Structure-activity relationship of pyrazolo pyrimidine derivatives as inhibitors of mitotic kinesin Eg5 and anticancer agents

Human kinesin Eg5 is a potential inhibiting site for cancer chemotherapy. Blocking metaphase by binding foreign inhibitors with Eg5 eventually leads to apoptotic cell death. Here, we report the pyrazolopyrimidine derivates as potent inhibitors of Eg5 that prevents mitotic kinesin progression. IC₅₀ values were evaluated against the motor domain of Eg5 using steady-state ATPase assay. To better understanding, we have performed molecular docking simulation. It reveals that the interactions of the proposed inhibitors with both the allosteric sites (helices α2, α3 and loopL5, and helices α4 & α6). Out of fifteen pyrazolopyrimidine derivates, three compounds (12, 25, and 27) have shown significant inhibition of Eg5. The synthesized compounds (12, 25, and 27) were tested for their in-vitro anticancer activity against cervical cancer cell line (HeLa).     

Perioperative cardiovascular complications versus perioperative bleeding in consecutive patients with known cardiac disease undergoing non-cardiac surgery. Focus on antithrombotic medication. The PRAGUE-14 registry

Background

Interruption of antithrombotic treatment before surgery may prevent bleeding, but at the price of increasing cardiovascular complications. This prospective study analysed the impact of antithrombotic therapy interruption on outcomes in non-selected surgical patients with known cardiovascular disease (CVD).

Methods

All 1200 consecutive patients (age 74.2 ± 10.2 years) undergoing major non-cardiac surgery (37.4 % acute, 61.4 % elective) during a period of 2.5 years while having at least one CVD were enrolled. Details on medication, bleeding, cardiovascular complications and cause of death were registered.

Results

In-hospital mortality was 3.9 % (versus 0.9 % mortality among 17,740 patients without CVD). Cardiovascular complications occurred in 91 (7.6 %) patients (with 37.4 % case fatality). Perioperative bleeding occurred in 160 (13.3 %) patients and was fatal in 2 (1.2 % case fatality). Multivariate analysis revealed age, preoperative anaemia, history of chronic heart failure, acute surgery and general anaesthesia predictive of cardiovascular complications. For bleeding complications multivariate analysis found warfarin use in the last 3 days, history of hypertension and general anaesthesia as independent predictive factors. Aspirin interruption before surgery was not predictive for either cardiovascular or for bleeding complications.

Conclusions

Perioperative cardiovascular complications in these high-risk elderly all-comer surgical patients with known cardiovascular disease are relatively rare, but once they occur, the case fatality is high. Perioperative bleeding complications are more frequent, but their case fatality is extremely low. Patterns of interruption of chronic aspirin therapy before major non-cardiac surgery are not predictive for perioperative complications (neither cardiovascular, nor bleeding). Simple baseline clinical factors are better predictors of outcomes than antithrombotic drug interruption patterns.