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S-Glycosyl Primary Sulfonamides-A New Structural Class for Selective Inhibition of Cancer-Associated Carbonic Anhydrases
被引:45
|作者:
Lopez, Marie
[1
]
Paul, Blessy
[1
]
Hofmann, Andreas
[1
]
Morizzi, Julia
[2
]
Wu, Quoc K.
[2
]
Charman, Susan A.
[2
]
Innocenti, Alessio
[3
]
Vullo, Daniela
[3
]
Supuran, Claudiu T.
[3
]
Poulsen, Sally-Ann
[1
]
机构:
[1] Griffith Univ, Eskitis Inst Cell & Mol Therapies, Nathan, Qld 4111, Australia
[2] Monash Univ, Fac Pharm & Pharmaceut Sci, Ctr Drug Candidate Optimisat, Parkville, Vic 3052, Australia
[3] Univ Florence, Lab Chim Bioinorgan, I-50019 Florence, Italy
基金:
澳大利亚研究理事会;
关键词:
ISOZYME-IX;
THERAPEUTIC APPLICATIONS;
DESIGN;
TRANSMEMBRANE;
ABSORPTION;
XII;
CRYSTALLOGRAPHY;
TOPIRAMATE;
EXPRESSION;
COMPLEXES;
D O I:
10.1021/jm900914e
中图分类号:
R914 [药物化学];
学科分类号:
100701 ;
摘要:
In this paper, we present. a. new class of carbonic anhydrase (CA) inhibitor that was designed to selectively target the extracellular domains of the cancer-relevant CA isozymes. The aromatic moiety of the classical zinc binding sulfonamide CA inhibitors is absent from these compounds and instead they incorporate a hydrophilic mono- or disaccharide fragment directly attached to the sulfonamide group to give S-glycosyl primary sulfonamides (1-10). The inhibition properties of these compounds at the physiologically abundant human CA isozymes I and II and cancer-associated IX and XII were determined, and all compounds had moderate potency with KiS in the micromolar range. We present the crystal structures of anomeric sulfonamides 4, 7, and 10 and the sugar sulfamate drug topiramate in complex with human recombinant CA II. From these structures, we have obtained valuable insights into ligand-protein interactions of these novel carb ohydrate-based sulfonamides with CA.
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页码:6421 / 6432
页数:12
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