Stereoselective Synthesis and Antiviral Activity of Methyl-SubstitutedcycloSal-Pronucleotides

Abstract

Methyl-substituted cycloSal-pronucleotides of d4TMP were synthesized with high diastereoselectivities in satisfying chemical yields. The individual diastereomers were tested against HIV-1 and HIV-2 infected wild-type CEM/0 and HIV-2 infected thymidine kinase deficient CEM cells. All diastereomers tested showed significant antiviral activity in CEM/0 and strong activity in CEM/TK(-) cell cultures. The antiviral activities were strongly dependent on the chirality at the phosphate group and the position of the methyl-group(s) in the cycloSal moiety. In CEM/TK(-) cell cultures the difference in antiviral potency was found to be 7- to 20-fold. The stability of each diastereomer was studied in aqueous phosphate buffer and in CEM/0 cell extracts. Large differences in the half-lives were found. A comparison of the relative lipophilicity of the methyl-substituted cycloSal triesters was performed based on the retention times obtained by reversed phase HPLC. The results obtained clearly confirm the importance of a diastereoselective synthesis of cycloSal-pronucleotides.

Synthesis of Nucleoside Phosphate and Phosphonate Prodrugs

“…Although the reaction conditions worked well for unsubstituted salicylic alcohol, the same sequence was surprisingly not applicable to the synthesis of 3- 85 and 5- 87 methyl- cyclo Sal derivatives due to racemization of both the chiral phosphoramidate reagents and the final nucleoside prodrugs. This led the authors to investigate the other chiral auxiliaries 191a – e (Scheme 57).…”

Prodrugs of Phosphonates and Phosphates: Crossing the Membrane Barrier

“…Through controlled synthesis of the phosphorus stereocenter, and judicious placement of a methyl substituent on the aromatic ring, it was possible to observe 7- to 20-fold differences in the antiviral activity of d4TMP pro-drugs (e.g. 39 ) [74]. The biochemical and/or physiological basis for such significant differences in activity is/are not yet clear, but they clearly validate the effort devoted to diastereoselective syntheses and justify additional research into the cycloSal prodrugs.…”

Nucleoside Diphosphate Prodrugs: Nonsymmetric DiPPro-Nucleotides

“…3,4 The use of prodrug forms of phosphorylated nucleoside analogues (pronucleotides) can circumvent rate limiting steps within the metabolic pathway by bypassing at least one, if not several involved activating enzymes. 5,6 This task has been successfully achieved in the past for the intracellular delivery of monophosphates of nucleoside analogues using prodrug strategies such as the cycloSal-, [7][8][9] Sate-, 10,11 bisPOM-12 and phosphoramidate-nucleotide approaches. 13,14 Remarkably, in contrast to numerous examples of successful nucleoside monophosphate prodrug approaches for the bypass of nucleoside kinases, the development of nucleoside 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 diphosphate (NDP) prodrugs has been very rarely addressed.…”