Carbonic anhydrase inhibitors. Regioselective synthesis of novel 1-substituted 1,4-dihydro-4-oxo-3-pyridinesulfonamides and their inhibition of the human cytosolic isozymes I and II and transmembrane cancer-associated isozymes IX and XII
A series of 1-substituted 1,4-dihydro-4-oxo-3-pyridinesulfonamide ( 2– 16) have been synthesized and investigated as inhibitors of four isoforms of zinc enzyme carbonic anhydrase (CA, EC 4.2.1.1), that is the cytosolic ubiquitous CA I and II, and cancer-associated isozymes CA IX and XII. Against the...
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Veröffentlicht in: | European journal of medicinal chemistry 2010-09, Vol.45 (9), p.3656-3661 |
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Zusammenfassung: | A series of 1-substituted 1,4-dihydro-4-oxo-3-pyridinesulfonamide (
2–
16) have been synthesized and investigated as inhibitors of four isoforms of zinc enzyme carbonic anhydrase (CA, EC 4.2.1.1), that is the cytosolic ubiquitous CA I and II, and cancer-associated isozymes CA IX and XII. Against the human isozymes hCA I the new compounds showed inhibition constants in the range of 1.09–12.1 μM, against hCA II in the range of 50.5–172 nM, against hCA IX in the range of 5.2–118 nM, and against hCA XII in the range of 8.7–381 nM, respectively. Compounds
2,
3,
5–
9,
11,
13 and
14 showed excellent hCA IX inhibitory efficacy, with
K
Is = 5.2–11.0 nM, being much more effective as compared to the clinically used sulfonamides
AAZ,
MZA,
EZA,
DCP and
IND (
K
Is = 24–50 nM). Compounds
2,
3,
5–
9,
11 and
13 were also very effective hCA XII inhibitors (
K
Is = 8.7–45.2 nM) which are comparable or more effective than those clinically used
EZA and
DCP (
K
Is = 22 and 50 nM), respectively.
A novel 1-substituted 1,4-dihydro-4-oxo-3-pyridinesulfonamides have been synthesized and investigated as inhibitors of carbonic anhydrase isozymes hCA I, II, IX and XII. Some of them showed excellent hCA IX and XII inhibitory efficacy.
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ISSN: | 0223-5234 1768-3254 |
DOI: | 10.1016/j.ejmech.2010.05.011 |