(2-Benzyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-8-yl)-acetic acid: An aldose reductase inhibitor and antioxidant of zwitterionic nature
Chemical structure of (2-benzyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-8-yl)-acetic acid (1) and stobadine [(−)-cis-2,8-dimethyl-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole] (2). Novel carboxymethylated pyridoindoles, characterized by antioxidant activity combined with the ability to inhibit al...
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| Published in: | Bioorganic & medicinal chemistry Vol. 19; no. 23; pp. 7181 - 7185 |
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| Main Authors: | , , , , , |
| Format: | Journal Article |
| Language: | English |
| Published: |
Amsterdam
Elsevier Ltd
01-12-2011
Elsevier |
| Subjects: | |
| Online Access: | Get full text |
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| Summary: | Chemical structure of (2-benzyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-8-yl)-acetic acid (1) and stobadine [(−)-cis-2,8-dimethyl-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole] (2).
Novel carboxymethylated pyridoindoles, characterized by antioxidant activity combined with the ability to inhibit aldose reductase, represent an example of a multitarget approach to the treatment of diabetic complications – severe diabetes-related health disorders of multifunctional nature. One of the novel carboxymethylated pyridoindoles, (2-benzyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-8-yl)-acetic acid (compound 1), was found to inhibit aldose reductase with the IC50 value 18.2±1.2μM. Owing to aldose reductase pharmacophore requirements for an acidic proton, most aldose reductase inhibitors contain an acetic acid moiety, ionized at physiological pH, resulting in poor bioavailability of the drugs. The presence of a basicity center at the tertiary nitrogen of the carboxymethylated pyridoindoles, in addition to the acidic carboxylic function, predisposes these compounds to form double-charged zwitterionic species. The zwitterionic nature of compound 1 may remarkably affect its pH-lipophilicity profile allowing for increased membrane penetration in the pH region around its isoelectric point, which lies close to the physiological pH 7.4. In the first part of this study, the presence of zwitterionic species was experimentally proved by the concentration-dependent effect of sodium 1-hexanesulphonate on the distribution profile of compound 1. Then a series of experiments was performed in the cellular system of isolated erythrocytes in vitro. Isolated rat erythrocytes exposed to peroxyl radicals, generated in the solution by decomposition of the hydrophilic azoinitiator AAPH or intracellularly by decay of lipophilic t-BuOOH, underwent progressive hemolysis. The onset of the hemolysis was shifted from the starting zero point by the time interval assigned as a lag period. In the presence of compound 1 the lag period was significantly prolonged. Finally, under conditions of a short-term experiment in STZ-diabetic rats in vivo, increase in sorbitol levels in erythrocytes was recorded. Compound 1 administered in the dose 50mg/kg/day (i.g.) significantly decreased the sorbitol level in the erythrocytes. To conclude, the physico-chemical proof of the zwitterionic nature of compound 1 was established and the results obtained in isolated red blood cells indicated good cellular availability of the compound. In addition, in diabetic rats, sorbitol accumulation in red blood cells was significantly inhibited by compound 1 administered intra-gastrically, suggesting its ready uptake into the central compartment. The zwitterionic principle thus may have significant consequences for increased bioavailability of drugs bearing an acidic function. |
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| Bibliography: | http://dx.doi.org/10.1016/j.bmc.2011.09.053 ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 23 |
| ISSN: | 0968-0896 1464-3391 |
| DOI: | 10.1016/j.bmc.2011.09.053 |