10 Feb

Aryl Phosphate Derivatives of Bromo-Methoxy-Azidothymidine: RESULTS(2)

RESULTS(2)Aryl Phosphate Derivatives of 5-Bromo-6-Methoxy-AZT Exhibited Potent Anti-HIV and Spermicidal Activities

Next, novel aryl phosphate derivatives of compound WHI-01 were synthesized by phosphorochloridate chemistry and examined for their anti-HIV efficacy in cell culture and spermicidal activity by CASA (Figs. 2 and 3). Compound WHI-04 with the unsubstituted aryl moiety at the R4 position elicited 3-fold greater spermicidal activity than WHI-01. Introduction of a p-methoxy (compound WHI-05, EC50 = 29 ^M), p-fluoro (compound WHI-06, EC50 = 15 ^M), or p-bromo (compound WHI-07, EC50 = 6 ^M) substituent at the R4 position in the aryl moiety further enhanced the spermicidal activity with an order of potentiation p-bromo > p-fluoro > p-methoxy Interestingly, the p-bromo substitution at the R4 position of the aryl moiety was also associated with a significant gain in anti-HIV function. buy ampicillin

The p-methoxy-substituted aryl phosphate derivative WHI-05 (5-bromo-6-methoxy-5,6-dihydro-3′-azidothy-midine-5′-(p-methoxyphenyl) methoxyalaninyl phosphate) had an EC50 value of 29 ^M in sperm motility assays and an IC50 value of 0.05 ^M in HIV replication assays.
Fig2Aryl Phosphate Derivatives
FIG. 2. Structure-activity relationships affecting the anti-HIV and spermicidal activity of aryl phosphate derivatives of 5-bromo-6-methoxy-AZT. Nine new derivatives of compound WHI-01 (WHI-compounds 4-12) were synthesized by phosphorochloridate chemistry. IC50 values were calculated from the concentration-response curves of decreases in HIV-1 replication in p24 antigen production assays. EC50 values calculated from the concentration-response curves for group B compounds are shown. EC50 values are mean of three independent experiments. NA, not applicable.

Fig3Aryl Phosphate Derivatives
FIG. 3. A) Concentration-dependent inhibition of sperm motility by 5-bromo-6-methoxy-AZT derivatives. The highly motile fraction of sperm was incubated for 3 h with increasing concentrations (4.6-300 ^M) of AZT, WHI compounds 01, 02, 03, 05, 07, 08, and 09, or 1% dMsO in the assay medium, and the percentage of motile sperm was evaluated by CASA. Each data point represents the mean from three independent experiments. B) Time-dependent sperm immobilization by bromo-methoxy-AZT derivatives. Motile sperm were incubated at 37°C in 0.5 ml of assay medium in the presence of 200 ^M WHI-01 or 100 ^M each of WHI-03, WHI-05, WHI-07, and N-9 or 1% DMSO alone. At timed intervals, sperm motility was assessed by CASA. For WHI-01, CASA was performed every 20 min for 150 min; for N-9, every 15 min for 120 min; for WHI-05, every 10 min for 70 min; and for WHI-03 and WHI-07, every 5 min for 40 min. Each data point represents the mean from three independent experiments. In A and B, the SD values were less than 10% of the mean values.

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