104182-40-3Relevant academic research and scientific papers
Characterization of Conformationally Constrained Benzanilide Scaffolds for Potent and Selective HDAC8 Targeting
Hassan, Muhammad Murtaza,Israelian, Johan,Nawar, Nabanita,Ganda, Giovanni,Manaswiyoungkul, Pimyupa,Raouf, Yasir S.,Armstrong, David,Sedighi, Abootaleb,Olaoye, Olasunkanmi O.,Erdogan, Fettah,Cabral, Aaron D.,Angeles, Fabrizio,Altintas, Rabia,De Araujo, Elvin D.,Gunning, Patrick T.
, p. 8634 - 8648 (2020/09/21)
Histone deacetylases (HDACs) are an attractive therapeutic target for a variety of human diseases. Currently, all four FDA-approved HDAC-targeting drugs are nonselective, pan-HDAC inhibitors, exhibiting adverse side effects at therapeutic doses. Although selective HDAC inhibition has been proposed to mitigate toxicity, the targeted catalytic domains are highly conserved. Herein, we describe a series of rationally designed, conformationally constrained, benzanilide foldamers which selectively bind the catalytic tunnel of HDAC8. The series includes benzanilides, MMH371, MMH409, and MMH410, which exhibit potent in vitro HDAC8 activity (IC50 = 66, 23, and 66 nM, respectively) and up to 410-fold selectivity for HDAC8 over the next targeted HDAC. Experimental and computational analyses of the benzanilide structure docked with human HDAC8 enzyme showed the adoption of a low-energy L-shaped conformer that favors HDAC8 selectivity. The conformationally constrained HDAC8 inhibitors present an alternative biological probe for further determining the clinical utility and safety of pharmacological knockdown of HDAC8 in diseased cells.
Method for lowering plasma levels of lipoprotein (a)
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, (2008/06/13)
Retinoids are effective to lower plasma levels of Lp (a) in mammals.
Retinobenzoic Acids. 1. Structure-Activity Relationships of Aromatic Amides with Retinoidal Activity
Kagechika, Hiroyuki,Kawachi, Emiko,Hashimoto, Yuichi,Himi, Toshiyuki,Shudo, Koichi
, p. 2182 - 2192 (2007/10/02)
Two types of aromatic amides, terephthalic monoanilides and (arylcarboxamido)benzoic acids, have been shown to possess potent retinoidal activities and can be classified as retinoids.The structure-activity relationships of these amides are discussed on the basis of differentiation-inducing activity on human promyelocytic leukemia cells HL-60.In generic formula 4 (X = NHCO or CONH), the necessary factors to elicit the retinoidal activities are a medium-sized alkyl group (isopropyl, tert-butyl, etc.) at the meta position and a carboxyl group at the para position of the other benzene ring.The bonding of the amide structure can be reversed, this moiety apparently having the role of locating the two benzene rings at suitable positions with respect to each other.Substitution at the ring position ortho to the amide group or N-methylation of the amido group caused loss of activity, presumably owing to the resultant change of conformation.It is clear that the mutual orientation of the benzylic methyl group(s) and the carboxyl group and their distance apart are essential factors determining the retinoidal activity.Among the synthesized compounds, 4-benzoic acid (Am80) and 4-benzoic acid (Am580) were several times more active than retinoic acid in the assay.They are structurally related to retinoic acid, as is clear from the biological activity of the hybrid compounds (M2 and R2).
