A new class of NO-donor pro-drugs triggered by γ-glutamyl transpeptidase with potential for reno-selective vasodilatation

Abstract

This communication describes the synthesis of a new class of N-hydroxyguanidine (NHG) pro-drugs which release nitric oxide (NO), triggered by the action of γ-glutamyl transpeptidase (γ-GT), and have potential for the treatment of acute renal injury/failure (ARI/ARF).

Fig. 1

LCMS trace of 4b incubated in Krebs buffer at 37 °C for 1 h (a) without γ-GT and glutamyl acceptor Gly–gly, 4b is intact; (b) with γ-GT (100 mU mL⁻¹) and glutamyl acceptor Gly–gly (5 mM), 4b is deglutamylated to give the species 15.

Scheme 1

Approach to γ-GT triggered release of NHG 1 and the reno-selective release of nitric oxide.

Scheme 2

Cyclization of direct coupling of NHGs with γ-glutamyl residue(s).

Scheme 3

Design of Glu/Gaba linked γ-glutamyl NO-donor pro-drugs of NHG and hydroxamic acid.

Scheme 4

Design and synthesis of aminobenzyl linked γ-glutamyl NO-donor pro-drugs of NHG: (i) 4-aminobenzylalcohol, EEDQ, DCM, rt, 12 h, 85%; (ii) PBr₃, THF, 0 °C, 2 h, 87%; (iii) BocNHOH, NaH, THF, 0 °C, 4 h, 83%; (iv) CF₃CO₂H, DCM, 92%; (v) 9a R = Ph or 9b R = PhCH₂CH₂ or 9c R = furfuryl, Et₃N, DMAP, DCM, 38–53%; (vi) [Pd(PPh₃)₄], PhSiH₃, DCM, 37–89%.

Scheme 5

Synthesis of N-hydroxyformamidine and its glutamyl pro-drug: (i) Me₂NCH(OMe₂), reflux, 2 h, quantitative; (ii) NH₂OHHCl, MeOH, 63%; (iii) 8, THF, reflux, 29%; (iv) [Pd(PPh₃)₄], PhSiH₃, DCM, rt, 6 h, 53%.