Brefeldin A and M-COPA block the export of RTKs from the endoplasmic reticulum via simultaneous inactivation of ARF1, ARF4, and ARF5.

Normal receptor tyrosine kinases (RTKs) need to reach the plasma membrane (PM) for ligand-induced activation, whereas its cancer-causing mutants can be activated before reaching the PM in organelles, such as the Golgi/trans-Golgi network (TGN). Inhibitors of protein export from the endoplasmic reticulum (ER), such as brefeldin A (BFA) and 2-methylcoprophilinamide (M-COPA), can suppress the activation of mutant RTKs in cancer cells, suggesting that RTK mutants cannot initiate signaling in the ER. BFA and M-COPA block the function of ADP-ribosylation factors (ARFs) that play a crucial role in ER-Golgi protein trafficking. However, among ARF family proteins, the specific ARFs inhibited by BFA or M-COPA, that is, the ARFs involved in RTKs transport from the ER, remain unclear. In this study, we showed that M-COPA blocked the export of not only KIT but also PDGFRA/EGFR/MET RTKs from the ER. ER-retained RTKs could not fully transduce anti-apoptotic signals, thereby leading to cancer cell apoptosis. Moreover, a single knockdown of ARF1, ARF3, ARF4, ARF5, or ARF6 could not block ER export of RTKs, indicating that BFA/M-COPA treatment cannot be mimicked by the knockdown of only one ARF member. Interestingly, simultaneous transfection of ARF1, ARF4, and ARF5 siRNAs mirrored the effect of BFA/M-COPA treatment. Consistent with these results, in vitro pulldown assays showed that BFA/M-COPA blocked the function of ARF1, ARF4, and ARF5. Taken together, these results suggest that BFA/M-COPA targets at least ARF1, ARF4, and ARF5; in other words, RTKs require the simultaneous activation of ARF1, ARF4, and ARF5 for their ER export.

(E)-Selective Weinreb Amide-Type Horner-Wadsworth-Emmons Reaction: Effect of Reaction Conditions, Substrate Scope, Isolation of a Reactive Magnesium Phosphonoenolate, and Applications.

An iPrMgCl-deprotonating Weinreb amide-type Horner-Wadsworth-Emmons (HWE) reaction was developed, and the effects of diverse reaction conditions, including the base, cation, solvent, and concentration, were investigated to broaden the substrate scope and achieve high (E)-selectivity. The Weinreb amide-type phosphonoenolate generated from iPrMgCl was found to be isolable, stable for at least over a half year, and applicable in the HWE reaction keeping high productivity and selectivity compared with the in situ generated phosphonoenolate. The results prompted us to perform an application study including successive elongation, synthesis of a biscyclopropane, and Weinreb ketone syntheses.

First Total Synthesis of Tanzawaic Acid B.

The first total synthesis of (+)-tanzawaic acid B, a natural polyketide bearing a pentadienoic ester and octalin moiety, has been accomplished. The synthetic improvement from previous synthetic conditions facilitated our gram-scale synthesis of the chiral octalin that possesses seven stereogenic centers and that is the core skeleton of almost all of the tanzawaic acid family.

Correction to "First Total Synthesis of Tanzawaic Acid B".

[This corrects the article DOI: 10.1021/acsomega.3c03634.].