187148-14-7Relevant academic research and scientific papers
Enantioselective Synthesis and Biological Evaluation of Sanglifehrin A and B and Analogs
Chang, Chia-Fu,Flaxman, Hope A.,Woo, Christina M.
, p. 17045 - 17052 (2021)
Sanglifehrin A and B are immunosuppressive macrocyclic natural products endowed with and differentiated by a unique spirocyclic lactam. Herein, we report an enantioselective total synthesis and biological evaluation of sanglifehrin A and B and analogs. Access to the spirocyclic lactam was achieved through convergent assembly of a key pyranone intermediate followed by a stereo-controlled spirocyclization. The 22-membered macrocyclic core was synthesized by ring-closing metathesis in the presence of 2,6-bis(trifluoromethyl) benzeneboronic acid (BFBB). The spirocyclic lactam and macrocycle fragments were united by a Stille coupling to furnish sanglifehrin A and B. Additional sanglifehrin B analogs with variation at the C40 position were additionally prepared. Biological evaluation revealed that the 2-CF3 analog of sanglifehrin B exhibited higher anti-proliferative activity than the natural products sanglifehrin A and B in Jurkat cells. Both natural products induced higher-order homodimerization of cyclophilin A (CypA), but only sanglifehrin A promoted CypA complexation with inosine-5′-monophosphate dehydrogenase 2 (IMPDH2). The synthesis reported herein will enable further evaluation of the spirolactam and its contribution to sanglifehrin-dependent immunosuppressive activity.
SANGLIFEHRIN ANALOGS AND USES THEREOF
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, (2021/07/17)
Provided are compounds for the treatment of fibrotic diseases. The compounds are sanglifehrin A and B and analogs of sanglifehrin A and B. Also provided are methods for preparing the compounds, pharmaceutical compositions comprising the compounds, and methods of treating autoimmune disease, cancer, and/or fibrotic diseases using the disclosed compounds.
