- Achiral Derivatives of Hydroxamate AR-42 Potently Inhibit Class i HDAC Enzymes and Cancer Cell Proliferation
-
AR-42 is an orally active inhibitor of histone deacetylases (HDACs) in clinical trials for multiple myeloma, leukemia, and lymphoma. It has few hydrogen bond donors and acceptors but is a chiral 2-arylbutyrate and potentially prone to racemization. We report achiral AR-42 analogues incorporating a cycloalkyl group linked via a quaternary carbon atom, with up to 40-fold increased potency against human class I HDACs (e.g., JT86, IC50 0.7 nM, HDAC1), 25-fold increased cytotoxicity against five human cancer cell lines, and up to 70-fold less toxicity in normal human cells. JT86 was ninefold more potent than racAR-42 in promoting accumulation of acetylated histone H4 in MM96L melanoma cells. Molecular modeling and structure-activity relationships support binding to HDAC1 with tetrahydropyran acting as a hydrophobic shield from water at the enzyme surface. Such potent inhibitors of class I HDACs may show benefits in diseases (cancers, parasitic infections, inflammatory conditions) where AR-42 is active.
- Tng, Jiahui,Lim, Junxian,Wu, Kai-Chen,Lucke, Andrew J.,Xu, Weijun,Reid, Robert C.,Fairlie, David P.
-
supporting information
p. 5956 - 5971
(2020/06/05)
-
- Pd(II)-Catalyzed Enantioselective C(sp3)-H Arylation of Free Carboxylic Acids
-
A monoprotected aminoethyl amine chiral ligand based on an ethylenediamine backbone was developed to achieve Pd-catalyzed enantioselective C(sp3)-H arylation of cyclopropanecarboxylic and 2-aminoisobutyric acids without using exogenous directing groups. This new chiral catalyst affords new disconnection for preparing diverse chiral carboxylic acids from simple starting materials that are complementary to the various ring forming approaches.
- Shen, Peng-Xiang,Hu, Liang,Shao, Qian,Hong, Kai,Yu, Jin-Quan
-
supporting information
p. 6545 - 6549
(2018/05/23)
-
- Electrophilic Bromolactonization of Cyclopropyl Diesters Using Lewis Basic Chalcogenide Catalysts
-
An efficient and regioselective electrophilic bromolactonization of cyclopropylmethyl diesters using triphenylphosphine sulfide (Ph3PS) or diphenyl selenide (Ph2Se) as the Lewis basic chalcogenide catalyst has been developed. It was observed that Ph3PS favored the formation of anti-diastereomer and yielded the multi-functional γ-lactones. Interestingly, the diastereoselectivity was reversed when using Ph2Se as a catalyst where the syn-product instead of the anti-product was favored. (Figure presented.).
- Gieuw, Matthew H.,Leung, Vincent Ming-Yau,Ke, Zhihai,Yeung, Ying-Yeung
-
supporting information
p. 4306 - 4311
(2018/10/02)
-
- Pyruvate kinase activators for use in therapy
-
Described herein are methods for using compounds that activate pyruvate kinase.
- -
-
Page/Page column 98
(2016/08/29)
-
- PIPERAZINE AND HOMOPIPERAZINE DERIVATIVES AS HIV ATTACHMENT INHIBITORS
-
Compounds of Formula I, including pharmaceutically acceptable salts thereof, are useful as HIV attachment inhibitors.
- -
-
Page/Page column 59-60
(2014/10/15)
-
- KAPPA OPIOID RECEPTOR AGONISTS
-
The present invention relates to a series of substituted compounds having the general formula (I), including their stereoisomers and/or their pharmaceutically acceptable salts. (I) Wherein A, m, Rls R2, R3, R4 are as defined herein. This invention also relates to methods of making these compounds including intermediates. The compounds of this invention are effective at the kappa (κ) opioid receptor (KOR) site. Therefore, the compounds of this invention are useful as pharmaceutical agents, especially in the treatment and/or prevention of a variety of central nervous system disorders (CNS), including but not limited to acute and chronic pain, and associated disorders, particularly functioning peripherally at the CNS.
- -
-
Page/Page column 46-47
(2012/02/05)
-
- THERAPEUTIC COMPOUNDS AND COMPOSITIONS
-
Compounds and compositions comprising compounds that modulate pyruvate kinase M2 (PKM2) are described herein. Also described herein are methods of using the compounds that modulate PKM2 in the treatment of cancer.
- -
-
Page/Page column 24
(2012/07/14)
-
- KINASE INHIBITORS AND METHOD OF TREATING CANCER WITH SAME
-
The present teachings provide a compound represented by Structural Formula (I): or a pharmaceutically acceptable salt thereof. Also described are a pharmaceutical composition and method of use thereof.
