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PDBsum entry 6eeh
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Lyase/lyase inhibitor
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PDB id
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6eeh
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References listed in PDB file
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Key reference
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Title
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4-Hydroxy-3-Nitro-5-Ureido-Benzenesulfonamides selectively target the tumor-Associated carbonic anhydrase isoforms IX and XII showing hypoxia-Enhanced antiproliferative profiles.
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Authors
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A.Nocentini,
E.Trallori,
S.Singh,
C.L.Lomelino,
G.Bartolucci,
L.Di cesare mannelli,
C.Ghelardini,
R.Mckenna,
P.Gratteri,
C.T.Supuran.
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Ref.
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J Med Chem, 2018,
61,
10860-10874.
[DOI no: ]
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PubMed id
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Abstract
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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.
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