The design and synthesis of didemnaketal A and B analogs (Immune deficiency)

Didemnaketals A and B, the natural products isolated from the Ascidian Didemnum sp. at Auluptagel Island, Palau, were found to inhibit HIV-1 protease with IC{dollar}sb{lcub}50{rcub}{dollar} values of 2 {dollar}mu{dollar}M and 10 {dollar}mu{dollar}M, respectively, by Faulkner and colleagues in 1991. The gross structures of the Didemnaketals were characterized through extensive NMR studies, but the absolute configurations of eight stereogenic centers in the pyran rings and the pentaester side chain were not determined due to limited supply of the parent natural products and have not yet been reported. The Didemnaketals are potent, non-nitrogen containing HIV-1 protease inhibitors with novel structures and good initial activity against HIV-1 protease.; A series of analogs of two subunits of Didemnaketal A, which include the C11 to C21 spiroketal-containing subunit and the C1 to C11 pentaester subunit, were designed and synthesized. Efficient synthesis toward the analogs of both subunits were developed. The stereoselective synthesis of the C1 to C11 analogs is amenable to solid phase and combinatorial synthesis of more stable compounds. The biological evaluations of these analogs indicated that the spiroketal-containing analogs do not inhibit HIV-1 protease and that the pentaester of the Didemnaketals is the key structural portion that interacts with the enzyme. The correct stereocenters needed for the maximum inhibition of the diastereomer was identified. Additional analogs of the C1 to C11 pentaester subunit in which one or more esters were converted to the corresponding hydroxyl groups result in lost activities against HIV-1 protease. The kinetic studies on the most potent compound (K{dollar}sb{lcub}rm i{rcub}{dollar} = 2.1 {dollar}mu{dollar}M) of this series suggested that the pentaester analogs of the Didemnaketals inhibit dimerization of HIV-1 protease monomers, which offer a potential new way to inhibit mutant strains of HIV-1 protease as all the clinically established inhibitors are designed to bind in the active site of the enzyme and to block the binding of the substrate. This novel class of compounds are among the most potent dimerization inhibitors of HIV-1 protease identified to date.