We have developed and applied a computational strategy to increase the affinity of fullerene-based inhibitors of the HIV protease. The result is a approximately 50-fold increase in affinity from previously tested fullerene compounds. The strategy is based on the design of derivatives which may potentially increase hydrophobic desolvation upon complex formation, followed by the docking of the hypothetical derivatives into the HIV protease active site and assessment of the model complexes so formed. The model complexes are generated by the program DOCK and then analyzed for desolvated hydrophobic surface. The amount of hydrophobic surface desolvated was compared with a previously tested compound, and if this amount was significantly greater, it was selected as a target. Using this approach, two targets were identified and synthesized, using two different synthetic approaches: a diphenyl C60 alcohol (5) based on a cyclopropyl derivative of Bingel (Chem.Ber. 1993, 126, 1957-1959) and a diisopropyl cyclohexyl C60 alcohol (4a) as synthesized by Ganapathi et al. (J. Org.Chem. 1995, 60, 2954-2955). Both showed tighter binding than the originally tested compound (diphenethylaminosuccinate methano-C60, Ki = 5 microM) with Ki values of 103 and 150 nM, respectively. In addition to demonstrating the utility of this approach, it shows that simple modification of fullerenes can result in high-affinity ligands of the HIV protease, for which they are highly complementary in structure and chemical nature.

Diels-Alder reaction of C 60 with the 1,3-dienes 7e-h, 8a, 8b, and 8d-h affords the "ball-andchain" systems 2e-h, 3a, 3b, and 3d-h bearing two chromophores linked via a rigid, hybrid saturated polynorbornane-bicyclo[2.2.0]hexane ("norbornylogous") hydrocarbon bridge. Analogous reaction with the bis(diene) 9 affords the soluble dumbbell system 4 bearing two C 60 chromophores. The norbornylogous bridge is a strong mediator of electron and energy transfer via a throughbond coupling mechanism. The norbornylogous donor-bridge-diene units 7d-h, 8a, 8b, and 8d-h were prepared in a straightforward manner from bicyclo[2.2.2]octane precursors by extending the bridges with linearly fused norbornane-bicyclo[2.2.0]hexane moieties through execution of the tandem Mitsudo-Smith series of reactions. The X-ray structure of the dimethoxybenzene-bridge-C 60 system 3a reveals favorable self-complementarity manifested by the unusual packing structure of 3a in the crystal. Molecular mechanics, semiempirical, and ab initio conformational analyses of compounds 2e, 3a, 3b, 3e, 3f, 3h, 68, and 70 (MM2, Sybyl, CVFF, AM1, HF/3-21G) were performed to quantify their ability to adopt two nondegenerate boat conformations, i.e., extended and folded conformers, as well as their kinetic barrier of interconversion. A similar treatment of the C 60 -bridge-C 60 system 4 revealed unusual preference for the folded-folded conformer (18.9 kcal/mol at CVFF level), which was not reproduced by the AM1 method (0.11 kcal/mol). The reduction potentials of the systems 2e, 3a, and 3e were about 0.1-0.5 V more negative than C 60 , and the third reduction potential (E 3 ) of the 6-bond system 2e was 0.14 V more negative than the corresponding wave for the 10-bond system 3e. This shift was attributed to the closer proximity of the dimethylaniline donor group to the C 60 surface for 2e vs 3e. IntroductionThe functionalization of buckminsterfullerene (C 60 ) is a burgeoning area of research, and a number of recent studies have demonstrated the ease by which this fascinating molecule undergoes a wide range of addition reactions with unsaturated systems. 1,2 We have exploited the Diels-Alder reaction between C 60 and 1,3-dienes to obtain a variety of highly stable adducts which have properties similar to those of C 60 . 2-4 A major reason for the intense interest in functionalized fullerenes lies in the exceptional electronic structure of the C 60 cage, reflected by its rich redox chemistry, its magnetic and electronic properties, and its photophysical behavior. 1a In particular, the characteristic electronic properties of fullerenes suggest that suitably functionalized derivatives may have important applications in fields as diverse as conductive materials 5 and biological chemistry. 3d,6

No abstract