Design, synthesis and biological evaluation of oleanolic acid derivatives and analogues

La diabète de type 2 est associée avec des désordres du métabolisme de glucose dans le foie et les système périphériques, résultant un niveau trop élevé du glucose dans le sang qui est responsable des conséquences graves à long terme. Un agent anti-diabétique idéal doit être capable de réduire le taux de glucose en états- alimentés et à jeun. Le contrôle du métabolisme hépatique du glucose est l'une des principales voies utilisées par l'insuline pour maintenir l'homéostasie du glucose dans le sang. Parmi les différentes possibilités d'influencer la production hépatique du glucose, l'inhibition de la glycogène phosphorylase (GP), enzyme responsable de la dégradation du glycogène, est une approche prometteuse pour le traitement de diabète de type 2. Plusieurs inhibiteurs de se sont montrent efficaces à baisser le taux de glucose dans des animaux et en essai clinique. Récemment, nous avons montré que l'acide oléanolique et d'autres triterpènes pentacycliques représentent une nouvelle classe d'inhibiteurs de glycogène phosphorylase. La structure aux rayons X révèlent que les triterpènes pentacycliques comme l'acide asiatique et l'acide maslinique fixent au site allostérique de OP. Les efforts intensifs ont été réalisés sur la modification structurale des triterpènes naturels afin de trouver des agents préventifs et thérapeutiques. Nous espérions que les dérives de triterpènes pentacycliques puissent être utilisés comme des nouveaux médicaments pour la régulation du métabolisme de glucose. Dans cette étude, nous avons synthétisé plusieurs dérivés de l'acide oléanolique et des conjugués avec des sucres et des nucléosides. Leur propriété inhibitrice vis-à-vis de la glycogène phosphorylase a été évalué avec la GPa du muscle du lapin (RMGPa). Certaines molécules présentent une inhibition de l'ordre de micromolaire.Type 2 diabetes mellitus is associated with disorelers in glucose metabolism by the liver and periphery resulting in elevated blood glucose levels which, in turn, are responsible for fatal long term complications. An ideal anti-diabetic agent should be capable of lowering blood glucose in both fed and fasted states. Control of die hepatic glycogen metabolism is one of the key events through which insulin maintains blood glucose homeostasis. Among other means for influencing glucose production in the liver, inhibition of glycogen phosphorylase (GP), the rate limiting enzyme of glycogen degradation, has been regarded as a promising therapeutic approach ta the treatment of type 2 diabetes. A couple of GP inhibitors have shown efficacy in lowering blood glucose in animal models and clinical trials. We have recently reported that oleanolic acid and related pentacyclic triterpenes represented a new class of inhibitors of glycogen phosphorylases. X-Ray crystallographic studies revealed the molecular basis of their inhibitory effect demonstrating that pentacyclic triterpenes such as asiatic and maslinic acids bind ta OP at the allosteric site. On the other hand, structural modifications based on natural triterpenes have been extensively explored ta find more patent pentacyclic triterpenes as preventive and therapeutic agents. Therefore, we believe that pentacyclic triterpenes will be used as new drugs in regulating glucose and lipid metabolism one day. Thus, in this study, we have synthesized several oleanolic acid derivatives and conjugates with sugar and nucleosides, and evaluated GP inhibitory activity against RMGPa. Some molecules exhibited inhibition in micromolar range. The structural analyses of these cornpounds can be further exploited (by chemical modification) towards the development of better GP inhibitors.CACHAN-ENS (940162301) / SudocSudocFranceF

Modelling snow ice and superimposed ice on landfast sea ice in Kongsfjorden, Svalbard

Snow ice and superimposed ice formation on landfast sea ice in a Svalbard fjord, Kongsfjorden, was investigated with a high-resolution thermodynamic snow and sea-ice model, applying meteorological weather station data as external forcing. The model shows that sea-ice formation occurs both at the ice bottom and at the snow/ice interface. Modelling results indicated that the total snow ice and superimposed ice, which formed at the snow/ice interface, was about 14 cm during the simulation period, accounting for about 15% of the total ice mass and 35% of the total ice growth. Introducing a time-dependent snow density improved the modelled results, and a time-dependent oceanic heat flux parameterization yielded reasonable ice growth at the ice bottom. Model results suggest that weather conditions, in particular air temperature and precipitation, as well as snow thermal properties and surface albedo are the most critical factors for the development of snow ice and superimposed ice in Kongsfjorden. While both warming air and higher precipitation led to increased snow ice and superimposed ice forming in Kongsfjorden in the model runs, the processes were more sensitive to precipitation than to air temperature.Keywords: Snow ice; superimposed ice; thermodynamic modelling; landfast sea ice; Kongsfjorden.(Published: 24 August 2015)Citation: Polar Research 2015, 34, 20828, http://dx.doi.org/10.3402/polar.v34.2082

