A Scalable Total Synthesis of Portimine A and B Reveals the Basis of Their Potent and Selective Anti-cancer Activity

Abstract

Marine derived cyclic imine toxins, portimine A and B, have attracted extensive attention owing to their intriguing chemical structure and promising anti-cancer therapeutic potential. However, access to large quantities is currently unfeasible and the molecular mechanism behind their potent activity is unknown. To address this, a scalable 15-step total synthesis of portimines is presented, which benefits from the logic used in two-phase terpenoid synthesis along with unique tactics such as exploiting ring-chain tautomerization and skeletal reorganization to minimize protecting group chemistry through “self-protection”. Critically, this total synthesis enabled a structural reassignment of portimine B and an in-depth functional evaluation of portimine A, revealing that it induces apoptosis selectively in human cancer cell lines with high potency. Finally, practical access to the portimines and analogs thereof simplified the development of photoaffinity analogs, which were used in chemical proteomic experiments to identify a primary target of portimine A as the 60S ribosomal export protein NMD3.

Synthesis of the spiroimine fragment of portimines A and B

“…28,31,[36][37][38][39][40][41][42][43][44] This challenge was also overcome in the strategy presented herein, as well as in Baran's recent synthesis of the [5,6]-spirocyclic core of portimine, by decoupling the formation of each center to allow "stepwise" control of the stereochemical outcome. 26 Other synthetic approaches include ringclosing olefin metathesis, 45 Claisen rearrangement/aldol cyclization, 46 consecutive sigmatropic rearrangements, 30 and intramolecular alkylation of cyano-epoxides. 47 Recently, Fujiwara and co-workers reported a racemic synthesis of the cyclo-hexane segment of the portimines from a cyclohexene derivative.…”

“…26 Additionally, through chemical proteomic experiments, the primary target of portimine A ( 1 ) was identified as the 60S ribosomal export protein NMD3. 26…”

“…[23][24][25] Most recently, Baran and co-workers described the total synthesis of portimines A (1) and B (2) over 15 steps, which enabled correction of the initially assigned structure for portimine B and an in-depth study of their biological activity. 26 Additionally, through chemical proteomic experiments, the primary target of portimine A (1) was identified as the 60S ribosomal export protein NMD3. 26…”

Natural Product Synthesis in the 21st Century: Beyond the Mountain Top

“…Soc. total synthesis article (full paper) 20 years ago and medicinal chemistry programs have existed for decades in academia. , Now, however, it is becoming commonplace to find target identification in the same paper as a complex total synthesis campaign , or preliminary SAR associated with functional assays like kinase inhibition . As pointed out by Schreiber, Anne Carpenter’s “cell painting” method allows collections to be profiled in a high-throughput, multiplexed way to identify phenotypic changes associated with compounds, independent of any a priori expectation of activity.…”