Tenofovir DF is an antiviral nucleotide with activity against human immunodeficiency virus type 1 (HIV-1). The pharmacokinetics, safety, and activity of oral tenofovir DF in HIV-1-infected adults were evaluated in a randomized, double-blind, placebo-controlled, escalating-dose study of four doses (75, 150, 300, and 600 mg given once daily). Subjects received a single dose of tenofovir DF or a placebo, followed by a 7-day washout period. Thereafter, subjects received their assigned study drug once daily for 28 days. Pharmacokinetic parameters were dose proportional and demonstrated no change with repeated dosing. Reductions in plasma HIV-1 RNA were dose related at tenofovir DF doses of 75 to 300 mg, but there was no increase in virus suppression between the 300-and 600-mg dose cohorts, despite dose-proportional increases in drug exposure. Grade III or IV adverse events were limited to laboratory abnormalities, including elevated creatine phosphokinase and liver function tests, which resolved with or without drug discontinuation and without sequelae. No patients developed detectable sequence changes in the reverse transcriptase gene.

Copper in its infrequently observed Cu(III) oxidation state has gained attention recently, in particular as a proposed constituent of O 2 -cleaving binuclear and trinuclear complexes. 1,2 A few discrete molecular species generally accepted as containing Cu(III) are known. 3 Assignment of the formal Cu(III) oxidation state in these compounds is based on a variety of spectroscopic, electrochemical, and structural evidence. In particular, their very short Cu-ligand bond distances relative to bond lengths in their Cu(II) counterparts suggest a higher oxidation state. However, a direct and unambiguous probe of the metal oxidation state is notably absent. 4 Metal K-edge X-ray absorption spectroscopy (XAS), because of its ability to probe directly the core-electronic environment of the absorbing metal, offers a means of explicitly examining the oxidation state of the copper. A specific probe of the metal oxidation state is particularly relevant, given the occurrence of ligand-centered oxidation in some Cu(II) systems. 5 More generally, defining differences between compounds with similar atomic compositions but differing electronic distributions, is potentially relevant to understanding variations in their reactivities. In particular, the (µ-η 2 :η 2 -peroxo)dicopper(II), 1b,6 bis-µ-oxyl dicopper(II), and bis-µ-oxo dicopper(III) 1 cores are all formally equivalent, though the latter two may be largely indistinguishable by most spectroscopic methods. 7 Here we report on a Cu K-edge XAS study of two binuclear copper complexes [(L ME ) 2 Cu 2 O 2 ] 2+ (1) and [(L TEED ) 2 Cu 2 O 2 ] 2+ , 1,9 (2) (Figure 1) showing that these complexes are best formally described as Cu(III) 2 (µ-O) 2 and giving the first direct spectroscopic evidence of stabilized Cu(III) in a Cu 2 O 2 rhomb.The Cu(III) valence state for complex 1 may be proposed on the basis of its remarkably short, crystallographically determined metal-ligand bond lengths. 10 Cu K-edge EXAFS analysis 11 confirms these bond distances as well as the notably short Cu-Cu distance of 2.73 Å for 1. 13,14 EXAFS analysis of 2 gives similar metrical details (Cu-O ) 1.80 Å, Cu-N ) 1.92 Å, Cu-Cu ) 2.75 Å). 14 Verification of these structures by EXAFS provides an internal check against possible decomposition in these thermally sensitive molecules. Analogous Cu-ligand and Cu-Cu distances are 0.1-0.2 Å longer in the 2e -, 2H + reduced bis-µ-hydroxo dicopper(II) forms of 1 and 2 (i.e., 3 and 4, respectively). 14,15 The Cu-Cu separation is ∼0.05 Å longer in related, recently reported Cu 2 O 2 complexes (e.g., [(Bn 3 -TACN) 2 Cu 2 O 2 ] 2+ ). 1b,16 For comparison with 1-4, two accepted Cu(III) speciessthe N 3 O tripeptide chelate complex Cu(III)-(H -2 Aib 3 ) 3a and the solid state material KCuO 2 17 shave been

In oxidations by copper enzymes, copper(III) species are increasingly being proposed as intermediates. A good model for such reactions is the oxidation of dihydroanthracene to anthracene by an isolated copper(III) imine/oxime complex [Eq. (1)].