TY - JOUR
T1 - Sulfonamides incorporating 1,3,5-triazine moieties selectively and potently inhibit carbonic anhydrase transmembrane isoforms IX, XII and XIV over cytosolic isoforms i and II
T2 - Solution and X-ray crystallographic studies
AU - Carta, Fabrizio
AU - Garaj, Vladimir
AU - Maresca, Alfonso
AU - Wagner, Jason
AU - Avvaru, Balendu Sankara
AU - Robbins, Arthur H.
AU - Scozzafava, Andrea
AU - McKenna, Robert
AU - Supuran, Claudiu T.
N1 - Funding Information:
This research was financed in part by a 7th FP EU grant (METOXIA) to A.S. and C.T.S., and in part by an NIH (GM 25154) and Maren Foundation grant to R.M. R.M. would also like to thank the Centre of Structure Biology, University of Florida, for their continued support to help maintain the in-house X-ray facilities.
PY - 2011/5/15
Y1 - 2011/5/15
N2 - Reaction of cyanuryl chloride with d,l-amino acids and amino alcohols afforded a new series of triazinyl-substituted benzenesulfonamides incorporating amino acyl/hydroxyalkyl-amino moieties. Inhibition studies of physiologically relevant human carbonic anhydrase (CA, EC 4.2.1.1) isoforms, such as CA I, II, IX, XII and XIV with these compounds are reported. They showed moderate-weak inhibition of the cytosolic, offtarget isozymes CA I and II, but many of them were low nanomolar inhibitors of the transmembrane, tumor-associated CA IX and XII (and also of CA XIV). The X-ray crystal structure of two of these compounds in adduct with CA II allowed us to understand the features associated with this strong inhibitory properties and possibly also their selectivity. Two of these compounds were also investigated for the inhibition of other human isoforms, that is, hCA IV, VA, VB, VI, VII and XIII, as well as inhibitors of the fungal pathogenic CAs Nce103 (Candida albicans) and Can2 (Cryptococcus neoformans), showing interesting activity. The 1,3,5-triazinyl-substituted benzenesulfonamides constitute thus a class of compounds with great potential for obtaining inhibitors targeting both α-class mammalian, tumor-associated, and β-class from pathogenic organisms CAs.
AB - Reaction of cyanuryl chloride with d,l-amino acids and amino alcohols afforded a new series of triazinyl-substituted benzenesulfonamides incorporating amino acyl/hydroxyalkyl-amino moieties. Inhibition studies of physiologically relevant human carbonic anhydrase (CA, EC 4.2.1.1) isoforms, such as CA I, II, IX, XII and XIV with these compounds are reported. They showed moderate-weak inhibition of the cytosolic, offtarget isozymes CA I and II, but many of them were low nanomolar inhibitors of the transmembrane, tumor-associated CA IX and XII (and also of CA XIV). The X-ray crystal structure of two of these compounds in adduct with CA II allowed us to understand the features associated with this strong inhibitory properties and possibly also their selectivity. Two of these compounds were also investigated for the inhibition of other human isoforms, that is, hCA IV, VA, VB, VI, VII and XIII, as well as inhibitors of the fungal pathogenic CAs Nce103 (Candida albicans) and Can2 (Cryptococcus neoformans), showing interesting activity. The 1,3,5-triazinyl-substituted benzenesulfonamides constitute thus a class of compounds with great potential for obtaining inhibitors targeting both α-class mammalian, tumor-associated, and β-class from pathogenic organisms CAs.
KW - 1,3,5-Triazine
KW - Carbonic anhydrase
KW - Isoform IX, XII
KW - Isoform-selective inhibitor
KW - Sulfonamide
KW - X-ray crystallography
UR - http://www.scopus.com/inward/record.url?scp=79956195097&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=79956195097&partnerID=8YFLogxK
U2 - 10.1016/j.bmc.2011.04.005
DO - 10.1016/j.bmc.2011.04.005
M3 - Article
C2 - 21515057
AN - SCOPUS:79956195097
SN - 0968-0896
VL - 19
SP - 3105
EP - 3119
JO - Bioorganic and Medicinal Chemistry
JF - Bioorganic and Medicinal Chemistry
IS - 10
ER -