Aryl H-phosphonates. 19. New anti-HIV pronucleotide phosphoramidate diesters containing amino- and hydroxypyridine auxiliaries (original) (raw)
Journal of Medicinal Chemistry, 2004
Two series of new lipophilic phosphonoformate and phosphonoacetate derivatives of AZT and d4T were synthesized and evaluated as anti-HIV agents. The efficacy of some of the synthesized compounds in cell cultures infected with HIV-1 was higher than that of the parent nucleosides and only slightly correlated to their stability in the phosphate buffer and human blood serum. The synthesized phosphonates are most probably prodrug forms of the corresponding nucleosides.
Synthetic applications of aryl H-phosphonates in nucleotide chemistry
Aryl nucleoside H-phosphonate diesters were found to be versatile synthetic intermediates for the preparation of various functionalized alkyl nucleoside H-phosphonates, dinucleoside H-phosphonates, and nucleoside H-phosphonamidates. SCHEME 1 Ar 2,4,6-trichlorophenyl; B heterocyclic base; Bz benzoyl; dmt 4,4′-O-dimethoxytrityl; Py pyridine; Pv pivaloyl; NEP 5,5-dimethyl-2-oxo-1,3,2-dioxaphosphinate-2-yl
Bioorganic & Medicinal Chemistry, 2009
Di-aryl nucleoside phosphotriesters have been explored as a new type of pronucleotides for the purpose of anti-HIV-1 therapy and efficient synthetic protocols, based on H-phosphonate chemistry, have been developed for the preparation of this class of compounds. It was found that anti-HIV-1 activity of the phosphotriesters bearing an antiviral nucleoside moiety (AZT, ddA) and also ddU was due, at least partially, to intracellular conversion into the corresponding nucleoside 5 0 -monophosphates, and their efficiency correlated well with the pK a values of the aryloxy groups present. j o u r n a l h o m e p a g e : w w w . e l s e v i e r . c o m / l o c a t e / b m c 4.1.5.10. 3 0 -Azido-3'-deoxythymidyn-5 0 -yl 2-chloropyridin-3-yl phosphate triethylammonium salt (4aj). Yield 0.14 g (71%). 1 H NMR (CDCl 3 ) d 11.87 (br s, 1H, exch. D 2 O), 9.00 (br s, 1H, exch. D 2 O), 8.07 (dd, J = 4.8 Hz, J = 1.5 Hz, 1H), 7.97 (dd, J = 8.4 Hz, J = 1.5 Hz, 1H), 7.66 (q, J = 0.9 Hz, 1H), 7.16 (dd, J = 8.4 Hz, J = 4.8 Hz, 1H), 6.26 (t, J = 6.6 Hz, 1H), 4.46-4.37 (m, 1H), 4.28-4.17 (m, 2H), 4.04-4.01 (m, 1H), 3.06 (q, J = 7.2 Hz, 6H), 2.40-2.25 (m, 2H), 1.89 (d, J = 0.9 Hz, 3H), 1.32 (t, J = 7.2 Hz, 9H); 31 P NMR (CDCl 3 ) d À5.99 (t, 3 J HP = 6.4 Hz); HRMS [MÀEt 3 NH + ] À : 457.0450, calcd for C 15 H 15 N 6 O 7 PCl: 457.0429. 4.1.5.11. 3 0 -Azido-3 0 -deoxythymidyn-5'-yl 5-chloropyridin-3-yl phosphate triethylammonium salt (4ak). Yield 0.15 g (79%). 1 H NMR (CDCl 3 ) d 11.86 (br s, 1H, exch. D 2 O), 8.82 (br s, 1H, exch. D 2 O), 8.45 (d, J = 1.5 Hz, 1H), 8.26 (d, J = 1.8 Hz, 1H), 7.71 (dd, J = 1.8 Hz, J = 1.5 Hz, 1H), 7.62 (q, J = 0.9 Hz, 1H), 6.26 (t, J = 6.3 Hz, 1H), 4.40-4.34 (m, 1H), 4.28-4.14 (m, 2H), 4.01 (br m, 1H), 3.06 (q, J = 7.2 Hz, 6H), 2.42-2.25 (m, 2H), 1.88 (d, J = 0.9 Hz, 3H), 1.34 (t, J = 7.2 Hz, 9H). 31 P NMR (CDCl 3 ) d -5.63 (t, 3 J HP = 6.4 Hz); HRMS [MÀEt 3 NH + ] À : 457.0420, calcd for C 15 H 15 N 6 O 7 PCl: 457.0429. 4.1.5.12. 2 0 ,3 0 -Dideoxyuridin-5'-yl phenyl phosphate triethylammonium salt (4ba). Yield 0.07 g (76%). 1 H NMR (CDCl 3 ) d 11.94 (br s, 1H, exch. D 2 O), 9.83 (br s, 1H, exch. D 2 O), 7.84 (d, J = 8.1 Hz, 1H), 7.22-7.15 (m, 4H), 6.98-6.93 (m, 1H), 6.00-5.96 (m, 1H), 5.51 (d, J = 8.1 Hz, 1H), 4.24-4.18 (m, 2H), 4.07-4.00 (m, 1H), 2.97 (q, J = 7.2 Hz, 6H), 2.29-2.22 (m, 1H), 1.97-1.87 (m, 3H), 1.24 (t,, J = 7.2 Hz, 9H). 31 P NMR (CDCl 3 ) d À5.83 (t, 3 J HP = 5.5 Hz); HRMS [MÀEt 3 NH + ] À : 367.0682, calcd for C 15 H 16 N 2 O 7 P: 367.0700. 4.1.5.13. 2 0 ,3 0 -Dideoxyuridin-5 0 -yl pyridin-3-yl phosphate triethylammonium salt (4bb). Yield 0.07 g (72%). 1 H NMR (CDCl 3 ) d 11.73 (br s, 1H, exch. D 2 O), 10.16 (br s, 1H, exch. D 2 O), 8.45 (br s, 1H), 8.2 (d, J = 4.4 Hz, 1H), 7.80 (d, J = 8.4 Hz, 1H), 7.62 (d, J = 8.8 Hz, 1H), 7.17 (dd, J = 8.8 and 4.4 Hz, 1H), 5.97-5.95 (m, 1H), 5.53 (d, J = 8.4 Hz, 1H), 4.21-4.17 (m, 2H), 4.05-4.00 (m, 1H), 2.99 (q, J = 7.2 Hz, 6H), 2.29-2.24 (m, 1H), 1.97-1.87 (m, 3H), 1.24 (t, J = 7.2 Hz, 9H). 31 P NMR (CDCl 3 ) d À5.88 (t, 3 J HP = 5.5 Hz); HRMS [MÀEt 3 NH + ] À : 368.0642, calcd for C 14 H 15 N 3 O 7 P: 368.0648.
