Bufadienolides are the major pharmacologic constituents of traditional Chinese medicine Chan'su, which is frequently used clinically for cancer treatment in China. Motivated by reducing or avoiding the cardiac toxicity of bufadienolides, we have designed, synthesized, and evaluated the fibroblast activation protein α (FAPα) activated tripeptide arenobufagin prodrugs with the purpose of improving the safety of arenobufagin (a representative bufadienolide). Among these FAPα-activated prodrugs, 3f exhibited the best hydrolytic efficiency by recombinant human FAPα (rhFAPα) and was activated in tumors. The LD of 3f was 6.5-fold higher than that of arenobufagin. We also observed that there are nonapparent changes in echocardiography, pathological section of cardiac muscle, and the lactate dehydrogenase activities (LDH) in 3f-treatment tumor-bearing mice, even when the dose reached 3 times the amount of parent drug arenobufagin that was used. Compound 3f also exhibits significant antitumor activity in vitro and in vivo. The improved safety profile and favorable anticancer properties of 3f warrant further studies of the potential clinical implications. Our study suggests that FAPα prodrug strategy is an effective approach for successful increasing the therapeutic window of bufadienolides.

Drug resistance caused by excessive and indiscriminate antibiotic usage has become a serious public health problem. The need of finding new antibacterial drugs is more urgent than ever before. Tyrosyl-tRNA synthase was proved to be a potent target in combating drug-resistant bacteria. In silico methodologies including molecular docking and 3D-QSAR were employed to investigate a series of newly reported tyrosyl-tRNA synthase inhibitors of furanone derivatives. Both internal and external cross-validation were conducted to obtain high predictive and satisfactory CoMFA model (q 2 = 0.611, r 2 pred = 0.933, r 2 m = 0.954) and CoMSIA model (q 2 = 0.546, r 2 pred = 0.959, r 2 m = 0.923). Docking results, which correspond with CoMFA/CoMSIA contour maps, gave the information for interactive mode exploration. Ten new molecules designed on the basis of QSAR and docking models have been predicted more potent than the most active compound 3-(4-hydroxyphenyl)-4-(2-morpholinoethoxy)furan-2(5H)-one (15) in the literatures. The results expand our understanding of furanones as inhibitors of tyrosyl-tRNA synthase and could be helpful in rationally designing of new analogs with more potent inhibitory activities.

The feasibility of D-D biliary reconstruction in pediatric LDLT using left-lobe graft has been discussed in few reports. The use of a trans-anastomotic biliary tube seemed to be the favorable method to avoid the complications according to these reports. We had performed left-lobe LDLT for seven pediatric cases and D-D was done originally. Three cases were converted to R-Y hepaticojejunostomy due to radical resection of hepatoduodenal ligament (n = 1) and severe kinking of D-D (n = 2). Four cases received D-D using 6-0 PDS interrupted sutures without external stent tube. One D-D case died of intra-cerebral hemorrhage 10 days after operation with a functioning graft. There was one biliary leakage in a D-D patient who required PTCD stent for 4 months without any sequale. From our limited experience, D-D biliary reconstruction without external stent tube in left-lobe LDLT is feasible in certain pediatric cases having normal extra-hepatic bile ducts. In smaller recipient with larger graft, the use of a trans-anastomotic biliary tube can prevent anastomotic kinking although we suggest R-Y biliary reconstruction is better for this condition.

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