- Pyrazole-based potent inhibitors of GGT1: Synthesis, biological evaluation, and molecular docking studies
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In this study, a series of pyrazole-based structural analogues of GGTI-DU40 (1) have been synthesized and biologically evaluated for geranylgeranyltransferase 1 (GGT1) and farnesyltransferase (FT) inhibition. The screening results revealed that 2 (IC50?=?2.4?μM) and 5 (IC50?=?3.1?μM) are potent GGT1 inhibitors (GGTIs), possessing higher inhibitory activity compared to the control compound 1 (IC50?=?3.3?μM). The anti-proliferative efficacy of these compounds was further assayed against MDA-MB-231?cells which indicated a significantly higher activity of 2 (IC50?=?7.6?μM) compared to 1 (IC50?=?23.0?μM). To examine the capacity of the synthesized compounds to inhibit GGT1 in an intact cell, western blot analysis was performed on the MDA-MB-231?cell line, which revealed very high inhibitory cellular activity of 2 and 5 and demonstrated their capacity to inhibit prenylation of endogenous proteins. Molecular docking studies of 2 against the crystal structure of GGT1 complexed with a geranylgeranyl pyrophosphate (GGPP) Analog and a CaaX (C?=?cysteine, aa?=?aliphatic amino acids, and X?=?any amino acid) portion of the KKKSKTKCVIL peptide substrate revealed several hydrogen bonding interactions and π-π contacts between 2 and the binding pocket of GGT1. Together these data suggest that compound 2 could proceed to in?vivo investigation to further assess its efficacy and cytotoxicity.
- Mansha, Muhammad,Kumari, Udayappan Udhaya,Cournia, Zoe,Ullah, Nisar
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p. 666 - 676
(2016/09/14)
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- Stereoselective synthesis of morpholines via copper-promoted oxyamination of alkenes
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A new copper(II) 2-ethylhexanoate-promoted addition of an alcohol and an amine across an alkene (oxyamination) is reported. The alcohol addition is intramolecular, while coupling with the amine occurs intermolecularly. Several 2-aminomethyl morpholines we
- Sequeira, Fatima C.,Chemler, Sherry R.
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supporting information
p. 4482 - 4485
(2012/10/29)
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- Asymmetric Synthesis of Functionalized Secondary Alcohols by Catalytic Ring-Cleavage Reactions of Cyclic Acetals Derived from (R)-1,3-Butanediol
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In the presence of a catalytic amount (0.1-0.2 molar amount) of a 2-phenyl-1,3,2-oxazaborolidin-5-one, prepared by the reaction of dichlorophenylborane and N-(trifluoromethylsulfonyl)-L- phenylalanine, and enol silyl ethers ((R2)2C=C-(R3)OTMS; R3 = t-BuS, EtS, EtO, Ph) (1.1-1.5 molar amount), chiral cyclic acetals 6 derived from (R)-1,3-butanediol and aldehydes undergo an efficient ring-cleavage reaction with the inversion of the stereochemistry at the acetal carbon to give the anti isomer of the corresponding products with high stereoselectivity. The reaction is applicable to acetals derived from aromatic, aliphatic, and α,β-unsaturated aldehydes. Not only enol silyl ethers, but also methallyltrimethylsilane and allyltributyltin, can be employed as nucleophiles, leading to the selective formation of the anti isomer of the corresponding allylated ring-cleavage products. Removal of the chiral auxiliary from these ring-cleavage products by a two-step sequence ((i) PCC (ii) Bn2NH2(CF3CO2)) furnishes enantiomerically enriched β-hydroxy carbonyl compounds and homoallyl alcohols. A modest level of kinetic resolution is observed in the ring cleavage of a racemic acetal catalyzed by a phenylboron compound derived from N-mesyl-L-phenylalanine.
- Kinugasa, Motoharu,Hanada, Toshiro,Egusa, Takayuki,Fujita, Katsuhiro,Oku, Akira
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p. 3639 - 3650
(2007/10/03)
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- 8-substituted-dibenz[b,f][1,4]oxazepine-10(11)-carboxylic acid, substituted hydrazides, pharmaceutical compositions, and methods for treating pain
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The present invention provides substituted dibenzoxazepine compounds of Formula I: STR1 wherein X is STR2 which are useful as analgesic agents for the treatment of pain, pharmaceutical compositions comprising a therapeutically-effective amount of a compound of Formula I in combination with a pharmaceutically-acceptable carrier, and a method for eliminating or ameliorating pain in an animal comprising administering a therapeutically-effective amount of a compound of Formula I to the animal.
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- OPTICAL ACTIVITY OF LACTONES AND LACTAMS-III CIRCULAR DICHROISM SPECTRA OF 5-OXAZOLIDINONES
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The synthesis and chiroptical properties of several 5-oxazolidinones derived from α-amino acids are reported.The existence of an equilibrium between the two enantiomeric envelope conformations of 5-membered ring has been inferred from CD and NMR spectra.I
- Polonski, T.
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p. 603 - 610
(2007/10/02)
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- A Potentially Useful Fluorogenic Amine, 4-Amino-7-nitrobenz-2-oxa-1,3-diazole. An Application as a Substrate for a Microdetermination of Chymotrypsin
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4-Amino-7-nitrobenz-2-oxa-1,3-diazole (1b) is a potentially useful key fluorogenic amine.As an example of the application of this amine, 7-(N-tosyl- and N-mesyl-L-phenylalanyl)amino-4-nitrobenz-2-oxa-1,3-diazole (2) were prepared and shown to be good fluorogenic substrates for the assay of chymotrypsin.Keywords - fluorometric enzyme assay; fluorogenic amine; 4-amino-7-nitrobenz-2-oxa-1,3-diazole; 7-(N-tosyl-L-phenylalanyl)amino-4-nitrobenz-2-oxa-1,3-diazole; 7-(N-mesyl-L-phenylalanyl)amino-4-nitrobenz-2-oxa-1,3-diazole; kinetic study
- Sato, Eisuke,Miyakawa, Makiko,Kanaoka, Yuichi
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p. 336 - 339
(2007/10/02)
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- STEREOCHEMICAL STUDIES - LVII. SYNTHESIS OF OPTICALLY ACTIVE COMPOUNDS BY THE NOVEL USE OF MESO-COMPOUNDS -1. EFFICIENT SYNTHESIS OF TWO STRUCTURAL TYPES OF OPTICALLY PURE PROSTAGLANDIN INTERMEDIATES.
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With an aim to overcome several inefficient aspects of ordinary methods of preparing optically active compounds, we have developed a new method which recommends utilization of symmetrically functionalized meso-compounds in place of racemic compounds.As shown in Scheme 1, when the meso-compound (I) is monofunctionalized by an optically active functional group (A) and each of the formed diastereomers (II and III) is subjected to further chemical elaborations including protective group transposition, it is theoretically possible to convert the total amount of the starting material (I) into the requisite optically pure product (VI or VII) by selecting synthetic schemes.By employing this novel concept, two structural types of the prostaglandin intermediates ((-)- and (+)-2a,b) have been prepared from the meso-diols (1a,b) by way of the two diastereomeric monoesters (13a,b and 14a,b) which are produced by the reactions 1a,b with N-mesyl- and N-phthaloyl-(S)-phenylalanyl chloride (3a,b).
- Nara, M,Terashima, S.,Yamada, S.
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p. 3161 - 3170
(2007/10/02)
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