09 Feb

Aryl Phosphate Derivatives of Bromo-Methoxy-Azidothymidine: RESULTS(1)

5-Bromo 6-Methoxy-Substituted Analogues of AZT Had Spermicidal Activity

The effects of several AZT analogues and derivatives on human sperm function and HIV replication in HIV-infected human PBMC were examined. Exposure of the highly motile fraction of human sperm to AZT, which inhibited HIV-1 replication in human PBMC in vitro with an IC50 value of 0.006 ^M, did not affect sperm motility even at concentrations as high as 300 ^M (Fig. 1). Further, sperm motion kinematics using CASA (Hamilton Thorne version 10) confirmed that AZT treatment did not alter the sperm motion parameters, such as the progressive motility, track speed, path velocity, straight-line velocity, straightness of the swimming pattern, linearity of the sperm tracks, beat-cross frequency, and the amplitude of lateral sperm head displacement. buy diabetes drugs

Introduction of a bromo at the 5-position (R2) and methoxy at the 6-position (R3) on the thymine base ring of AZT to yield 5-bromo-6-methoxy-5,6-dihydro-AZT (compound WHI-01) resulted in gain of significant spermicidal (as determined by sperm motility assay) function (EC50 = 104 ^M) without decreasing the anti-HIV activity (Fig. 1). Replacement of the azide group (R1) in the pentose ring with an NH2 group (compound WHI-03) substantially enhanced the spermicidal activity (EC50 = 12 ^M), but it also caused a 50-fold loss in the anti-HIV activity. The addition of bromo and methoxy functional groups was essential for the spermicidal activity of WHI-03 since 3′-amino-3 ‘-deoxythymidine (compound WHI-02), which was used as a control, was not spermicidal (EC50 > 300 ^M) (Fig. 1).
Fig1Aryl Phosphate Derivatives
FIG. 1. Anti-HIV and spermicidal activity profiles of bromo-methoxy-AZT analogues. The inhibitory effects of the listed compounds on the replication of HIV-1 in human PBMC in vitro were evaluated as described previously. The results are expressed as the IC50 (HIV), i.e., the concentration required to inhibit by 50% the activity of HIV-1 replication as measured by assays of p24 antigen production. SIA was determined by CASA as described in Materials and Methods. EC50 (SIA) values represent the concentration required to decrease sperm motility by 50% as measured from the concentration-response curves using CASA. EC50 values were calculated from three separate experiments.

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