Abstract
A novel series of potent chiral inhibitors of histone deacetylase (HDAC) is described that contains an oxazoline capping group and a N-(2-aminophenyl)-benzamide unit. Among several new inhibitors of this type exhibiting Class I selectivity and potent inhibition of HDAC3-NCoR2, in vitro assays for the inhibition of HDAC1, HDAC2, and HDAC3-NCoR2 by N-(2-aminophenyl)-benzamide 15k gave respective IC50 values of 80, 110, and 6 nM. Weak inhibition of all other HDAC isoforms (HDAC4, 5, 6, 7, and 9: IC50 > 100 000 nM; HDAC8: IC50 = 25 000 nM; HDAC10: IC50 > 4000 nM; HDAC11: IC50 > 2000 nM) confirmed the Class I selectivity of 15k. 2-Aminoimidazolinyl, 2-thioimidazolinyl, and 2-aminooxazolinyl units were shown to be effective replacements for the pyrimidine ring present in many other 2-(aminophenyl)-benzamides previously reported, but the 2-aminooxazolinyl unit was the most potent in inhibiting HDAC3-NCoR2. Many of the new HDAC inhibitors showed higher solubilities and lower binding to human serum albumin than that of Mocetinostat. Increases in histone H3K9 acetylation in the human cell lines U937 and PC-3 was observed for all three oxazolinyl inhibitors evaluated; those HDAC inhibitors also lowered cyclin E expression in U937 cells but not in PC-3 cells, indicating underlying differences in the mechanisms of action of the inhibitors on those two cell lines.
Highlights
Epigenetic mechanisms[1] are relevant to a wide range of diseases including cancer, diabetes, heart disease, and neurological disorders
Several analogues with planar rings in the capping group other than pyrimidine were less potent against HDAC1 and several cell lines than was Mocetinostat.[41]
Convergent routes were established to histone deacetylase (HDAC) inhibitors containing a variety of enantiopure heterocyclic capping groups by use of a preassembled N-(2-aminophenyl)-benzamide unit, which is a new methodology that has been shown to be applicable to the synthesis of several five-membered heterocyclic systems linked by a 2-amino or 2-thio substituent
Summary
Epigenetic mechanisms[1] are relevant to a wide range of diseases including cancer, diabetes, heart disease, and neurological disorders. S-Alkylation of (S)-4phenylimidazolidine-2-thione (4)[32] with N-(2-aminophenyl)-4(chloromethyl)benzamide (1)[33] in acetone at reflux afforded thioimidazoline 5 in 66% yield (Scheme 1), a succinct route that did not require protection of the arylamino group. Heating isothiocyanate 234 with diamine 3 in THF at reflux afforded thiourea 6 (57%), which was quantitatively cyclized in acetone in the presence of iodomethane to give aminoimidazoline 7, which was deprotected using TFA in dichloromethane to give the required aminoimidazoline 8 (47%). Thioureas (S)-13a and (S)-13b using yellow mercuric oxide were effective, the need for several equivalents of this toxic reagent led to a search for a more benign synthetic method One example of such a cyclization using iodomethane has been described,[39] and this method was found to be applicable to the preparation of a wide variety of N-(β-hydroxyethyl)thioureas, 14c−l. Boc deprotection using TFA in dichloromethane afforded the corresponding dihydrooxazoles 15c−l
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
