Design and synthesis of substituted pyrido[3,2-d]-1,2,3-triazines as potential Pim-1 inhibitors.

A novel series of substituted pyrido[3,2-d]-1,2,3-triazines were designed and synthesized as Pim-1 inhibitors through scaffold hopping. Most of the derivatives showed potent in vitro Pim-1 inhibitory activities and anti-proliferative effects toward prostate cancer cells. Among them, 6b, 6h and 6m showed the best Pim-1 inhibitory activity with IC50 values of 0.69, 0.60 and 0.80 µM, respectively. Furthermore, compounds 6b, 6i, 6j and 6m showed strong inhibitory activity to human prostate cancer LNcap and PC-3 cell lines with IC50 values at low micromolar level. Structure-activity relationship analysis revealed that appropriate substitutions at C-6 positions contributed to the kinase inhibition and antiproliferative effects. Moreover, western blot assay suggested that 6j could decrease the levels of p-BAD and p-4E-BP1 in a dose-dependent manner in PC-3 cells. Docking studies showed that 3-N of the scaffold formed a hydrogen bond with Lys67, aromatic 4-aniline formed a key π-π stack with Phe49. Taken together, this study might provide the first sight for developing the pyrido[3,2-d]-1,2,3-triazine scaffold as novel Pim-1 inhibitors.

Treatment of refractory giant macular hole by vitrectomy with internal limiting membrane transplantation and autologous blood.

AIM: To investigate the effect of internal limiting membrane transplantation and autologous blood on treating refractory giant macular hole. METHODS: Thirty-seven eyes with giant macular hole of the smallest hole diameter >700 µm, the maximum diameter of the substrate >1000 µm and hole formation factor <0.6 underwent surgical treatment. The patients were randomly divided into two groups. Nineteen eyes with surgical flip of the internal limiting membrane in group A, 18 eyes with internal limiting membrane transplantation in group B who underwent the tamponade of internal limiting membrane into the hole, autologous plasma was used to seal the hole. The patients were followed up for 3mo, optical coherence tomography and best corrected visual acuity (BCVA) were recorded before and after operation, and the results were statistically analyzed. RESULTS: At 3mo after operation, BCVA of the two groups was significantly improved compared with that before operation (tA=4.192, tB=4.374, P<0.05). But there was no significant difference in visual acuity between the two groups (χ2=0.128, P>0.05). At 3mo after operation, the closure rate of group A was 68.4%, and 100% in group B. (χ2=5.628, P<0.05). The defect diameter of inner segment/outer segment at 3mo after the operation was significantly lower than that before operation (tA=12.287, tB=15.481, P<0.05), and the difference was statistically significant (t=2.552, P<0.05). CONCLUSION: Internal limiting membrane transplantation combined with autologous whole blood can improve the postoperative closure rate of the refractory large aperture, and can effectively improve the postoperative visual acuity.