Betulinic acid (BA) has been shown to be maturation and entry inhibitor of various HIV-1 strains. Because of its novel mode of action and relatively low toxicity, there has been a great interest in the elaboration of the BA core in search of highly active analogs. As a result, various betulinic acid derivatives have been synthesized to date. The derivatization so far has been restricted to C3 and C28 positions. This is primarily due to the utilization of commercially available betulinic acid as a starting material for the synthesis of these analogs. As a result, the unnatural analogs bearing a novel carboskeletal framework have remained inaccessible to date. The aforementioned analogs could only be furnished via total synthesis of the core of betulinic acid. It is hypothesized that the alternations in the BA backbone would furnish analogs with a potent, selective antiretroviral activity.
This proposal describes two major modifications to the BA core. The first set of modifications is based on the working hypothesis that the inclusion of heteroatoms in the BA core will render analogs with potent, subtype specific anti-HIV activity. One of the major problems associated with BA analogs is their poor water solubility. To address this issue, the second set modifications are proposed. These novel analogs are expected to display improved aqueous solubility and thus, improved pharmacokinetic or "drug-like" properties.
From the synthetic perspective, the reaction protocols are designed to provide a facile, convergent synthesis of the desired analogs. They offer significant improvements to the previously established synthetic procedures. Lastly, the modular approach will permit the extension of this methodology for the synthesis of a small focused library of analogous derivatives.