TY - JOUR
T1 - Largazole and analogues with modified metal-binding motifs targeting histone deacetylases
T2 - Synthesis and biological evaluation
AU - Bhansali, Pravin
AU - Hanigan, Christin L.
AU - Casero, Robert A.
AU - Tillekeratne, L. M.Viranga
PY - 2011/11/10
Y1 - 2011/11/10
N2 - The histone deacetylase inhibitor largazole 1 was synthesized by a convergent approach that involved several efficient and high yielding single pot multistep protocols. Initial attempts using tert-butyl as thiol protecting group proved problematic, and synthesis was accomplished by switching to the trityl protecting group. This synthetic protocol provides a convenient approach to many new largazole analogues. Three side chain analogues with multiple heteroatoms for chelation with Zn 2+ were synthesized, and their biological activities were evaluated. They were less potent than largazole 1 in growth inhibition of HCT116 colon carcinoma cell line and in inducing increases in global H3 acetylation. Largazole 1 and the three side chain analogues had no effect on HDAC6, as indicated by the lack of increased acetylation of α-tubulin.
AB - The histone deacetylase inhibitor largazole 1 was synthesized by a convergent approach that involved several efficient and high yielding single pot multistep protocols. Initial attempts using tert-butyl as thiol protecting group proved problematic, and synthesis was accomplished by switching to the trityl protecting group. This synthetic protocol provides a convenient approach to many new largazole analogues. Three side chain analogues with multiple heteroatoms for chelation with Zn 2+ were synthesized, and their biological activities were evaluated. They were less potent than largazole 1 in growth inhibition of HCT116 colon carcinoma cell line and in inducing increases in global H3 acetylation. Largazole 1 and the three side chain analogues had no effect on HDAC6, as indicated by the lack of increased acetylation of α-tubulin.
UR - http://www.scopus.com/inward/record.url?scp=80455162618&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=80455162618&partnerID=8YFLogxK
U2 - 10.1021/jm200432a
DO - 10.1021/jm200432a
M3 - Article
C2 - 21936551
AN - SCOPUS:80455162618
SN - 0022-2623
VL - 54
SP - 7453
EP - 7463
JO - Journal of medicinal chemistry
JF - Journal of medicinal chemistry
IS - 21
ER -