TY - JOUR
T1 - Ring-opened tetrahydro-γ-carbolines display cytotoxicity and selectivity with histone deacetylase isoforms
AU - Nepali, Kunal
AU - Lee, Hsueh-Yun
AU - Lai, Mei-Jung
AU - Ojha, Ritu
AU - Wu, Tung Yun
AU - Wu, Gu Xian
AU - Chen, Mei-Chuan
AU - Liou, Jing-Ping
N1 - Publisher Copyright:
© 2016 Elsevier Masson SAS
PY - 2017/2/15
Y1 - 2017/2/15
N2 - This study is focused on modification of the indole moiety and the N1-zinc binding domain of tubastatin A, and the effects of such changes on biological activity. Fourteen N-substituted indoles (5–18) were synthesized and structure-activity relationship studies indicated that the change of the tetrahydro-γ-carboline in tubastatin A led to substituted indoles (compounds 7, 11, and 15) which showed significant improvements of selective inhibition for HDAC6 over HDAC1 and HDAC2 in comparison to ACY1215, a compound undergoing clinical trials. In addition, attachment of different hydroxamic acid groups, the zinc binding motif at the N1 position, contributes to the antiproliferative activity in cancer cells. Several synthetic compounds exhibited potent growth inhibition in a broad spectrum of tumor cell lines, induced irreversible growth arrest capacities by suppressing colony formation ability and activated the apoptosis pathway. The data provide compelling evidence that our newly synthesized compounds with type B to D hydroxamic acid groups as the zinc binding motif at the N1 position are potent selective inhibitors of HDAC6 and could be investigated preclinically as potential anticancer drugs.
AB - This study is focused on modification of the indole moiety and the N1-zinc binding domain of tubastatin A, and the effects of such changes on biological activity. Fourteen N-substituted indoles (5–18) were synthesized and structure-activity relationship studies indicated that the change of the tetrahydro-γ-carboline in tubastatin A led to substituted indoles (compounds 7, 11, and 15) which showed significant improvements of selective inhibition for HDAC6 over HDAC1 and HDAC2 in comparison to ACY1215, a compound undergoing clinical trials. In addition, attachment of different hydroxamic acid groups, the zinc binding motif at the N1 position, contributes to the antiproliferative activity in cancer cells. Several synthetic compounds exhibited potent growth inhibition in a broad spectrum of tumor cell lines, induced irreversible growth arrest capacities by suppressing colony formation ability and activated the apoptosis pathway. The data provide compelling evidence that our newly synthesized compounds with type B to D hydroxamic acid groups as the zinc binding motif at the N1 position are potent selective inhibitors of HDAC6 and could be investigated preclinically as potential anticancer drugs.
KW - Anticancer agents
KW - Histone deacetylase inhibitors
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U2 - 10.1016/j.ejmech.2016.12.039
DO - 10.1016/j.ejmech.2016.12.039
M3 - Article
C2 - 28038324
AN - SCOPUS:85007047170
SN - 0223-5234
VL - 127
SP - 115
EP - 127
JO - European Journal of Medicinal Chemistry
JF - European Journal of Medicinal Chemistry
ER -