Antitumor and Antibacterial Derivatives of Oridonin: A Main Composition of Dong-Ling-Cao

Isodon rubescens has been used as a traditional green tea for more than 1000 years and many medicinal functions of I. rubescens are also very useful, such as its well-known antitumor and antibacterial activities. Oridonin, a bioactive ent-kaurane diterpenoid, is the major ingredient of this medicinal tea. Herein, 22 novel oridonin derivatives were designed and synthesized. The antibacterial activity was evaluated for the first time. Compound 12 was the most promising one with MIC of 2.0 μg/mL against B. subtilis, which was nearly 3-fold stronger than positive control chloromycetin. The antiproliferative property was also assayed and compound 19 showed stronger activity than taxol. The apoptosis-inducing ability, cell cycle arrest effect at S phase and influence of mitochondrial membrane potential by 19 in CaEs-17 cancer cells were first disclosed. Based on the above results, the cell apoptosis induced by compound 19 in CaEs-17 cells was most probably involved in the intrinsic apoptotic pathway

Synthesis, Biological Activity, and Apoptotic Properties of NO-Donor/Enmein-Type ent-Kauranoid Hybrids

Herein, we reported on a series of synthetic nitric oxide-releasing enmein-type diterpenoid hybrids (9a–i). All the target compounds showed potent antibacterial activity against selected Gram-positive bacteria S. aureus and B. subtilis. The antiproliferative activity against human tumor K562, MGC-803, CaEs-17 and Bel-7402 cells, and human normal liver cells L-02 was tested and the structure activity relationships (SARs) were also concluded. Compounds 9b and 9d showed the best activity against S. aureus and B. subtilis with the same minimal inhibitory concentrations (MICs) of 4 and 2 μg/mL, respectively. The derivative 9f displayed IC50 values of 1.68, 1.11, 3.60 and 0.72 μM against the four cancer cell lines above and 18.80 μM against normal liver cells L-02; meanwhile, 9f also released a high level of NO at the time point of 60 min of 22.24 μmol/L. Furthermore, it was also found that 9f induced apoptosis via the mitochondria-related pathway and arrested cell cycle of Bel-7402 cells at S phase. These findings might be important to explore new chemical entities for the main causes of in-hospital mortality of S. aureus infection, combined with a solid tumor

Oridonin, a Promising ent-Kaurane Diterpenoid Lead Compound

Oridonin belongs to ent-kaurane tetracyclic diterpenoid and was first isolated from Isodon species. It exhibits inhibitory activities against a variety of tumor cells, and pharmacological study shows that oridonin could inhibit cell proliferation, DNA, RNA and protein synthesis of cancer cells, induce apoptosis and exhibit an antimutagenic effect. In addition, the large amount of the commercially-available supply is also very important for the natural lead oridonin. Moreover, the good stability, suitable molecular weight and drug-like property guarantee its further generation of a natural-like compound library. Oridonin has become the hot molecule in recent years, and from the year 2010, more than 200 publications can be found. In this review, we summarize the synthetic medicinal chemistry work of oridonin from the first publication 40 years ago and share our research experience of oridonin for about 10 years, which may provide useful information to those who are interested in this research field

Naturally Occurring Pentacyclic Triterpenes as Inhibitors of Glycogen Phosphorylase: Synthesis, Structure-Activity Relationships, and X-ray Crystallographic Studies

Twenty-five naturally occurring pentacyclic triterpenes, 15 of which were synthesized in this study, were biologically evaluated as inhibitors of rabbit muscle glycogen phosphorylase a (GPa). From SAR studies, the presence of a sugar moiety in triterpene saponins resulted in a markedly decreased activity (7, 18-20) or no activity (21, 22). These saponins, however, might find their value as potential natural prodrugs which are much more water-soluble than their corresponding aglycones. To elucidate the mechanism of GP inhibition, we have determined the crystal structures of the GPb-asiatic acid and GPb-maslinic acid complexes. The X-ray analysis indicates that the inhibitors bind at the allosteric activator site, where the physiological activator AMP binds. Pentacyclic triterpenes represent a promising class of multiple-target antidiabetic agents that exert hypoglycemic effects, at least in part, through GP inhibition