Probing chelation motifs in HIV integrase inhibitors.

A series of HIV integrase (HIV-1 IN) inhibitors were synthesized to evaluate the role of the metal-binding group (MBG) in this class of metalloenzyme inhibitors. A total of 21 different raltegravir-chelator derivative (RCD) compounds were prepared that differed only in the nature of the MBG. These IN strand-transfer inhibitors (INSTIs) were evaluated in vitro in cell-free enzyme activity assays, and the in vitro results were further validated in cell culture experiments. All of the active compounds showed selective inhibition of the strand-transfer reaction over 3'-processing, suggesting a common mode of action with raltegravir. The results of the in vitro activity suggest that the nature of the MBG donor atoms, the overall MBG structure, and the specific arrangement of the MBG donor atom triad are essential for obtaining maximal HIV-1 IN inhibition. At least two compounds (RCD-4, RCD-5) containing a hydroxypyrone MBG were found to display superior strand-transfer inhibition when compared to an abbreviated analogue of raltegravir (RCD-1). By isolating and examining the role of the MBG in a series of INSTIs, we have identified a scaffold (hydroxypyrones) that may provide access to a unique class of HIV-1 IN inhibitors, and may help overcome rising raltegravir resistance.

Reductions of aliphatic and aromatic nitriles to primary amines with diisopropylaminoborane.

Diisopropylaminoborane [BH(2)N(iPr)(2)] in the presence of a catalytic amount of lithium borohydride (LiBH(4)) reduces a large variety of aliphatic and aromatic nitriles in excellent yields. BH(2)N(iPr)(2) can be prepared by two methods: first by reacting diisopropylamineborane [(iPr)(2)N:BH(3)] with 1.1 equiv of n-butyllithium (n-BuLi) followed by methyl iodide (MeI), or reacting iPrN:BH(3) with 1 equiv of n-BuLi followed by trimethylsilyl chloride (TMSCl). BH(2)N(iPr)(2) prepared with MeI was found to reduce benzonitriles to the corresponding benzylamines at ambient temperatures, whereas diisopropylaminoborane prepared with TMSCl does not reduce nitriles unless a catalytic amount of a lithium ion source, such as LiBH(4) or lithium tetraphenylborate (LiBPh(4)), is added to the reaction. The reductions of benzonitriles with one or more electron-withdrawing groups on the aromatic ring generally occur much faster with higher yields. For example, 2,4-dichlorobenzonitrile was successfully reduced to 2,4-dichlorobenzylamine in 99% yield after 5 h at 25 degrees C. On the other hand, benzonitriles containing electron-donating groups on the aromatic ring require refluxing in tetrahydrofuran (THF) for complete reduction. For instance, 4-methoxybenzonitrile was successfully reduced to 4-methoxybenzylamine in 80% yield. Aliphatic nitriles can also be reduced by the BH(2)N(iPr)(2)/cat. LiBH(4) reducing system. Benzyl cyanide was reduced to phenethylamine in 83% yield. BH(2)N(iPr)(2) can also reduce nitriles in the presence of unconjugated alkenes and alkynes such as the reduction of 2-hexynenitrile to hex-5-yn-1-amine in 80% yield. Unfortunately, selective reduction of a nitrile in the presence of an aldehyde is not possible as aldehydes are reduced along with the nitrile. However, selective reduction of the nitrile group at 25 degrees C in the presence of an ester is possible as long as the nitrile group is activated by an electron-withdrawing substituent. It should be pointed out that lithium aminoborohydrides (LABs) do not reduce nitriles under ambient conditions and behave as bases with aliphatic nitriles as well as nitriles containing acidic alpha-protons. Consequently, both LABs and BH(2)N(iPr)(2) are complementary to each other and offer methods for the selective reductions of multifunctional compounds.