C-nucleosides are composed of an aromatic moiety linked to a carbohydrate derivative thanks to a stable carbon-carbon bond rather than a hydrolysable carbon-nitrogen bond present in regular nucleosides. C-nucleosides are generally synthesized by two main approaches. In the first approach heterocyclic bases are built, starting from a functional group introduced at the anomeric position of the carbohydrate. The second approach is based on the direct attachment of aromatic or heterocylic moieties to the protected ribose derivative. Two C-nucleosides, tiazofurin and benzamide riboside, show a potent inhibitory activity against Inosine Monophosphate Dehydrogenase (IMPDH) when converted to their corresponding tiazofurin- and benzamide adenine dinucleotide (TAD and BAD). We will discuss the synthesis of TAD analogues containing a substituent at the C2 of adenine ring that inhibit IMPDH with Ki in 1-10 nM range. We will also report modified BAD analogues with inhibitory activity against NAD kinase and M. tuberculosis enoyl ACP reductase.

SYNTHESIS OF NAD ANALOGS AS SELECTIVE INHIBITORS OF INOSINE MONOPHOSPHATE DEHYDROGENASE

PETRELLI, Riccardo;
2007

Abstract

C-nucleosides are composed of an aromatic moiety linked to a carbohydrate derivative thanks to a stable carbon-carbon bond rather than a hydrolysable carbon-nitrogen bond present in regular nucleosides. C-nucleosides are generally synthesized by two main approaches. In the first approach heterocyclic bases are built, starting from a functional group introduced at the anomeric position of the carbohydrate. The second approach is based on the direct attachment of aromatic or heterocylic moieties to the protected ribose derivative. Two C-nucleosides, tiazofurin and benzamide riboside, show a potent inhibitory activity against Inosine Monophosphate Dehydrogenase (IMPDH) when converted to their corresponding tiazofurin- and benzamide adenine dinucleotide (TAD and BAD). We will discuss the synthesis of TAD analogues containing a substituent at the C2 of adenine ring that inhibit IMPDH with Ki in 1-10 nM range. We will also report modified BAD analogues with inhibitory activity against NAD kinase and M. tuberculosis enoyl ACP reductase.
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11581/202501
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