Expedient synthesis and biological evaluation of alkenyl acyclic nucleoside phosphonate prodrugs

Abstract

The importance of phosphonoamidate prodrugs (ProTides) of acyclic nucleoside phosphonate (ANPs) is highlighted by the approval of Tenofovir Alafenamide Fumarate for the treatment of HIV and HBV infections. In the present paper we are reporting an expedient, one-pot, two-steps synthesis of allyl phosphonoamidates and diamidates that offers a time saving strategy when compared to literature methods. The use of these substrates in the cross metathesis reactions with alkenyl functionalised thymine and uracil nucleobases is reported. ANPs prodrugs synthesized via this methodology were evaluated for their antiviral activities against DNA and RNA viruses. It is anticipated that the use of 5,6,7,8-tetrahydro-1-napthyl as aryloxy moiety is capable to confer antiviral activity among a series of otherwise inactive uracil ProTides.

Cytotoxicity of phosphoramidate, bis-amidate and cycloSal prodrug metabolites against tumour and normal cells

“…Both ED 50 values are within reported concentration ranges used for the in vitro biological evaluation of phosphoramidate prodrugs. 17,18,28…”

“…Both ED 50 values are within reported concentration ranges used for the in vitro biological evaluation of phosphoramidate prodrugs. 17,18,28 Interestingly, 2-naphthol showed 4-fold greater cytotoxicity on BxPC3 cells than 1-naphthol as determined using real time xCELLigence monitoring (Fig. 5).…”

“…Furthermore, these concentrations are within the reported maximum plasma concentrations of several FDA approved anti-cancer agents. [17][18][19][20]28,32 The concentration of prodrug metabolite reached is influenced by the rate of metabolism. For example, phosphoramidate derivatives of ManNAc-6phosphate were metabolised by 80-90% within 2 hours in human serum.…”

Efficient Synthesis of Phosphonamidates through One‐Pot Sequential Reactions of Phosphonites with Iodine and Amines

“…Several strategies have been developed for the synthesis of phosphonamidates, including (1) the classic aminolysis of phosphonochloridates from pre‐generated phosphonic acid diesters or monoesters with chlorinating reagents [1b,c, 2a,b, 3, 7a, 8] (Scheme 1 a); (2) Atherton–Todd reaction between amines and H‐phosphinates in the presence of CCl 4 or Cl 2 [7b,c, 9] (Scheme 1 b); (3) direct coupling of amines and phosphonic acids or salts in the presence of PPh 3 and 2,2′‐dithiodipyridine or other coupling reagents [1d–h, 4, 10] (Scheme 1 c); (4) Staudinger phosphonite reaction of phosphonites and organic azides [11] (Scheme 1 d). These methods have their own advantages as well as some major disadvantages.…”