Probing Molecular Interactions between Human Carbonic Anhydrases (hCAs) and a Novel Class of Benzenesulfonamides
Probing Molecular Interactions between Human Carbonic Anhydrases (hCAs) and a Novel Class of Benzenesulfonamides
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DOI：
10.1021/acs.jmedchem.7b00264
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发表时间：
2017-05-25
影响因子：
7.3
通讯作者：
Gitto, Rosaria
中科院分区：
文献类型：
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作者：
Bruno, Elvira;Buemi, Maria Rosa;Gitto, Rosaria
在对hCA Ⅱ与4-（3，4-二氢-1H-异喹啉-2-羰基）苯磺酰胺（3）（PDB代码4 Z1 J）配合物的X-射线晶体学研究的基础上，设计了一系列新的4-（1-芳基-3，4-二氢-1H-异喹啉-2-羰基）苯磺酰胺（23-33）。具体而言，我们的想法是通过引入额外的疏水/亲水官能团来提高对可药用异构体的选择性。在合成和测试的化合物中，（R，S）-4-（6，7-二羟基-1-苯基-3，4-四氢异喹啉-1H-2-羰基）苯磺酰胺（30）对脑表达的hCA VII（Ki = 0.20 nM）表现出显著的抑制作用，并且对更广泛分布的hCA I和hCA II同种型表现出选择性。通过对映体选择性HPLC，我们溶解外消旋混合物，并确定两种对映体（30 a和30 b）是hCA VII的等效抑制剂。晶体学和对接研究揭示了这些抑制剂与碳酸酐酶（CA）催化位点的主要相互作用，从而强调了非极性接触对于此类hCA抑制剂的相关作用。
On the basis of X-ray crystallographic studies of the complex of hCA II with 4-(3,4-dihydro-1H-isoquinoline-2-carbonyl)benzenesulfonamide (3) (PDB code 4Z1J), a novel series of 4-(1-aryl-3,4-dihydro-1H-isoquinolin-2-carbonyl)-benzenesulfonamides (23-33) was designed. Specifically, our idea was to improve the selectivity toward druggable isoforms through the introduction of additional hydrophobic/hydrophilic functionalities. Among the synthesized and tested compounds, the (R,S)-4-(6,7-dihydroxy-1-phenyl-3,4-tetrahydroisoquinoline-1H-2-carbonyl)benzenesulfonamide (30) exhibited a remarkable inhibition for the brain-expressed hCA VII (K-i = 0.20 nM) and selectivity over wider distributed hCA I and hCA II isoforms. By enantioselective HPLC, we solved the racemic mixture and ascertained that the two enantiomers (30a and 30b) are equiactive inhibitors for hCA VII. Crystallographic and docking studies revealed the main interactions of these inhibitors into the carbonic anhydrase (CA) catalytic site, thus highlighting the relevant role of nonpolar contacts for this class of hCA inhibitors.