11020282

Source:http://linkedlifedata.com/resource/pubmed/id/11020282

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Predicate	Object
rdf:type	pubmed:Citation
lifeskim:mentions	umls-concept:C0002520, umls-concept:C0007028, umls-concept:C0014442, umls-concept:C0021469, umls-concept:C0022173, umls-concept:C0043481, umls-concept:C0178696, umls-concept:C0243077, umls-concept:C0623362, umls-concept:C0871161, umls-concept:C0919336, umls-concept:C1513016, umls-concept:C1551336
pubmed:issue	20
pubmed:dateCreated	2000-10-24
pubmed:abstractText	The 14 different carbonic anhydrase (CA, EC 4.2.1.1) isozymes as well as the 23 different matrix metalloproteinases (MMPs) isolated up to now in higher vertebrates play important physiological functions in these organisms. Unsubstituted sulfonamides act as high-affinity inhibitors for the first type of these enzymes, whereas hydroxamates strongly inhibit the latter ones. Since the active site geometry around the zinc ion in these two types of metalloenzymes is rather similar, we tested whether sulfonylated amino acid hydroxamates of the type RSO(2)NX-AA-CONHOH (X = H, benzyl, substituted benzyl; AA = amino acid moiety, such as Gly, Ala, Val, Leu) with well-known inhibitory properties against MMPs and Clostridium histolyticum collagenase (ChC, another zinc enzyme related to the MMPs) might also act as CA inhibitors. We also investigated whether N-hydroxysulfonamides of the type RSO(2)NHOH (which are effective CA inhibitors) inhibit MMPs and ChC. Here we report several potent sulfonylated amino acid hydroxamate CA inhibitors (with inhibition constants in the range of 5-40 nM, against the human isozymes hCA I and hCA II, and 10-50 nM, against the bovine isozyme bCA IV), as well as preliminary SAR for this new class of non-sulfonamide CA inhibitors. Some N-hydroxysulfonamides also showed inhibitory properties (in the micromolar range) against MMP-1, MMP-2, MMP-8, MMP-9, and ChC. Thus, the SO(2)NHOH group is a new zinc-binding function for the design of MMP inhibitors. Both CA as well as MMPs are involved, among others, in carcinogenesis and tumor invasion processes. On the basis of these findings, we suggest that the mechanism of antitumor action with some hydroxamate inhibitors might also involve inhibition of some CA isozymes (such as CA IX, CA XII, and CA XIV) present only in tumor cell membranes, in addition to collagenases/gelatinases of the MMP type. Our data also suggest that it should be possible to develop dual enzyme inhibitors that would strongly inhibit both these metalloenzymes, CAs and MMPs, based on the nature of the R, AA, and X moieties in the above formula. Compact X (such as H) and AA (such as Gly) moieties favor CA over MMP inhibition, whereas bulkier X (benzyl, substituted benzyl, etc.) and AA (such as Val, Leu) moieties and substituted-aryl R groups are advantageous for obtaining potent MMP and ChC inhibitors, which show lower affinity for CA.
pubmed:language	eng
pubmed:journal	http://linkedlifedata.com/resource/pubmed/journal/9716531
pubmed:citationSubset	IM
pubmed:chemical	http://linkedlifedata.com/resource/pubmed/chemical/Amino Acids, http://linkedlifedata.com/resource/pubmed/chemical/Carbonic Anhydrase Inhibitors, http://linkedlifedata.com/resource/pubmed/chemical/Carbonic Anhydrases, http://linkedlifedata.com/resource/pubmed/chemical/Cobalt, http://linkedlifedata.com/resource/pubmed/chemical/Collagenases, http://linkedlifedata.com/resource/pubmed/chemical/Hydroxamic Acids, http://linkedlifedata.com/resource/pubmed/chemical/Matrix Metalloproteinase 1, http://linkedlifedata.com/resource/pubmed/chemical/Matrix Metalloproteinase 2, http://linkedlifedata.com/resource/pubmed/chemical/Matrix Metalloproteinase 8, http://linkedlifedata.com/resource/pubmed/chemical/Matrix Metalloproteinase 9, http://linkedlifedata.com/resource/pubmed/chemical/Protease Inhibitors, http://linkedlifedata.com/resource/pubmed/chemical/Sulfonamides, http://linkedlifedata.com/resource/pubmed/chemical/Sulfones, http://linkedlifedata.com/resource/pubmed/chemical/Zinc
pubmed:status	MEDLINE
pubmed:month	Oct
pubmed:issn	0022-2623
pubmed:author	pubmed-author:ScozzafavaAA, pubmed-author:SupuranC TCT
pubmed:issnType	Print
pubmed:day	5
pubmed:volume	43
pubmed:owner	NLM
pubmed:authorsComplete	Y
pubmed:pagination	3677-87
pubmed:dateRevised	2006-11-15
pubmed:meshHeading	pubmed-meshheading:11020282-Amino Acids, pubmed-meshheading:11020282-Animals, pubmed-meshheading:11020282-Carbonic Anhydrase Inhibitors, pubmed-meshheading:11020282-Carbonic Anhydrases, pubmed-meshheading:11020282-Cattle, pubmed-meshheading:11020282-Clostridium, pubmed-meshheading:11020282-Cobalt, pubmed-meshheading:11020282-Collagenases, pubmed-meshheading:11020282-Humans, pubmed-meshheading:11020282-Hydroxamic Acids, pubmed-meshheading:11020282-Matrix Metalloproteinase 1, pubmed-meshheading:11020282-Matrix Metalloproteinase 2, pubmed-meshheading:11020282-Matrix Metalloproteinase 8, pubmed-meshheading:11020282-Matrix Metalloproteinase 9, pubmed-meshheading:11020282-Protease Inhibitors, pubmed-meshheading:11020282-Spectrophotometry, pubmed-meshheading:11020282-Structure-Activity Relationship, pubmed-meshheading:11020282-Sulfonamides, pubmed-meshheading:11020282-Sulfones, pubmed-meshheading:11020282-Zinc
pubmed:year	2000
pubmed:articleTitle	Carbonic anhydrase and matrix metalloproteinase inhibitors: sulfonylated amino acid hydroxamates with MMP inhibitory properties act as efficient inhibitors of CA isozymes I, II, and IV, and N-hydroxysulfonamides inhibit both these zinc enzymes.
pubmed:affiliation	Laboratorio di Chimica Inorganica e Bioinorganica, Università degli Studi, Via Gino Capponi 7, I-50121 Florence, Italy.
pubmed:publicationType	Journal Article, Research Support, Non-U.S. Gov't