Identification of novel piperazine-tethered phthalazines as selective CDK1 inhibitors endowed with in vitro anticancer activity toward the pancreatic cancer.

Pharmacologic inhibition of the oncogenic protein kinases using small molecules is a promising strategy to combat several human malignancies. CDK1 is an example of such a valuable target for the management of pancreatic ductal adenocarcinomas (PDAC); its overexpression in PDAC positively correlates with the size, histological grade and tumor aggressiveness. Here we report the identification of novel series of 1-piperazinyl-4-benzylphthalazine derivatives (8a-g, 10a-i and 12a-d) as promising anticancer agents with CDK1 inhibitory activity. The anti-proliferative activity of these agents was first screened on a panel of 11 cell lines representing 5 cancers (pancreas, melanoma, leukemia, colon and breast), and then confirmed on two CDK1-overexpressing PDAC cell lines (MDA-PATC53 and PL45 cells). Phthalazines 8g, 10d and 10h displayed potent activity against MDA-PATC53 (IC50 = 0.51, 0.88 and 0.73 µM, respectively) and PL45 (IC50 = 0.74, 1.14 and 1.00 µM, respectively) cell lines. Furthermore, compounds 8g, 10d and 10h exhibited potent and selective inhibitory activity toward CDK1 with IC50 spanning in the range 36.80-44.52 nM, whereas they exerted weak inhibitory effect on CDK2, CDK5, AXL, PTK2B, FGFR, JAK1, IGF1R and BRAF kinases. Western blotting of CDK1 in MDA-PATC53 cells confirmed the ability of target phthalazines to diminish the CDK1 levels, and cell cycle analyses revealed their ability to arrest the cell cycle at G2/M phase. In conclusion, a panel of potent and selective CDK1 inhibitors were identified which can serve as lead compounds for designing further CDK1 inhibitors.

Discovery of novel thiazolyl-pyrazolines as dual EGFR and VEGFR-2 inhibitors endowed with in vitro antitumor activity towards non-small lung cancer.

New series of thiazolyl-pyrazoline derivatives (7a-7d, 10a-10d and 13a-13f) have been synthesised and assessed for their potential EGFR and VEGFR-2 inhibitory activities. Compounds 10b and 10d exerted potent and selective inhibitory activity towards the two receptor tyrosine kinases; EGFR (IC50 = 40.7 ± 1.0 and 32.5 ± 2.2 nM, respectively) and VEGFR-2 (IC50 = 78.4 ± 1.5 and 43.0 ± 2.4 nM, respectively). The best anti-proliferative activity for the examined thiazolyl-pyrazolines was observed against the non-small lung cancer cells (NSCLC). Compounds 10b and 10d displayed pronounced efficacy against A549 (IC50 = 4.2 and 2.9 µM, respectively) and H441 cell lines (IC50 = 4.8 and 3.8 µM, respectively). Moreover, our results indicated that 10b and 10d were much more effective towards EGFR-mutated NSCLC cell lines (NCI-H1650 and NCI-H1975 cells) than gefitinib. Finally, compounds 10b and 10d induce G2/M cell cycle arrest and apoptosis and inhibit migration in A549 cancerous cells.

Haptic tuck for reverse optic capture of a single-piece acrylic toric or other single-piece acrylic intraocular lenses.

We describe a new technique for capsule fixation of 1-piece acrylic toric intraocular lens (IOL) or other 1-piece acrylic IOLs in the presence of a large posterior capsule tear resulting in an open capsule. To keep the thick haptics out of the sulcus, reverse optic capture is necessary, with the haptics below the capsule and the optic edges above the capsule. This is done by placing the IOL in the sulcus and if it is a toric IOL, with the toric marks on the optic aligned with the corneal marks. Then, each haptic is separately tucked through the anterior continuous curvilinear capsulorhexis (CCC) opening, leaving the optic edges above the capsule. This technique achieves reverse optic capsulorhexis capture without the challenge of injecting the IOL through the CCC with an open posterior capsule. We propose the term haptic tuck for reverse optic capture for this technique.

Incidence of implantable Collamer lens-induced cataract.

OBJECTIVE: Although the literature on the implantable Collamer lens (ICL) suggests an increasing rate of anterior subcapsular cataract (ASC) development with increasing age and decreasing anterior chamber depth (ACD), the exact correlation is not known. We performed a retrospective observation study of 1653 eyes and calculated the incidence of ICL removal with cataract extraction and intraocular lens placement (CE-IOL) as a result of ASC, in correlation to patient's age and ACD. DESIGN: Retrospective observation study. SETTING: The Gimbel Eye Centre, Calgary, Alberta, Canada. METHODS: We analyzed ICL V4 model (Visian ICL; STAAR Surgical, Monrovia, CA) implanted in 1653 eyes with myopia from 2000 to 2012 at the Gimbel Eye Centre, Calgary. Myopic patients aged 19 years and older with no history of cataracts were included. The rate of ICL removal with cataract extraction was calculated. Parameters such as age, sex, refractive sphere, refractive cylinder, length of follow-up, and ACD were collected. Cataract-free survival with comparison of FDA and non-FDA cohorts was conducted using Kaplan-Meier survival curves with the log-rank test. In addition, covariates adjusted hazards ratios and 95% confidence intervals were calculated using Cox regression. RESULTS: Of the 1653 eyes included in this study, a total of 46 eyes underwent ICL removal with CE-IOL. The length of follow-up varied between 2 and 14 years. CONCLUSIONS: This retrospective study demonstrated that the rate of developing ASCs positively correlated with age and negatively correlated with ACD.