In addition to our total synthesis research, our group has continued and accelerated collaborative programs with drug discovery companies under the auspices of the State Key Laboratory of Chemical Oncogenomics at Peking University Shenzhen Graduate School. We have designed a new strategy for developing “non-immunosuppressive” cyclosporine as an anti-inflammatory drug. In this initiative, we developed a novel and concise semi-synthesis of CRV431 (a potential drug candidate for metabolic dysfunction-associated fatty liver disease, MAFLD) in four steps, achieving a total yield of 35% from cyclosporine (see OL 2021, 23, 3421). Our group also extended this “non-immunosuppressive” strategy by targeting extracellular cyclophilin A, resulting in the synthesis of a novel non-immunosuppressive cyclosporine derivative, 4MCsA. This derivative covalently binds to albumin, forming an albumin-binding cyclosporine A, which inhibits chemotactic activity and inflammation by targeting extracellular Cyclophilin A (CypA) without inducing immunosuppressive effects or cellular toxicity (ChemMedChem, 2021, 16, 3649).
During the COVID-19 pandemic, our group also investigated potential antiviral compounds and isolated (–)-anisomelic acid from the traditional Chinese medicine of Anisomeles indica (L.) Kuntze (Labiatae) in 2020. (–)-Anisomelic acid effectively inhibited COVID-19 replication and viral-induced cytopathic effects, with EC50 values of 1.1 and 4.3 μM, respectively. Challenge studies in SARS-CoV-2-infected K18-hACE2 mice demonstrated that oral administration of anisomelic acid and subcutaneous dosing of remdesivir reduced viral titers in lung tissue comparably. To facilitate drug discovery, our group developed an enantioselective semi-synthesis of (–)-anisomelic acid from the naturally enriched and commercially available starting material (+)-costunolide in five steps with an overall yield of 27%, providing (–)-anisomelic acid at a kilogram-scale.
