ABSTRACT
A new class of potent liver injury protective compounds, phychetins A-D (1-4) featuring an unique 6/6/5/6/5 pentacyclic framework, were isolated and structurally characterized from a Chinese medicinal plant Phyllanthus franchetianus. Compounds 2-4 are three pairs of enantiomers that were initially obtained in a racemic manner, and were further separated by chiral HPLC preparation. Compounds 1-4 were proposed to be originated biosynthetically from a coexisting lignan via an intramolecular Friedel-Crafts reaction as the key step. A bioinspired total synthesis strategy was thus designated, and allowed the effective syntheses of compounds 2-4 in high yields. Some of compounds exhibited significant anti-inflammatory activities in vitro via suppressing the production of pro-inflammatory cytokine IL-1ß. Notably, compound 4, the most active enantiomeric pair in vitro, displayed prominent potent protecting activity against liver injury at a low dose of 3 mg/kg in mice, which could serve as a promising lead for the development of acute liver injury therapeutic agent.
ABSTRACT
A class of novel, easily accessible and air-stable 1-[bis(trifluoromethyl)phosphine]-1'-oxazolinylferrocene ligands has been synthesized from ferrocene. It became apparent that these ligands can be used in the regio- and enantioselective Pd-catalyzed allylic alkylation of monosubstituted allyl substrates in a highly efficient manner. Excellent regio- and enantioselectivity could be obtained for a wide range of substrates.
ABSTRACT
Highly potent DPP-4 inhibitors have been identified by hybrid compound design based on linagliptin and alogliptin. The most promising compound 2h (IC50 = 0.31 nM) exhibited 8.5-fold and 2.5-fold more potent activity than that of alogliptin (IC50 = 2.63 nM) and linagliptin (IC50 = 0.77 nM), respectively. Compound 2h had a good inhibition selectivity for DPP-4 over DPP-8/9 and thus was selected for further biological evaluation, including oral glucose tolerance, plasma DPP-4 inhibitory activity, pharmacokinetic profile, acute toxicity and hERG inhibition. The assay results showed that 2h displayed significant in vivo glucose-lowering effect and low risk of toxicity. Further studies are expected to confirm 2h as a potential drug candidate for the treatment of type 2 diabetes.
Subject(s)
Dipeptidyl Peptidase 4/metabolism , Dipeptidyl-Peptidase IV Inhibitors/chemistry , Dipeptidyl-Peptidase IV Inhibitors/pharmacology , Piperidines/chemistry , Piperidines/pharmacology , Purines/chemistry , Purines/pharmacology , Quinazolines/chemistry , Quinazolines/pharmacology , Uracil/analogs & derivatives , Diabetes Mellitus, Type 2/drug therapy , Dipeptidyl Peptidase 4/chemistry , Dipeptidyl-Peptidase IV Inhibitors/metabolism , Dipeptidyl-Peptidase IV Inhibitors/therapeutic use , Drug Design , Humans , Linagliptin , Models, Molecular , Piperidines/metabolism , Piperidines/therapeutic use , Protein Conformation , Purines/metabolism , Purines/therapeutic use , Quinazolines/metabolism , Quinazolines/therapeutic use , Structure-Activity Relationship , Substrate Specificity , Uracil/chemistry , Uracil/metabolism , Uracil/pharmacology , Uracil/therapeutic useABSTRACT
The first enantioselective total synthesis of (-)-8-deoxyserratinine has been achieved in 15 steps from enone 4 with 7% overall yield. The key features include a highly efficient Helquist annulation to furnish the cis-fused 6/5 bicycle, facile construction of the aza nine-membered ring system employing double N-alkylation strategy, as well as asymmetric Shi epoxidation, delivering the desired beta-epoxide stereospecifically.