6ebe: Difference between revisions
New page: '''Unreleased structure''' The entry 6ebe is ON HOLD Authors: Singh, S., McKenna, R., Supuran, C.T., Nocentini, A., Lomelino, C., Lucarini, E., Bartolucci, G., Mannelli, L.D.C., Ghelard... |
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The | ==Bioreductive 4-hydroxy-3-nitro-5-ureido-benzenesulfonamides selectively target the tumor-associated carbonic anhydrase isoforms IX and XII and show hypoxia-enhanced cytotoxicity against human cancer cell lines.== | ||
<StructureSection load='6ebe' size='340' side='right'caption='[[6ebe]], [[Resolution|resolution]] 1.88Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[6ebe]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6EBE OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6EBE FirstGlance]. <br> | |||
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.88Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=J3V:4-hydroxy-3-nitro-5-({[4-(trifluoromethyl)phenyl]carbamoyl}amino)benzene-1-sulfonamide'>J3V</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr> | |||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=6ebe FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6ebe OCA], [https://pdbe.org/6ebe PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6ebe RCSB], [https://www.ebi.ac.uk/pdbsum/6ebe PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6ebe ProSAT]</span></td></tr> | |||
</table> | |||
== Disease == | |||
[https://www.uniprot.org/uniprot/CAH2_HUMAN CAH2_HUMAN] Defects in CA2 are the cause of osteopetrosis autosomal recessive type 3 (OPTB3) [MIM:[https://omim.org/entry/259730 259730]; also known as osteopetrosis with renal tubular acidosis, carbonic anhydrase II deficiency syndrome, Guibaud-Vainsel syndrome or marble brain disease. Osteopetrosis is a rare genetic disease characterized by abnormally dense bone, due to defective resorption of immature bone. The disorder occurs in two forms: a severe autosomal recessive form occurring in utero, infancy, or childhood, and a benign autosomal dominant form occurring in adolescence or adulthood. Autosomal recessive osteopetrosis is usually associated with normal or elevated amount of non-functional osteoclasts. OPTB3 is associated with renal tubular acidosis, cerebral calcification (marble brain disease) and in some cases with mental retardation.<ref>PMID:1928091</ref> <ref>PMID:1542674</ref> <ref>PMID:8834238</ref> <ref>PMID:9143915</ref> <ref>PMID:15300855</ref> | |||
== Function == | |||
[https://www.uniprot.org/uniprot/CAH2_HUMAN CAH2_HUMAN] Essential for bone resorption and osteoclast differentiation (By similarity). Reversible hydration of carbon dioxide. Can hydrate cyanamide to urea. Involved in the regulation of fluid secretion into the anterior chamber of the eye.<ref>PMID:10550681</ref> <ref>PMID:11831900</ref> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Human carbonic anhydrases (CA, EC, 4.2.1.1) IX and XII are overexpressed in cancer cells as adaptive response to hypoxia and acidic conditions characteristic of many tumors. In addition, hypoxia facilitates the activity of specific oxido-reductases that may be exploited to selectively activate bioreductive prodrugs. Here, new selective CA IX/XII inhibitors, as analogues of the antitumor phase II drug SLC-0111 are described, namely ureido-substituted benzenesulfonamides appended with a nitro-aromatic moiety to yield an antiproliferative action increased by hypoxia. These compounds were screened for the inhibition of the ubiquitous hCA I/II and the target hCA IX/XII. Six X-ray crystallographies with CA II and IX/mimic allowed for the rationalization of the compounds inhibitory activity. The effects of some such compounds on the viability of HT-29, MDA-MB-231, and PC-3 human cancer cell lines in both normoxic and hypoxic conditions were examined, providing the initiation toward the development of hypoxia-activated antitumor CAIs. | |||
4-Hydroxy-3-nitro-5-ureido-benzenesulfonamides Selectively Target the Tumor-Associated Carbonic Anhydrase Isoforms IX and XII Showing Hypoxia-Enhanced Antiproliferative Profiles.,Nocentini A, Trallori E, Singh S, Lomelino CL, Bartolucci G, Di Cesare Mannelli L, Ghelardini C, McKenna R, Gratteri P, Supuran CT J Med Chem. 2018 Nov 28. doi: 10.1021/acs.jmedchem.8b01504. PMID:30433782<ref>PMID:30433782</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
[[Category: | <div class="pdbe-citations 6ebe" style="background-color:#fffaf0;"></div> | ||
[[Category: Ghelardini | |||
[[Category: | ==See Also== | ||
[[Category: | *[[Carbonic anhydrase 3D structures|Carbonic anhydrase 3D structures]] | ||
[[Category: | == References == | ||
[[Category: | <references/> | ||
[[Category: | __TOC__ | ||
[[Category: | </StructureSection> | ||
[[Category: | [[Category: Homo sapiens]] | ||
[[Category: | [[Category: Large Structures]] | ||
[[Category: Bartolucci G]] | |||
[[Category: Ghelardini C]] | |||
[[Category: Gratteri P]] | |||
[[Category: Lomelino C]] | |||
[[Category: Lucarini E]] | |||
[[Category: Mannelli LDC]] | |||
[[Category: McKenna R]] | |||
[[Category: Nocentini A]] | |||
[[Category: Singh S]] | |||
[[Category: Supuran CT]] | |||