Novel Phosphoramidate Prodrugs of N-Acetyl-(d)-Glucosamine with Antidegenerative Activity on Bovine and Human Cartilage Explants

Abstract

(D)-Glucosamine and other nutritional supplements have emerged as safe alternative therapies for osteoarthritis (OA), a chronic and degenerative articular joint disease. In our preceding paper, a series of novel O-6 phosphate N-acetyl (d)-glucosamine prodrugs aimed at improving the oral bioavailability of N-acetyl-(d)-glucosamine as its putative bioactive phosphate form were shown to have greater chondroprotective activity in vitro when compared to the parent agent. In order to extend the SAR studies, this work focuses on the O-3 and O-4 phosphate prodrugs of N-acetyl-(d)-glucosamine bearing a 4-methoxy phenyl group and different amino acid esters on the phosphate moiety. Among the compounds, the (l)-proline amino acid-containing prodrugs proved to be the most active of the series, more effective than the prior O-6 compounds, and well processed in chondrocytes in vitro. Data on human cartilage support the notion that these novel O-3 and O-4 regioisomers may represent novel promising leads for drug discovery for osteoarthritis.

Synthesis of Phosphoramidate Prodrugs: ProTide Approach

“…After that the Pro-Tide technology was successfully and extensively applied to a high number of nucleoside phosphates endowed with antiviral and anticancer activity (Derudas et al, 2009(Derudas et al, , 2010aMehellou et al, 2009Mehellou et al, , 2010McGuigan et al, 2010aMcGuigan et al, ,b, 2012Meneghesso et al, 2012). The ProTide technology was also investigated for phosphonate prodrugs (Ballatore et al, 2001) and recently applied for the delivery of sugar monophospate as potential anti-osteoarthritic drugs (McGuigan et al, 2008;Serpi et al, 2012). Among several 2 -C-methylribonucleosides, the 2 -C-methylguanosine, showed great promise as potential therapies against the hepatitis C virus (HCV; Madela and McGuigan, 2012).…”

Kinase-independent phosphoramidate S1P 1 receptor agonist benzyl ether derivatives

“…Conditions: DCM, 0 °C -RT, 24 h, 77%. Reagents and conditions: (a) 8, NaH, DMF, 24 h, 77%; (b) 9, iPrMgCl, THF, -78 °C -RT, 3 h, 42%; (c) p-TsOH monohydrate, MeOH, 50 °C, 24 h, 85%; (d) KOH, EtOH, 90 °C, 24 h, 56%.The synthesis of phosphoramidate compounds was achieved using previously published procedures 23,24. A total of six different phosphoramidate benzyl ether derivatives (16 -21) were synthesised.…”

“…Stacked 31 P NMR spectra showing metabolism of 16 in human serum to the desired monophosphate over 12 hoursNeuronal Cell Lysate ExperimentNeuronal cell lysate and activator was used to conduct a cell lysate experiment following previously described experimental procedures 23,28,29. The main product of the processing of 16was the desired monophosphate.…”

ProTides of N-(3-(5-(2′-deoxyuridine))prop-2-ynyl)octanamide as potential anti-tubercular and anti-viral agents

“…To date, this approach has been widely applied mainly to antiviral 16 and anticancer nucleoside analogues 17 and more recently also to N-acetyl glucosamine to treat osteoarthritis. 18 Typically, two enzymatic cleavages are involved in the cellular bio-activation of antiviral and anticancer ProTides, either in the viral infected or human cancer cell. 19 Firstly, a carboxypeptidase-type enzyme may mediate the cleavage of the ester moiety.…”