- -
-
Page/Page column 88
(2011/10/31)
-
- Imidazolium salts as phase transfer catalysts for the dialkylation and cycloalkylation of active methylene compounds
-
The efficient synthesis of 1,1-disubstituted derivatives and the construction of cyclopropane and cyclopentane ring systems via dialkylation and cycloalkylation reactions of active methylene compounds using imidazolium salts as phase transfer catalyst is described. The dialkylation and cycloalkylation reactions of active methylene compounds in the presence of readily available imidazolium salts (ionic liquids) as phase transfer catalysts were performed to afford the respective dialkylated or cycloalkylated products. This method is very efficient for the synthesis of 1,1-disubstituted derivatives and cyclopropane and cyclopentane ring systems in a facile manner.
- Muthusamy, Sengodagounder,Gnanaprakasam, Boopathy
-
p. 635 - 638
(2007/10/03)
-
- A novel chromium trioxide catalyzed oxidation of primary alcohols to the carboxylic acids
-
A novel CrO3 catalyzed oxidation of primary alcohols to the carboxylic acids is reported. The oxidation proceeds smoothly with only 1-2 mol % of CrO3 and 2.5 equivalents of H3IO6 in wet MeCN to give the carboxylic acids in excellent yield. No significant racemization is observed for alcohols with adjacent chiral centers. Secondary alcohols are cleanly oxidized to ketones.
- Zhao, Mangzhu,Li, Jing,Song, Zhiguo,Desmond, Richard,Tschaen, David M.,Grabowski, Edward J. J.,Reider, Paul J.
-
p. 5323 - 5326
(2007/10/03)
-
- N-Methyl-N--1-phenylcyclopropanecarboxylic amides - analogs of U50488 with much reduced opiate affinity and loss of κ-selectivity
-
(+/-)-N-methyl-N--1-phenylcyclopropanecarboxylic amide (1) and its dichloro analog (2) were synthesized.Compounds 1 and 2 are related to the κ-selective opiate U-50488 in that the benzylic methylene moiety in U-50488 has been replaced by a cyclopropane ring.As compared to U-50488, a 600-fold reduction in kappa-affinity was observed with these 2 compounds; while the reduction in μ-affinity was less than 2-fold.Unlike U-50488, 1 and 2 also show measurable δ-binding.To explain the observed anomaly, the steric interaction between the N-methyl group and the cyclopropane ring and the tendency of the cyclopropane ring to conjugate with the neighboring phenyl group, both affecting the accessible conformations of the amide side chains of 1 and 2, are cosidered important factors.
- Cheng, CY,Lu, HY,Lee, FM
-
p. 125 - 128
(2007/10/02)
-
- Deamination Reactions, 45. Decomposition of 1-Arylcyclopropanediazonium Ions
-
1-Arylcyclopropanediazonium ions have been generated by alkaline cleavage of the analogous nitrosocarbamates in methanol.With increasing ?-donor capacity of the aryl groups, retention of the three-membered ring was enhanced while the stereoselectivity (as probed with the aid of 2-D labels) was diminished or entirely lost (4-methoxyphenyl).Where applicable, the stereoselectivity of ring opening is inferior to that of nucleophilic displacement.The data may be interpreted in terms of competing reactions (ks, kc, kΔ) of the cyclopropanediazonium ions.
- Kirmse, Wolfgang,Rode, Jutta
-
p. 3694 - 3703
(2007/10/02)
-
- SUBSTITUTION OF THE CARBOXYL GROUP BY BROMINE IN PHENYLCYCLOPROPANECARBOXYLIC ACIDS
-
The substitution of the carboxyl group by bromine in isomeric phenylcyclopropanecarboxylic acids and their noncyclic analog 2-methyl-2-phenylpropionic acid was investigated.The direction of the reaction depends significantly on the nature of the solvent, the temperature, and the mutual arrangement of the phenyl radical and the carboxyl group.A new preparative method was developed for the synthesis of 1-phenyl-1-cyclopropanecarboxylic acid.
- Sychkova, L. D.,Shabarov, Yu. S.
-
p. 1775 - 1779
(2007/10/02)
-
- Soft drugs: III. A new class of anticholinergic agents
-
A new class of antimuscarinic drugs was designed and synthesized. The compounds are 'soft' quaternary ammonium esters in which there is only one carbon atom separating the ester oxygen and the quaternary head. The compounds are potent anticholinergics when derived from hindered 'umbrella' acids and cholinergics when derivatives of simple aliphatic acids. The more potent anticholinergics have up to 10 times higher acetylcholine antagonist activity than atropine, but they have a much shorter duration of action. The compounds cleave hydrolytically with simultaneous destruction of the quaternary head. The compounds are promising as selective, local agents, particularly as inhibitors of eccrine sweating.
- Bodor,Woods,Raper,et al.
-
p. 474 - 480
(2007/10/02)
-
