Recent investigations suggest that gut microbiota affects the brain activity through the microbiota-gut-brain axis under both physiological and pathological disease conditions like Parkinson’s disease. Further dopamine synthesis in the brain is induced by dopamine producing enzymes that are controlled by gut microbiota via the microbiota-gut-brain axis. Also alpha synuclein deposition and the associated neurodegeneration in the enteric nervous system that increase intestinal permeability, oxidative stress, and local inflammation, accounts for constipation in Parkinson’s disease patients. The trigger that causes blood brain barrier leakage, immune cell activation and inflammation, and ultimately neuroinflammation in the central nervous system is believed to be due to the chronic low-grade inflammation in the gut. The non-motor symptoms that appear years before motor symptoms could be reliable early biomarkers, if they could be correlated with the established and reliable neuroimaging techniques or behavioral indices. The future directions should therefore, focus on the exploration of newer investigational techniques to identify these reliable early biomarkers and define the specific gut microbes that contribute to the development of Parkinson’s disease. This ultimately should pave the way to safer and novel therapeutic approaches that avoid the complications of the drugs delivered today to the brain of Parkinson’s disease patients.
Carboline and its naturally obtained analogs are of importance due to their wide range of biological properties. In the present review, we intend to discuss the main trends in the synthesis of-carboline analogs based on pyridine derivatives (including the Fischer synthesis, Graebe-Ullmann reaction, photochemical cyclization, arylation of substituted pyridines, quinolines, etc.) and indole derivatives in order to compare the potential of finding novel drugs in this series. In other words the development, current status and innovative new options for the design and synthesis of-carboline analogs are reviewed here. Published data about the various pharmacological functions and the spectroscopy of compounds belonging to this series are summarized. It also discusses the scope, future perspectives and the problems yet to be explored with respect to the synthesis of functionalised bioactive heteroannulated-carbolines in search of novel drugs.
The effect of ethanol extract of Phyllanthus maderaspatensis (PME), a popular south Indian dietary supplement, was studied for its chemoprotective property on adriamycin (ADR)-induced toxicity and oxidative stress in mice. Adriamycin toxicity was evaluated biochemically by measuring the serum concentration of lactate dehydrogenase (LDH) and creatinine phosphokinase (CPK). Genotoxicity was evaluated by measuring the frequency of micronucleated polychromatic erythrocytes (MNPCEs) in bone marrow cells. Oxidative stress in the heart tissue was estimated by measuring the glutathione (GSH) levels in the homogenate. The treatment of mice with different doses of PME (400 mg/kg and 600 mg/kg body weight, p.o.,) for 7 days before the administration of a single i.p. dose of ADR (15 mg/kg) exhibited significant protection in a dose-dependent manner. The results clearly indicate that PME has a protective effect against ADR-induced toxicity, as revealed by the decrease in the concentrations of LDH, CPK, and the frequency of MNPCEs. The increased levels of GSH are indicative of the antioxidant property of PME.
Background: :
Current drugs used for the treatment of hormone-dependent breast cancer function as
anti-estrogens in the breast, in addition to Estrogen Receptor (ER) agonists in the uterus, thus elevate a woman’s
risk of developing uterine cancer. This is due to the lack of selective binding and partial agonistic effect of these
drugs towards estrogen receptors. In recent years, therefore, researchers have turned their attention towards
antiestrogens devoid of these agonist properties and thus have a mechanism of action different from the existing
drugs.
Objective::
In this context, we report here the design, development and in vitro evaluation of some novel pharmacophores
containing coumarin and fatty acid scaffolds for their anti-breast cancer activity.
Methods: :
A library of coumarin-fatty acid conjugates was designed using structure-based drug design approach.
The conjugates which have shown good in silico results were then synthesized, characterized and evaluated for
their anti-breast cancer activity by MTT assay, Apoptotic assay, Cell proliferation assay, Estrogen binding assay
and Gene expression study.
Results:
Out of the fifteen compounds screened, two compounds, SAC-2 and LNAC-2, showed good activity
with IC50 values 22µg/ml, 25μg/ml, respectively. These compounds suppressed the proliferation of ER overexpressed
MCF-7 cells, increased ERα degradation and hence inactivate the ERα pathway. ER binding assay and
gene expression RT-PCR study reveal that SAC-2 downregulated the expression of ERα receptor and AKT-1 gene.
Conclusion::
Compound SAC-2 is a good antagonist to ER and hence has a potential for treating breast cancer
and other cancers where AKT plays an important role.
The enzyme, α-topoisomerase II (α-Topo II), is known to regulate efficiently the topology of DNA. It is highly expressed in rapidly proliferating cells and plays an important role in replication, transcription and chromosome organisation. This has prompted several investigators to pursue α-Topo II inhibitors as anticancer agents. δ-Carboline, a natural product, and its synthetic derivatives are known to exert potent anticancer activity by selectively targeting α-Topo II. Therefore, it is of interest to design carboline derivatives fused with pyrrolidine-2,5-dione in this context. δ-Carbolines fused with pyrrolidine-2,5-dione are of interest because the succinimide part of fused heteroaromatic molecule can interact with the ATP binding pocket via the hydrogen bond network with selectivity towards α-Topo II. The 300 derivatives designed were subjected to the Lipinski rule of 5, ADMET and toxicity prediction. The designed compounds were further analysed using molecular docking analysis on the active sites of the α-Topo II crystal structure (PDB ID:1ZXM). Molecular dynamic simulations were also performed to compare the binding mode and stability of the protein-ligand complexes. Compounds with ID numbers AS89, AS104, AS119, AS209, AS239, AS269, and AS299 show good binding activity compared to the co-crystal ligand. Molecular Dynamics simulation studies show that the ligand binding to α-Topo II in the ATP domain is stableand the protein-ligand conformation remains unchanged. Binding free energy calculations suggest that seven molecules designed are potential inhibitors for α-Topo II for further consideration as anticancer agents.
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