:Thiazoles; C527895:largazole; C030011:carbene; D008697:Methane
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