No abstract

A study on the use of derivatized carbohydrates as C2-symmetric HIV-1 protease inhibitors has been undertaken. L-Mannaric acid (6) was bis-O-benzylated at C-2 and C-5 and subsequently coupled with amino acids and amines to give C2-symmetric products based on C-terminal duplication. Potent HIV protease inhibitors, 28 Ki = 0.4 nM and 43 Ki = 0.2 nM, have been discovered, and two synthetic methodologies have been developed, one whereby these inhibitors can be prepared in just three chemical steps from commercially available materials. A remarkable increase in potency going from IC50 = 5000 nM (23) to IC50 = 15 nM (28) was observed upon exchanging -COOMe for -CONHMe in the inhibitor, resulting in the net addition of one hydrogen bond interaction between each of the two -NH- groups and the HIV protease backbone (Gly 48/148). The X-ray crystal structures of 43 and of 48 have been determined (Figures 5 and 6), revealing the binding mode of these inhibitors which will aid further design.

N-Formyl-3,3‘,4,4‘-tetrahydrospiro[naphthalene-1(2H),2‘(1‘H)-pyridine] (2) and N-Formyl-3‘,4‘-dihydrospiro[indan-1,2‘(1‘H)-pyridine] (3) were resolved into enantiomers, compound 3 partly and compound 2 completely, by chromatography on triacetylcellulose. The CD spectra were recorded and compared with theoretical spectra calculated by a semiempirical method, using geometries from empirical force-field calculations. In the observed CD spectra, the carbonyl n → π* transitions did not give rise to visible bands, but their signs and energies were found by analysis of CD spectra in solvents of different polarity. The theoretical spectra of 2 and 3 showed complete agreement with the observed spectra in sign and qualitatively in intensity, for the five transitions observed between 190 and 280 nm, which permitted a safe assignment of the absolute configurations. The enantiomers of 2 and 3 with the aryl rings located on the same side of the tetrahydropyridine ring showed CD spectra, which were nearly mirror images, thus demonstrating the risk of deducing absolute configurations by a direct comparison of CD spectra.