3D-QSAR and docking studies of pentacycloundecylamines at the sigma-1 (σ1) receptor.

Pentacycloundecylamine (PCU) derived compounds have been shown to be promising lead structures for the development of novel drug candidates aimed at a variety of neurodegenerative and psychiatric diseases. Here we show for the first time a 3D quantitative structure-activity relationship (3D-QSAR) for a series of aza-PCU-derived compounds with activity at the sigma-1 (σ1) receptor. A comparative molecular field analysis (CoMFA) model was developed with a partial least squares cross validated (q(2)) regression value of 0.6, and a non-cross validated r(2) of 0.9. The CoMFA model was effective at predicting the sigma-1 activities of a test set with an r(2) >0.7. We also describe here the docking of the PCU-derived compounds into a homology model of the sigma-1 (σ1) receptor, which was developed to gain insight into binding of these cage compounds to the receptor. Based on docking studies we evaluated in a [(3)H]pentazocine binding assay an oxa-PCU, NGP1-01 (IC50=1.78µM) and its phenethyl derivative (IC50=1.54µM). Results from these studies can be used to develop new compounds with specific affinity for the sigma-1(σ1) receptor.

Curcumin and neurodegenerative diseases: a perspective.

INTRODUCTION: Curcumin, a dietary polyphenol found in the curry spice turmeric, possesses potent antioxidant and anti-inflammatory properties and an ability to modulate multiple targets implicated in the pathogenesis of chronic illness. Curcumin has shown therapeutic potential for neurodegenerative diseases including Alzheimer's disease (AD) and Parkinson's disease (PD). AREAS COVERED: This article highlights the background and epidemiological evidence of curcumin's health benefits and its pharmacodynamic and pharmacokinetic profile. Curcumin's ability to counteract oxidative stress and inflammation and its capacity to modulate several molecular targets is reviewed. We highlight the neuroprotective properties of curcumin including pre-clinical evidence for its pharmacological effects in experimental models of AD and PD. The bioavailability and safety of curcumin, the development of semi-synthetic curcuminoids as well as novel formulations of curcumin are addressed. EXPERT OPINION: Curcumin possesses therapeutic potential in the amelioration of a host of neurodegenerative ailments as evidenced by its antioxidant, anti-inflammatory and anti-protein aggregation effects. However, issues such as limited bioavailability and a paucity of clinical studies examining its therapeutic effectiveness in illnesses such as AD and PD currently limit its therapeutic outreach. Considerable effort will be required to adapt curcumin as a neuroprotective agent to be used in the treatment of AD, PD and other neurodegenerative diseases.

Dietary phytochemicals in the chemoprevention and treatment of hepatocellular carcinoma: in vivo evidence, molecular targets, and clinical relevance.

Hepatocellular carcinoma (HCC), one of the most common and lethal cancers, is a growing menace in modern society. Until recently, the majority of detected cases of liver cancer have been found in the developing nations of Asia and Africa; however, its occurrence has significantly increased in the United States. HCC occurs due to several etiologies, such as alcoholism, dietary carcinogens, iron overload, viral hepatitis, as well as several hepatic chronic diseases. In view of the limited treatment options, such as surgery and transplantation, a critical need exists to examine alternative approaches. The use of phytochemicals obtained from dietary sources provides a novel and fascinating preventive and therapeutic approach against HCC. Dietary phytochemicals possess potent antioxidant and anti-inflammatory properties which are extremely critical to combat the significant oxidative stress and inflammation implicated in liver cancer. An impressive number of phytochemicals have shown considerable promise as candidates for the prevention and treatment of HCC. In this article, we systematically review the in vivo pre-clinical evidence documenting the chemopreventive and therapeutic potential of several important dietary phytochemicals in HCC. This review critically examines the molecular mechanisms of the pharmacological effects of the aforementioned animal studies. Clinical and epidemiological studies are also highlighted in this review. Emerging issues such as bioavailability, dose optimization, targeted drug delivery, role of botanical extracts and synergy are also discussed. Finally, current challenges, limitations, future directions, innovative concepts and novel hypotheses for the use of dietary phytochemicals in the chemoprevention and amelioration of human HCC are presented.