Isolation, Structure Determination, and Anti-HIV Evaluation of Tigliane-Type Diterpenes and Biflavonoid from <i>Stellera chamaejasme</i>

Five novel tigliane-type diterpenes, stelleracins A–E (<b>3</b>–<b>7</b>), a novel flavanone dimer, chamaeflavone A (<b>8</b>), and six known compounds were isolated from the roots of <i>Stellera chamaejasme</i>. Their structures were elucidated by extensive spectroscopic analyses. The isolated compounds were evaluated for anti-HIV activity in MT4 cells. New compounds <b>3</b>–<b>5</b> showed potent anti-HIV activity (EC₉₀ 0.00056–0.0068 μM) and relatively low or no cytotoxicity (IC₅₀ 4.4–17.2 μM). These new compounds represent promising new leads for development into anti-AIDS clinical trial candidates

Isolation, Structure Determination, and Anti-HIV Evaluation of Tigliane-Type Diterpenes and Biflavonoid from <i>Stellera chamaejasme</i>

Five novel tigliane-type diterpenes, stelleracins A–E (<b>3</b>–<b>7</b>), a novel flavanone dimer, chamaeflavone A (<b>8</b>), and six known compounds were isolated from the roots of <i>Stellera chamaejasme</i>. Their structures were elucidated by extensive spectroscopic analyses. The isolated compounds were evaluated for anti-HIV activity in MT4 cells. New compounds <b>3</b>–<b>5</b> showed potent anti-HIV activity (EC₉₀ 0.00056–0.0068 μM) and relatively low or no cytotoxicity (IC₅₀ 4.4–17.2 μM). These new compounds represent promising new leads for development into anti-AIDS clinical trial candidates

Carbamoyl Pyridone HIV‑1 Integrase Inhibitors 3. A Diastereomeric Approach to Chiral Nonracemic Tricyclic Ring Systems and the Discovery of Dolutegravir (S/GSK1349572) and (S/GSK1265744)

We report herein the discovery of the human immunodeficiency virus type-1 (HIV-1) integrase inhibitors dolutegravir (S/GSK1349572) (<b>3</b>) and S/GSK1265744 (<b>4</b>). These drugs stem from a series of carbamoyl pyridone analogues designed using a two-metal chelation model of the integrase catalytic active site. Structure–activity studies evolved a tricyclic series of carbamoyl pyridines that demonstrated properties indicative of once-daily dosing and superior potency against resistant viral strains. An inherent hemiaminal ring fusion stereocenter within the tricyclic carbamoyl pyridone scaffold led to a critical substrate controlled diastereoselective synthetic strategy whereby chiral information from small readily available amino alcohols was employed to control relative and absolute stereochemistry of the final drug candidates. Modest to extremely high levels of stereochemical control were observed depending on ring size and position of the stereocenter. This approach resulted in the discovery of <b>3</b> and <b>4</b>, which are currently in clinical development