Identification of Novel Aryl Carboxamide Derivatives as Death-Associated Protein Kinase 1 (DAPK1) Inhibitors with Anti-Proliferative Activities: Design, Synthesis, In Vitro, and In Silico Biological Studies.

Death-associated protein kinase 1 (DAPK1) is a serine/threonine protein kinase involved in diverse fundamental cellular processes such as apoptosis and autophagy. DAPK1 isoform plays an essential role as a tumor suppressor and inhibitor of metastasis. Consequently, DAPK1 became a promising target protein for developing new anti-cancer agents. In this work, we present the rational design and complete synthetic routes of a novel series of eighteen aryl carboxamide derivatives as potential DAPK1 inhibitors. Using a custom panel of forty-five kinases, a single dose of 10 µM of the picolinamide derivative 4a was able to selectively inhibit DAPK1 kinase by 44.19%. Further investigations revealed the isonicotinamide derivative 4q as a promising DAPK1 inhibitory lead compound with an IC50 value of 1.09 µM. In an in vitro anticancer activity assay using a library of 60 cancer cell lines including blood, lung, colon, CNS, skin, ovary, renal, prostate, and breast cancers, four compounds (4d, 4e, 4o, and 4p) demonstrated high anti-proliferative activity with mean % GI ~70%. Furthermore, the most potent DAPK1 inhibitor (4q) exhibited remarkable activity against leukemia (K-562) and breast cancer (MDA-MB-468) with % GI of 72% and 75%, respectively.

Anatomical structures in the maxillary sinus related to lateral sinus elevation: a cone beam computed tomographic analysis.

OBJECTIVES: The objective of this study is to evaluate the anatomical structures in the maxillary sinus with relation to lateral approach sinus elevation utilizing cone beam computed tomography (CT) scans taken prior to sinus elevation surgery. MATERIALS AND METHODS: A total of 150 CT images were acquired from 150 patients (90 men and 60 women; mean age, 49.4 years, range 23-86 years) who were being treated with implant-supported restorations in the posterior edentulous maxilla. Of the 150 CT scans, 65 were of the right sinus and 85 of the left sinus. Measurements of the anatomical structures in the maxillary sinus were conducted on the CT images. RESULTS: In the mean width of the lateral wall, there were statistically significant values among the measurement points (P < 0.05). The anterior area of the sinus lateral wall was thicker than the posterior lateral wall. There was a statistically significant difference between the vessel diameter and lateral wall width (P < 0.05). As sinus lateral wall width increased, so did the vessel diameter. The mean distance to the inferior border of the vessel from the sinus floor and from the alveolar crest was 8.25 and 17.03 mm, respectively. The intraosseous group among the vessel position was 64.3%, so the intraosseous vessel could be visualized in CT scans at 64.3%. In angle A, the group of less than 30° was 4.8%. Schneiderian membrane perforation by narrow angle had a low risk. The prevalence of the septa related to Schneiderian membrane perforation was 44%. The distance to the inferior border of the vessel from the alveolar crest being less than 15 mm was 31%. The vessel diameter greater than 1 mm was 37.8%. CONCLUSIONS: Based on present research about utilizing cone beam CT scans for sinus elevation, the alteration of the lateral approach sinus elevation technique is highly recommended if complications such as membrane perforation or bleeding are expected.