Design, synthesis and biological evaluation of betulin analogs as anti-HIV agents (Immune deficiency)

Three specific goals were identified in this research: (1) synthesis and evaluation of betulin derivatives modified in the betulin skeleton, (2) synthesis and evaluation of betulin derivatives with various acyl side chains at the C3 and C28 positions, (3) synthesis and evaluation of mono-and tri-acyl betulins and related amides. The overall goals were to study the structure-activity relationships of this compound class, and, finally, to study the mechanisms of action of the promising compounds.; Triester 4 and 2,3-dihydro 10 were two-fold more potent than betulin (1), but the TI values were not impressive. Transformation of dihydroxy functional groups to keto/aldehyde or addition of a third hydroxyl group led to a two-fold drop in activity. Bioisosteric replacement of oxygen with nitrogen yielded the aminobetulin 9, by a reaction sequence of PCC oxidation, oxime formation and reductive amination; however, this modification resulted in complete loss of activity.; Fifteen new 3,28-di-O-acylated betulin and dihydrobetulin derivatives (12-26) were synthesized and evaluated for anti-HIV activity against H9 lymphocytes. Generally, betulin analogs showed stronger biological activity than their dihydrobetulin counterparts (cf. 12 and 20, 14 and 22, 15 and 23, 16 and 24, and 17 and 25). For various 3{dollar}spprime{dollar}-substituted glutaryl compounds, the order of anti-HIV effects from strong to weak inhibition was 3{dollar}spprime{dollar},3{dollar}spprime{dollar}-dimethyl, 3{dollar}spprime{dollar}-methyl, 3{dollar}spprime{dollar}-ethyl-3{dollar}spprime{dollar}-methyl, followed by 3{dollar}spprime{dollar},3{dollar}spprime{dollar}-tetramethylene glutaryl derivatives (15 {dollar}>{dollar} 14 {dollar}>{dollar} 16 {dollar}>{dollar} 17, 23 {dollar}>{dollar} 22 {dollar}>{dollar} 24 {dollar}>{dollar} 25). The most potent compound, 15, had 3{dollar}spprime{dollar},3{dollar}spprime{dollar}-dimethylglutaryl groups and displayed significant anti-HIV potency with an EC{dollar}sb{lcub}50{rcub}{dollar} value of 0.00066 {dollar}mu{dollar}M and a TI of 21,515.; The importance of the C-3 acyl group to the anti-HIV effect was strengthened by the results with compounds 27-30, which are without a C-3 acyl group. Monoacylated betulins 27-30, 3-keto 31-34, and 2,3-dihydro 35-36 had EC{dollar}sb{lcub}50{rcub}{dollar} values in the range of 4.3-12.7 {dollar}mu{dollar}M, much lower than those of diacylated compounds. In addition, no significant change in anti-HIV activity was observed for various 3{dollar}spprime{dollar},3{dollar}spprime{dollar}-substitutions. (Abstract shortened by UMI.)...