Acute lung injury/acute respiratory distress syndrome (ALI/ARDS) is one of the most common complications in COVID-19. Elastase has been recognized as an important target to prevent ALI/ARDS in the patient of COVID-19. Cyclotheonellazole A (CTL-A) is a natural macrocyclic peptide reported to be a potent elastase inhibitor. Herein, we completed the first total synthesis of CTL-A in 24 linear steps. The key reactions include three-component MAC reactions and two late-stage oxidations. We also provided seven CTL-A analogues and elucidated preliminary structure–activity relationships. The in vivo ALI mouse model further suggested that CTL-A alleviated acute lung injury with reductions in lung edema and pathological deterioration, which is better than sivelestat, one approved elastase inhibitor. The activity of CTL-A against elastase, along with its cellular safety and well-established synthetic route, warrants further investigation of CTL-A as a candidate against COVID-19 pathogeneses.

Ac oncise,s calable,s ix-step (longest linear sequence) synthetic route to ovatodiolide scaffolds was developed for the first time.T his protecting-group-free route features tandem ring-opening metathesis/ring-closing metathesis reactions to install the macrocycle-fused butenolide ring and at andem allylboration/lactonization to build the amethylene-g-lactone.Our syntheses have enabled the determination of the hitherto unknown stereochemical configurations of this family of natural products.P reliminary tests of structure-activity relationships were conducted with four natural ovatodiolides and three analogues.F urther assays indicated that the synthetic natural product isoovatodiolide can significantly decrease the population of hepatic cancer stem cells and reduce the tumorsphere-forming capability of HepG2 cells.

A Pt(iv)-triple-prodrug, comprising VPA, 5-FU, regulated TS, HDAC, and γH2AX, showing higher efficiency and lower toxicity than cisplatin.

The natural product, BE‐43547A2, decreases pancreatic cancer cell stemness. However, its anticancer molecular mechanisms have not been fully established. Based on structure–activity relationships of BE‐43547A2, we synthesized a probe and investigated its potential targets using an in situ click reaction. We found that BE‐43547A2 exerts its anticancer effects by covalently binding the cysteine234 (C234) residue of eukaryotic translation elongation factor 1 alpha 1 (eEF1A1). This binding mode was confirmed by a series of experiments including a xenograft mouse model. We also determined that eEF1A1 plays an important role in regulating pancreatic cancer cell stemness. Analyses of 99 clinical pancreatic cancer samples revealed that eEF1A1 expressions are closely correlated with clinicopathological grade and patient survival. In conclusion, eEF1A1 is involved in pancreatic cancer progression and is therefore, a promising novel covalent target for pancreatic cancer treatment.

Total synthesis of rakicidin F was accomplished in 20 linear steps (0.68% overall yield), which enabled the configural determination of its six stereogenic centers as 2R, 15R, 16R, 17S, 19S,...