7/30/2019 Galli Ubaldina

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SYNTHESIS AND BIOLOGICAL EVALUATION OF ANALOGUES OF FK866, A

POTENT INHIBITOR OF HUMAN NMPRTase, A CRUCIAL ENZYME IN THE

SALVAGE PATHWAY OF NAD+

BIOSYNTHESIS

Galli Ubaldina; Tron Gian Cesare; Genazzani Armando A.

Dipartimento di Scienze Chimiche, Alimentari, Farmaceutiche e Farmacologiche, Universit degli Studi del

Piemonte Orientale, Via Bovio 6, 28100 Novara, Italy.

Galli@pharm.unipmn.it

Nicotinamide adenine dinucleotide (NAD+) plays important roles in many cellular processes, both as a coenzyme

for redox reactions and as a substrate in several biochemical reactions, including mono- and poly-ADP-

ribosylation, protein deacetylation, and ADP-ribose cyclization.1

Over the past few decades, it has been shown that enzymes involved in NAD+ metabolism are attractive targetsin medicinal chemistry against a variety of human diseases including cancer, multiple sclerosis, and

neurodegeneration.1

Nicotinamide phosphoribosyltranferase (NMPRTase) is a crucial enzyme in the salvage pathway of NAD+

biosynthesis, regulating NAD+

levels in cells undergoing substantial NAD+

turnover. Tumoral cells have a highrate of NAD

+turnover due to an elevated ADP-ribosylation activity, predominantly mediated by poly(ADP-

ribose) polymerases (PARPs) and for this reason the NMPRTase expression is upregulated.FK866 is a potent highly specific competitive inhibitor of NMPRTase, which reduces NAD + levels in tumoral

cells and ultimately causes cell death with little toxicity to normal cells.1

This compound (now renamed APO866) is in Phase II clinical trials against cancer.

Given the interest in FK866 and the therapeutic potential of new analogues, we have replaced the amide bond

with a 1,4-disubstituted triazole ring, as it has been postulated that this substitution is bioisosteric.2

Triazole analogues were synthesized using the click chemistry copper-catalyzed [3+2] azide-alkyne

cycloaddition.3

The simplicity of this reaction coupled with its amenability to parallel synthesis allowed the generation of a

library of 1,4-disubstituted triazole analogues of FK866. The compounds were tested both for their ability to

deplete intracellular NAD+ levels and to induce cytotoxicity. Our data show that some triazole-analogues retain

activity, showing that the triazole ring is well tolerated into the binding site.4

NO

HN

Triazole replacement

FK866

clickingNADlevelsoff!

O

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1. Khan, J. A.; Forouhar, F.; Tao, X.; Tong, L.Expert Opin. Ther. Targets 2007, 11, 695-705.

2. a) Kolb, H. C.; Sharpless, K. B. Drug Discovery Today 2003, 8, 1128-1137; b) Tron, G. C.; Pirali, T.;

Billington, R. A.; Canonico, P. L.; Sorba, G.; Genazzani, A. A.Med. Res.Rev.2008, 28, 278-308.

3. Rostovtsev, V.; Green, L. G.; Fokin, V. V.; Sharpless, K. B.Angew. Chem. Int. Ed.2002, 41, 2596-2599.

4. Galli, U.; Ercolano, E.; Carraro, L.; Blasi Roman, C. R.; Sorba, G.; Canonico, P. L.; Genazzani, A. A.; Tron,G. C.; Billington, R. A. ChemMedChem. 2008, 3, 771-779.