- Coordination compounds based on 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid
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Syntheses of 2,6-bis[((3S)-3-(methoxycarbonyl)-1,2,3,4- tetrahydroisoquinolin-2-yl)carbonyl]pyridine and its coordination compounds with Cu2+, Co2+, Co3+, or Fe3+ are described. By means of 1H- and s
- Jansa, Petr,Machacek, Vladimir,Nachtigall, Petr,Wsol, Vladimir,Svobodova, Marketa
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- Design and synthesis of N-(5-chloro-2,4-dihydroxybenzoyl)-(R)-1,2,3,4-tetrahydroisoquinoline-3-carboxamides as novel Hsp90 inhibitors
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Heat shock protein 90 (Hsp90) is an attractive chemotherapeutic target for antitumor drug development. Herein, we reported the design and synthesis of two series of novel N-(5-chloro-2,4-dihydroxybenzoyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamides as Hsp90 inhibitors using (S)-Tic (1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid) (A1-13) and (R)-Tic (B1-13) as scaffold, respectively. Cellular thermal shift assay (CETSA) screening showed that compounds B1-13 with (R)-Tic scaffold exhibited potent ability to stabilize Hsp90α. Compound B7 showed not only the most potent ability to induce thermal stabilization of Hsp90α but also the strongest cytotoxicity. The IC50 values of B7 were 0.98 μM and 1.74 μM against the proliferation of human breast cancer MDA-MB-231 and human cervical cancer HeLa cell lines, respectively. Moreover, CETSA melt and ITDRFCETSA (isothermal dose-response fingerprint) curves confirmed that B7 bound to Hsp90α in 293T cells. Western blotting results indicated that B7 induced the degradation of Hsp90 clients CDK4, Her2, Cdc-2 and C-raf. In addition, docking and Molecular dynamics (MD) refinement of the B7-Hsp90 complex showed that the binding model of B7 to Hsp90 was similar with that of 8-benzyladenines. The overall properties warrant compound B7 a promising lead for the development of Hsp90 inhibitor antitumor drugs.
- Liang, Chuanpeng,Hao, Huilin,Wu, Xingkang,Li, Zhenyu,Zhu, Jing,Lu, Chunhua,Shen, Yuemao
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- Hydantoins and thiohydantoins derived from 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid
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The reaction of methyl (S)-1,2,3,4-tetrahydroisoquinoline-3-carboxylate with isocyanates (phenyl, naphthalen-l-yl, cyclohexyl, (S)-1-methylbenzyl) in ether has been used to prepare N-substituted methyl (3S)-2-aminocarbonyl-1,2,3,4-tetrahydroisoquinoline-3
- Jansa, Petr,Wsol, Vladimir,Bertolasi, Valerio,Machacek, Vladimir
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p. 2527 - 2547
(2008/02/04)
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- HETEROCYCLES FROM NITRILE IMINES. PART IV. CHIRAL 4,5-DIHYDRO-1,2,4-TRIAZIN-6-ONES
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The reaction of nitrile imines (II) with α-amino esters (III) proceeds with no detectable racemization and constitutes a convenient synthetic route to 4,5-dihydro-1,2,4-triazin-6-ones (IV).Permangamate oxidation of heterocycles (IV) affords the corresponding 1,2,4-triazin-6-ones (V).The reaction of (II) with β-amino esters gives the respective acyclic amidrazone adducts (VI).
- El-Abadelah, Mustafa M.,Hussein, Ahmad Q.,Thaher, Bassam A.
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p. 1879 - 1895
(2007/10/02)
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- Synthesis and Evaluation of 3-Substituted Analogues of 1,2,3,4-Tetrahydroisoquinoline as Inhibitors of Phenylethanolamine N-Methyltransferase
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1,2,3,4-Tetrahydroisoquinoline (THIQ) and aryl-substituted derivatives of THIQ are potent inhibitors of the enzyme that catalyzes the formation of epinephrine - phenylethanolamine N-methyltransferase (PNMT, E.C. 2.1.1.28).In previous studies, we found that substitution of the 3-position of THIQ with a methyl group resulted in enhanced activity as an inhibitor for 3-methyl-THIQ (8) with respect to THIQ itself.To more fully delineate this region of the PNMT active site, we have synthesized and evaluated other 3-substituted THIQ analogues that vary in both steric and electronic character.Extension of the methyl side chain in 8 by a single methylene unit results in diminished potency for 3-ethyl-THIQ (13), suggesting that this zone of the active site is spatially compact; furthermore, the region of steric intolerance may be located principally on only "one side" of the 3-position of bound THIQs, since the carbonyl containing (bent) analogues 3-(methoxycarbonyl)-THIQ (10) and 3-(aminocarbonyl)-THIQ (12) are much less capable of forming a strong enzyme-inhibitor dissociable complex compared to straight-chain derivatives possessing a similar steric component.The good activity of 3-(hydroxymethyl)-THIQ (11) as a PNMT inhibitor cannot be explained solely by steric tolerance for this side chain.We believe that an active-site amino acid residue capable of specific (i.e., hydrogen bond) interactions is located in close proximity to the 3-position of bound THIQs and that association of the OH functionality with this active-site residue results in the enhanced in vitro potency of this analogue (Ki = 2.4 μM) compared to that of THIQ (Ki = 10.3 μM).Incorporation of a hydroxymethyl substituent onto the 3-position of the potent PNMT inhibitor 7,8-dichloro-THIQ (SKF 64139, Ki = 0.24 μM) did not result in the same enhancement in inhibitor potency for 17 (Ki = 0.38 μM).This result suggests that simultaneous binding in an optional orientation of the aromatic halogens, secondary amine, and side-chain hydroxyl functionalities to the PNMT active site is not allowed in this analogue.
- Grunewald, Gary L.,Sall, Daniel J.,Monn, James A.
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p. 824 - 830
(2007/10/02)
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- Substituted iminodiacids, their preparation and pharmaceutical compositions containing them
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Compounds of the general formula: STR1 wherein: the ring A is saturated and n=0 or 1, or the ring A is a benzene ring and n=1, R1 represents a lower alkyl group which can carry an amino group, R2 represents a hydrogen atom or a lower alkyl group, R3 represents a straight or branched alkyl group, a mono- or di-cycloalkylalkyl or phenylalkyl group having no more than a total of 9 carbon atoms, or a substituted alkyl group, and also the salts thereof. These compounds are useful as therapeutic drugs.
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