Bioorganic & Medicinal Chemistry, 2006
Aryl nucleoside 5 0 -H-phosphonates 4 bearing AZT or 2 0 ,3 0 -dideoxyuridine moieties were subjected to reaction with various aromatic aldehydes to produce nucleoside 5 0 -a-hydroxyphosphonate derivatives 2 as potential anti-HIV agents. Stability of the title compounds in cell culture media was investigated and three distinct decomposition pathways were identified. The anti-HIV activity of hydroxyphosphonates 2 correlates well with the type and extent of their chemical or enzymatic degradation in culture medium (RPMI 1640 containing 10% FBS), suggesting that aryl nucleoside 5 0 -hydroxyphosphonates 2 act as depot forms of the parent antiviral nucleosides. 0.1 M PB, pH 7.4 or RPMI/FBS AZT = 3'-deoxy-3'-azidothymidin-5'-yl Ph = phenyl Ar = 4-methoxyphenyl PB = 0.1 M phosphate buffer pH 7.4 FBS = fetal bovine serum RPMI = RPMI 1640 Scheme 1. Decomposition of 1 in PB, pH 7.4, and RPMI/FBS 10% (v/v) 37°C.
New prodrugs of two pyrimidine acyclic nucleoside phosphonates: Synthesis and antiviral activity
Bioorganic & Medicinal Chemistry, 2017
New 2,4-diamino-6-[2-(phosphonomethoxy)ethoxy]pyrimidine (PMEO-DAPy) and 1-[2-(phosphonomethoxy)ethyl]-5-azacytosine (PME-5-azaC) prodrugs were prepared with a pro-moiety consisting of carbonyloxymethyl esters (POM, POC), alkoxyalkyl esters, amino acid phosphoramidates and/or tyrosine. The activity of the prodrugs was evaluated in vitro against different virus families. None of the synthesized prodrugs demonstrated activity against RNA viruses but some of them proved active against herpesviruses [including herpes simplex virus (HSV), varicella-zoster virus (VZV), and human cytomegalovirus (HCMV)]. The bis(POC) and the bis(amino acid) phosphoramidate prodrugs of PMEO-DAPy inhibited herpesvirus replication at lower doses than the parent compound although the selectivity against HSV and VZV was only slightly improved compared to PMEO-DAPy. The mono-octadecyl ester of PME-5-azaC emerged as the most potent and selective PME-5-azaC prodrug against HSV, VZV and HCMV with EC 50 's of 0.15-1.12 mM while PME-5-azaC only had marginal anti-herpesvirus activity. Although the bis (hexadecylamido-L-tyrosyl) and the bis(POM) esters of PME-5-azaC were also very potent anti-herpesvirus drugs, these were less selective than the mono-octadecyl ester prodrug.
Bioorganic & Medicinal Chemistry, 2006
A series of phosphoramidate and phosphate prodrugs of DOT were synthesized via dichlorophosphate or H-phosphonate chemistry and evaluated for their anti-HIV activity against LAI M184V mutants in PBM cells as well as for their cytotoxicity. The antiviral and cytotoxic profiles of the prodrugs were compared with that of the parent compound (DOT), and it was found that four aryl phosphoramidates 5, 18, 20, and 26 showed a significant enhancement (8-to 12-fold) in anti-HIV activity without cytotoxicity. Chemical stability of these prodrugs was evaluated in phosphate buffer at pH values of biological relevance (i.e., pH 2.0 and 7.4). Enzymatic hydrolysis was also studied in esterase or lipase in buffer solution. Chemical stability studies indicate that the phosphoramidates have good chemical stability at pH 2.0 and at pH 7.4 phosphate buffer. Phosphoramidate prodrugs were hydrolyzed in vitro by esterase or lipase and found to be better substrates for lipases than for esterases. 1,3-Diol cyclic phosphates showed potent anti-HIV activity without increasing the cytotoxicity compared with that of DOT and have good chemical and enzymatic stability. Long-chain lipid phosphates, although showed potent anti-HIV activity, exhibited increased cytotoxicity.