Novel Isoquinolinamine and Isoindoloquinazolinone Compounds Exhibit Antiproliferative Activity in Acute Lymphoblastic Leukemia Cells

Nitrogen-containing heterocycles such as quinoline, quinazolinones and indole are scaffolds of natural products and have broad biological effects. During the last years those structures have been intensively synthesized and modified to yield new synthetic molecules that can specifically inhibit the activity of dysregulated protein kinases in cancer cells. Herein, a series of newly synthesized isoquinolinamine (FX-1 to 8) and isoindoloquinazolinone (FX-9, FX-42, FX-43) compounds were evaluated in regards to their anti-leukemic potential on human B- and T-acute lymphoblastic leukemia (ALL) cells. Several biological effects were observed. B-ALL cells (SEM, RS4;11) were more sensitive against isoquinolinamine compounds than T-ALL cells (Jurkat, CEM). In SEM cells, metabolic activity decreased with 10 μM up to 26.7% (FX-3), 25.2% (FX-7) and 14.5% (FX-8). The 3-(p-Tolyl) isoquinolin-1-amine FX-9 was the most effective agent against B- and T-ALL cells with IC50 values ranging from 0.54 to 1.94 μM. None of the tested compounds displayed hemolysis on erythrocytes or cytotoxicity against healthy leukocytes. Anti-proliferative effect of FX-9 was associated with changes in cell morphology and apoptosis induction. Further, influence of FX-9 on PI3K/AKT, MAPK and JAK/STAT signaling was detected but was heterogeneous. Functional inhibition testing of 58 kinases revealed no specific inhibitory activity among cancer-related kinases. In conclusion, FX-9 displays significant antileukemic activity in B- and T-ALL cells and should be further evaluated in regards to the mechanisms of action. Further compounds of the current series might serve as templates for the design of new compounds and as basic structures for modification approaches.

Comparative kinematic gait analysis in young and old Beagle dogs

Age-related involution in dogs involves loss of muscle mass and changes in connective tissue and articular cartilage. The aim of this study was to examine whether an age-related influence on joint mobility can be detected in the absence of disease. Five young (mean age 2.0 years) and five old (mean age 10.4 years) healthy and sound Beagle dogs underwent computer-assisted gait analysis during locomotion on a treadmill. Shoulder, elbow, carpal, hip, stifle, and tarsal joint angles including joint angle progression curves, minimum and maximum joint angles, and range of motion (ROM) in degrees were analyzed. The old group had a smaller maximum joint angle (p = 0.037) and ROM (p = 0.037) of the carpal joint; there were similar tendencies in the shoulder, elbow, and carpal joints. Descriptive analysis of the progression curves revealed less flexion and extension of the forelimb joints. The results indicate restricted joint mobility of the forelimb in old dogs, primarily of the carpal joint. Results in the joints of the hindlimb were inconsistent, and the contrasting alterations may be due to a compensatory mechanism. As most alterations were found in the distal joints, these should receive particular attention when examining elderly dogs.