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16β‐Methylcorticoids are among the most important glucocorticoid steroids for the treatment of various dermatological disorders, respiratory infections, and other allergic reactions elicited during inflammatory responses of the human body. Betamethasone dipropionate, clobetasol propionate, and beclomethasone dipropionate are particularly noteworthy for their synthetic intractability. Despite five decades of research, these 16β‐methylcorticoids have remained challenging synthetic targets owing to insurmountable issues of reactivity, selectivity, and cost efficiency associated with all previously explored strategies. We herein report our practicability‐oriented strategy toward the unified stereoselective synthesis of 16β‐methylcorticoids in 12.6–14.0 % overall yield from commercially available 9α‐hydroxyandrost‐4‐ene‐3,17‐dione (9α‐OH‐AD). In this approach, the chiral C16β‐Me and C17α‐OH groups of the corticosteroid D ring were installed via a substrate‐controlled diastereo‐ and enantioselective Mn‐catalyzed oxidation‐reduction hydration of Δ4,9(11),16‐triene‐3,20‐dione. The C1−C2 double bond of the corticosteroid A ring was constructed using an unprecedented engineered 3‐ketosteroid‐Δ1‐dehydrogenase (MK4‐KstD)‐catalyzed regioselective Δ1‐dehydrogenation of Δ4,9(11)‐diene‐3,21‐dione. This strategy provides a general method and a key precursor for the divergent synthesis of a variety of glucocorticoids and related steroidal drugs. [ABSTRACT FROM AUTHOR]

Under complex geological conditions of fault system, stratum and terrain, an accurate inversion of the in-situ stress field is a challenging and hot issue in the study on engineering geology. Focusing on the accurate inversion of fine in-situ stress field for deep-buried tunnel under complex geological conditions, and the influence of major geological factors on the stress state, we took the Jiangranshan tunnel of the express way from Shuangjiang to Cangyuan in southwest Yunnan as a case to perform the study. We first established the fine geological model of the Jiangranshan tunnel area by integrating the fine DEM data and the geological survey data. Then, taking the measured in-situ stress data in the tunnel site and the measured GPS data of velocity field as the integrated constraints, we carried out the inversion of fine in-situ stress field in the engineering region of Jiangranshan tunnel. On the basis of the inversion results, we analyzed the characteristics of fine in-situ stress field in the tunnel site and the influence of main geological conditions on the current in-situ stress field. Finally, we estimated the engineering geological stability of the surrounding rock mass of the Jiangranshan tunnel. The results show that the simulated displacement velocity field in the Jiangranshan tunnel area is basically consistent with the GPS observation results, revealing that the inversion model adopted in this study can well reflect the current tectonic stress environment of the engineering region. The simulation results show that the level of the in-situ stress field in the western part of the study area is relatively high, while it is low in the eastern part. The direction of the maximum principal stress shows partial deflection in the study area. The influence of the nearly E-W-striking Xiaoheijiang fault--the largest fault in the study area--on the in-situ stress is that it causes the slight deflection of the direction of the maximum principal stress; however, it does not cause abrupt change of the in-situ stress magnitude. The secondary faults and topography show little effect on the in-situ stress field, which is limited to very small area and does not cause notable disturbance of the in-situ stress field. The results reveal that the maximum, intermediate, and minimum principal stresses along the tunnel mainly distribute in 7.47--27.23 MPa, 1.59--15.12 MPa, and 0.01--6.71 MPa, respectively, and does not show obviously abnormal characteristics. The engineering geological stability of the surrounding rock mass of the Jiangranshan tunnel is estimated by the stress intensity index (i.e., the ratio of the maximum tangential stress to the uniaxial compress strength of rock). The estimation results, which are determined by integrating the stress field simulation results and the mechanical properties of the typical rocks obtained from the laboratory tests, show that the stress intensity indexes of the Jiangranshan tunnel mainly range between 0.20--0.48. It indicates that the surrounding rock masses of the Jiangranshan tunnel are mainly in a stable state or in a slight rockburst risk under the current in-situ stress conditions. The conclusion can be drawn from the case study that under the complex geological conditions, the fine geological model suitable for the scale of engineering area can be established by using the fine DEM and actual fault and strata data, which can effectively reveal the characteristics of the in-situ stress field in engineering area and the influence of the main geological conditions. This study provides not only the profound understanding of the in-situ stress field of the Jiangranshan tunnel area, but also the implications for the fine inversion of in-situ stress field under complex geological conditions in Yunnan and other similar areas. In addition, this study can directly support the stability evaluation of the surrounding rock of the deep-buried Jiangranshan tunnel. [ABSTRACT FROM AUTHOR]

P2Y 12 antagonists are widely used as antiplatelet agents for the prevention and treatment of arterial thrombosis. Based on the scaffold of a known P2Y 12 antagonist AZD1283, a series of novel bicyclic pyridine derivatives were designed and synthesized. The cyclization of the ester substituent on the pyridine ring to the ortho-methyl group led to lactone analogues of AZD1283 that showed significantly enhanced metabolic stability in subsequent structure-pharmacokinetic relationship studies. The metabolic stability was further enhanced by adding a 4-methyl substituent to the piperidinyl moiety. Compound 58l displayed potent inhibition of platelet aggregation in vitro as well as antithrombotic efficacy in a rat ferric chloride model. Moreover, 58l showed a safety profile that was superior to what was observed for clopidogrel in a rat tail-bleeding model. These results support the further evaluation of compound 58l as a promising drug candidate.