- Exploring the influence of the protein environment on metal-binding pharmacophores
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The binding of a series of metal-binding pharmacophores (MBPs) related to the ligand 1-hydroxypyridine-2-(1H)-thione (1,2-HOPTO) in the active site of human carbonic anhydrase II (hCAII) has been investigated. The presence and/or position of a single methyl substituent drastically alters inhibitor potency and can result in coordination modes not observed in small-molecule model complexes. It is shown that this unexpected binding mode is the result of a steric clash between the methyl group and a highly ordered water network in the active site that is further stabilized by the formation of a hydrogen bond and favorable hydrophobic contacts. The affinity of MBPs is dependent on a large number of factors including donor atom identity, orientation, electrostatics, and van der Waals interactions. These results suggest that metal coordination by metalloenzyme inhibitors is a malleable interaction and that it is thus more appropriate to consider the metal-binding motif of these inhibitors as a pharmacophore rather than a "chelator". The rational design of inhibitors targeting metalloenzymes will benefit greatly from a deeper understanding of the interplay between the variety of forces governing the binding of MBPs to active site metal ions.
- Martin, David P.,Blachly, Patrick G.,McCammon, J. Andrew,Cohen, Seth M.
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supporting information
p. 7126 - 7135
(2014/11/07)
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- Regiocontrolled carbonylsulfanylations at ortho-position of phenols and at α-position of ketones using chlorocarbonylsulfenyl chloride
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Bu3N/AlCl3-promoted [3+2] cyclocondensation between phenols and chlorocarbonylsulfenyl chloride (CCSC; 3) gave 1,3-benzoxathiol-2-ones (2), wherein the acylation of phenols with CCSC (3) and the intramolecular and regioselective ortho-sulfenylation successively proceeded in a one-pot manner. 2-Sulfanylphenols (1) were produced from 2 by mild hydrolysis using NaOH. An analogous Bu3N-promoted [3+2] cyclocondensation between ketones and 3 gave 1,3-oxathioles (7), wherein the α-CH2- position of the ketones was regioselectively sulfenylated.
- Yoshida, Yoshihiro,Ogura, Masahiro,Tanabe, Yoo
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p. 681 - 692
(2007/10/03)
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- FORMATION OF BENZOTHIA CROWNS IN REACTION OF THE DIALLYL DERIVATIVE OF 2-MERCAPTO-4-METHYLPHENOL WITH SCl2
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The reaction of SCl2 with 1-allyloxy-2-allylthio-4-methylbenzene gave a mixture of 2,9,11,18-tetrachloromethyldi(4-methylbenzo)-1,7,10,13-tetrathia-18-crown-6- and 2,9,11,18-tetrachloromethyldi-(4-methylbenzo)-1,7,10,15-tetrathia-18-crown-6.
- Anisimov, A. V.,Grishkyan, A. A.,Gaisina, Kh. A.,Viktorova, E. A.
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p. 1084 - 1086
(2007/10/02)
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- SHORT COMMUNICATION SULFONATION AND SULFATION IN THE REACTION OF 4-METHYLPHENOL WITH CONCENTRATED SULFURIC ACID
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The sulfonation of 4-methylphenol in concentrated sulfuric acid ranging in concentration from 81.6-112.2percent H2SO4 has been studied.In ca. 98.5percent H2SO4 the initial product is exclusively the 2-sulfonic acid (1-2-S) and the eventual one 1-2,6-S2.In fuming sulfuric acid, the additional products are the cyclic sulfate sulfonate anhydride 2, 2-5-S, and 2-3, 5-S2.Theprecursor of 2-5-S is 2 and that of 2-6-S 1-2,6-S2.In 112.2percent H2SO4 2-5-S yields slowly 2-3,5-S2 (cf.Scheme 1)
- Cerfontain, Hans,Koeberg-Telder, Ankie
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p. 223 - 226
(2007/10/02)
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