Design, synthesis and systematic evaluation of cytotoxic 3-heteroarylisoquinolinamines as topoisomerases inhibitors.

A series of 3-heteroarylisoquinolinamines were designed, synthesized and evaluated for cytotoxicity, topoisomerases (topos) inhibitory activities and cell cycle inhibition. Several of the 3-heteroarylisoquinolines exhibited selective cytotoxicity against human ductal breast epithelial tumor (T47D) cells over non-cancerous human breast epithelial (MCF-10A) and human prostate cancer (DU145) cells. Most of the derivatives showed greater cytotoxicity in human colorectal adenocarcinoma (HCT-15) cells than camptothecin (CPT), etoposide and doxorubicin (DOX). Generally, 3-heteroarylisoquinolinamines displayed greater affinity for topo I than topo II. 3-Heteroarylisoquinolinamines with greater topo I inhibitory effect exhibited potent cytotoxicity. Piperazine-substituted derivative, 5b, with potent topo I and moderate topo II activities intercalated between DNA bases and interacted with topos through H-bonds at the DNA cleavage site of a docking model. Moreover, flow cytometry indicated that cytotoxic 3-heteroarylisoquinolinamines led to accumulation of human cervical (HeLa) cancer cells in the different phases of the cell cycle before apoptosis. Taken together, 3-heteroarylisoquinolinamines possessed potent cytotoxicity with topos and cell cycle inhibitory activities.

Inhaled essential oil from Chamaecyparis obtuse ameliorates the impairments of cognitive function induced by injection of ß-amyloid in rats.

CONTEXT: Chamaecyparis obtusa Sieb. & Zucc., Endlicher (Cupressaceae) forest bathing or aromatherapy has been shown in various studies to have biological functions such as anticancer, antiallergies, antiinflammatory, and antioxidant activity. However, no reports exist on the pharmacological or biological activities of the essential oil of C. obtusa (EOCO) or its effects on central nervous system. OBJECTIVE: The aggregation and formation of ß-amyloid peptides (Aß) into fibrils are central events in the pathogenesis of Alzheimer's disease (AD), and overproduction and aggregation of Aß into oligomers have been known to trigger neurotoxicity. In this study, we investigated the effects of inhaled EOCO on cognitive function and neuronal apoptosis in rats intrahippocampally injected with Aß. MATERIALS AND METHODS: To model AD, 4 µg of aggregated Aß was injected into the hippocampus. To test the effects of EOCO, behavioral performance in the Morris water maze was tested 4 days after injection. After behavioral testing, brain sections were prepared for TTC staining and TUNEL assay. RESULTS: Inhaled EOCO protected spatial learning and memory from the impairments induced by Aß(1-40) injection. In addition, the behavioral deficits accompanying Aß(1-40)-induced AD were attenuated by inhalation of EOCO. Furthermore, acetylcholinesterase (AChE) activity and neuronal apoptosis were significantly inhibited in rats treated with Aß(1-40) and EOCO compared to rats treated only with Aß(1-40). DISCUSSION AND CONCLUSION: EOCO suppressed both AD-related neuronal cell apoptosis and AD-related dysfunction of the memory system. Thus, the results of this study support EOCO as a candidate drug for the treatment of AD.

Design, docking, and synthesis of novel indeno[1,2-c]isoquinolines for the development of antitumor agents as topoisomerase I inhibitors.

An intramolecular radical cyclization reaction of 4-bromo-3-arylisoquinolines 11a-c allowed the efficient synthesis of 11-methylindenoisoquinolines 2a-c. 5-(2-Aminoethylamino)indeno[1,2-c]isoquinolin-11-one 4 was also prepared in the convenient manner. The synthesized compounds were tested in vitro for cytotoxicity and DNA-topoisomerase 1 (top 1) inhibitory activity. The dramatic enhancement of top 1 inhibitory activity of 4 was explained by a docking study using the FlexX program.

Transcriptional silencing of the RUNX3 gene by CpG hypermethylation is associated with lung cancer.

RUNX family transcription factors are integral components of TGF-beta signaling pathways and have been implicated in cell cycle regulation, differentiation, apoptosis, and malignant transformation. It was noted previously that allele loss and loss of expression of RUNX3 are causally involved in gastric carcinogenesis. Our results demonstrate that RUNX3 is inactivated by aberrant DNA methylation in approximately 19% of lung cancer cell lines and 24% of primary lung cancer specimens. RUNX3 methylation is tumor-specific, since it is not observed in surrounding normal lung tissues. Our results suggest that loss of RUNX3 expression by DNA hypermethylation is frequently associated with the evolution of lung cancer.