Abstract:
:A series of indolylsulfonylcinnamic hydroxamates has been synthesized. Compound 12, (E)-3-(3-((1H-pyrrolo[2,3-b]pyridin-1-yl)sulfonyl)phenyl)-N-hydroxyacrylamide, which has a 7-azaindole core cap, was shown to have antiproliferative activity against KB, H460, PC3, HSC-3, HONE-1, A549, MCF-7, TSGH, MKN45, HT29, and HCT116 human cancer cell lines. Pharmacological studies indicated that 12 functions as a potent HDAC inhibitor with an IC50 value of 0.1 μM. It is highly selective for histone deacetylase 6 (HDAC6) and is 60-fold more active than against HDAC1 and 223-fold more active than against HDAC2. It has a good pharmacokinetic profile with oral bioavailability of 33%. In in vivo efficacy evaluations in colorectal HCT116 xenografts, compound 12 suppresses tumor growth more effectively than SAHA (1, N-hydroxy-N'-phenyloctanediamide) and is therefore seen as a suitable candidate for further investigation.
journal_name
J Med Chemjournal_title
Journal of medicinal chemistryauthors
Lee HY,Tsai AC,Chen MC,Shen PJ,Cheng YC,Kuo CC,Pan SL,Liu YM,Liu JF,Yeh TK,Wang JC,Chang CY,Chang JY,Liou JPdoi
10.1021/jm401899xsubject
Has Abstractpub_date
2014-05-22 00:00:00pages
4009-22issue
10eissn
0022-2623issn
1520-4804journal_volume
57pub_type
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