Carbonic anhydrase inhibitors: Hypoxia-activatable sulfonamides incorporating disulfide bonds that target the tumor-associated isoform IX.
An approach for designing bioreductive, hypoxia-activatable carbonic anhydrase (CA, EC 4.2.1.1) inhibitors targeting the tumor-associated isoforms is reported. Sulfonamides incorporating 3,3'-dithiodipropionamide/2,2'-dithiodibenzamido moieties were prepared and reduced enzymatically/chemically in conditions present in hypoxic tumors, leading to thiols. The X-ray crystal structure of the most promising compound, 4-(2-mercaptophenylcarboxamido)benzenesulfonamide, which as disulfide showed a K(I) against hCA IX of 653 nM (in reduced form of 9.1 nM), in adduct with hCA II showed the inhibitor making favorable interactions with Gln92, Val121, Phe131, Leu198, Thr199, Thr200, Pro201, and Pro202, whereas the sulfamoyl moiety was coordinated to the Zn2+ ion. The same interactions were preserved in the adduct with hCA IX, but in addition, a hydrogen bond between the SH moiety of the inhibitor and the amide nitrogen of Gln67 was evidenced, which may explain the almost 2 times more effective inhibition of the tumor-associated isozyme over the cytosolic isoform.
De Simone
Giuseppina
G
Istituto di Biostrutture e Bioimmagini-CNR, Via Mezzocannone 16, 80134 Naples, Italy. gdesimone@unina.it
Vitale
Rosa Maria
RM
Di Fiore
Anna
A
Pedone
Carlo
C
Scozzafava
Andrea
A
Montero
Jean-Louis
JL
Winum
Jean-Yves
JY
Supuran
Claudiu T
CT
D000951:Antigens, Neoplasm / Q000737:chemistry*; D024402:Carbonic Anhydrase II / Q000737:chemistry; D000071231:Carbonic Anhydrase IX; D002257:Carbonic Anhydrase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry; D002256:Carbonic Anhydrases / Q000737:chemistry*; D018360:Crystallography, X-Ray; D004220:Disulfides / Q000737:chemistry*; D004789:Enzyme Activation; D006801:Humans; D006860:Hydrogen Bonding; D000860:Hypoxia / Q000201:enzymology; D007527:Isoenzymes / Q000737:chemistry / Q000378:metabolism; D008958:Models, Molecular; D015394:Molecular Structure; D009369:Neoplasms / Q000201:enzymology; D011355:Prodrugs / Q000138:chemical synthesis* / Q000737:chemistry; D011485:Protein Binding; D013329:Structure-Activity Relationship; D013438:Sulfhydryl Compounds / Q000138:chemical synthesis* / Q000737:chemistry; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000737:chemistry
C514064:4-(2-mercaptophenylcarboxamido)benzenesulfonamide; D000951:Antigens, Neoplasm; D002257:Carbonic Anhydrase Inhibitors; D004220:Disulfides; D007527:Isoenzymes; D011355:Prodrugs; D013438:Sulfhydryl Compounds; D013449:Sulfonamides; D024402:Carbonic Anhydrase II; C089226:CA9 protein, human; D000071231:Carbonic Anhydrase IX; D002256:Carbonic Anhydrases