Current Medicinal Chemistry (v.21, #17)

Is the Clinical Use of Cannabis by Oncology Patients Advisable? by Gil Bar-Sela, Adva Avisar, Ron Batash, Moshe Schaffer (1923-1930).
The use of the cannabis plant for various medical indications by cancer patients has been rising significantly inthe past few years in several European countries, the US and Israel. The increase in use comes from public demand for themost part, and not due to a scientific basis. Cannabis chemistry is complex, and the isolation and extraction of the activeingredient remain difficult. The active agent in cannabis is unique among psychoactive plant materials, as it contains nonitrogen and, thus, is not an alkaloid. Alongside inconclusive evidence of increased risks of lung and head and neck cancersfrom prolonged smoking of the plant produce, laboratory evidence of the anti-cancer effects of plant components exists,but with no clinical research in this direction. The beneficial effects of treatment with the plant, or treatment withmedicine produced from its components, are related to symptoms of the disease: pain, nausea and vomiting, loss of appetiteand weight loss. The clinical evidence of the efficacy of cannabis for these indications is only partial. However, recentscientific data from studies with THC and cannabidiol combinations report the first clinical indication of cancer-relatedpain relief. The difficulties of performing research into products that are not medicinal, such as cannabis, have not alloweda true study of the cannabis plant extract although, from the public point of view, such studies are greatly desirable.

Disturbed Tryptophan Metabolism in Cardiovascular Disease by H. Mangge, I. Stelzer, E.Z. Reininghaus, D. Weghuber, T.T. Postolache, D. Fuchs (1931-1937).
Atherosclerosis (AS), a major pathologic consequence of obesity, is the main etiological factor of cardiovasculardisease (CVD), which is the most common cause of death in the western world. A systemic chronic low grade immune-mediated inflammation (scLGI) is substantially implicated in AS and its consequences. In particular, proinflammatorycytokines play a major role, with Th1-type cytokine interferon-γ (IFN-γ) being a key mediator. Amongvarious other molecular and cellular effects, IFN-γ activates the enzyme indoleamine 2,3-dioxygenase (IDO) in monocytederivedmacrophages, dendritic, and other cells, which, in turn, decreases serum levels of the essential amino acid tryptophan(TRP). Thus, people with CVD often have increased serum kynurenine to tryptophan ratios (KYN/TRP), a result ofan increased TRP breakdown. Importantly, increased KYN/TRP is associated with a higher likelihood of fatal cardiovascularevents. A scLGI with increased production of the proinflammatory adipokine leptin, in combination with IFN-γ andinterleukin-6 (IL-6), represents another central link between obesity, AS, and CVD. Leptin has also been shown to contributeto Th1-type immunity shifting, with abdominal fat being thus a direct contributor to KYN/TRP ratio. However,TRP is not only an important source for protein production but also for the generation of one of the most important neurotransmitters,5-hydroxytryptamine (serotonin), by the tetrahydrobiopterin-dependent TRP 5-hydroxylase. In prolongedstates of scLGI, availability of free serum TRP is strongly diminished, affecting serotonin synthesis, particularly in thebrain. Additionally, accumulation of neurotoxic KYN metabolites such as quinolinic acid produced by microglia, can contributeto the development of depression via NMDA glutamatergic stimulation. Depression had been reported to be associatedwith CVD endpoints, but it most likely represents only a secondary loop connecting excess adipose tissue, scLGIand cardiovascular morbidity and mortality. Accelerated catabolism of TRP is further involved in the pathogenesis of theanemia of scLGI. The pro-inflammatory cytokine IFN-γ suppresses growth and differentiation of erythroid progenitorcells, and the depletion of TRP limits protein synthesis and thus hemoglobin production, and, through reduction in oxygensupply, may contribute to ischemic vascular disease. In this review we discuss the impact of TRP breakdown and the relatedcomplex mechanisms on the prognosis and individual course of CVD. Measurement of TRP, KYN concentrations,and calculation of the KYN/TRYP ratio will contribute to a better understanding of the interplay between inflammation,metabolic syndrome, mood disturbance, and anemia, all previously described as significant predictors of an unfavorableoutcome in patients with CVD. The review leads to a novel framework for successful therapeutic modification of severalcardinal pathophysiological processes leading to adverse cardiovascular outcome.

Pharmacophore and Binding Analysis of Known and Novel B-RAF Kinase Inhibitors by F. Baska, I. Szabadkai, A. Sipos, N. Breza, C. Szantai-Kis, L. Kekesi, R. Garamvolgyi, Z. Nemes, F. Baska, L. Neumann, R. Torka, A. Ullrich, G. Keri, L. Orfi (1938-1955).
The extensively investigated serine/threonine kinase, B-RAF, is a member of the RAS/RAF/MEK/ERK pathway.It plays important role in the regulation of cell growth, differentiation and survival. The mutation of B-RAF occursfrequently in melanomas and colon tumors; therefore, it is considered as an outstanding therapeutic target. In recent yearsa great number of B-RAF inhibitors have been reported and this number is expected to increase. The aim of our work wasto compare the structures and binding mode of the published B-RAF inhibitors, and then to apply the correlations foundfor the explanation of our experimental results. In the first part of this paper we describe the main pharmacophore featuresof the co-crysallized B-RAF inhibitors published in the literature, focusing on the binding modes and common structuralelements. In the second part we present and characterize our recently developed B-RAF inhibitor family by application ofin silico methods and in vitro kinetic profiling. The inhibitory activity of these compounds was determined in biochemicalkinase- and cell-based assays. The docking and assay results support our conclusion that the presented compound familybelongs to the type I 1/2subgroup, they inhibit B-RAF and B-RAF(V600E) mutant in a sub-micromolar range and most ofthem show selectivity towards B-RAF(V600E) mutant expressing cell lines with equal or even better IC50 values thansorafenib.

Recent Progress in the Research of Small Molecule HIV-1 RNase H Inhibitors by Lili Cao, Weiguo Song, Erik De Clercq, Peng Zhan, Xinyong Liu (1956-1967).
Reverse transcription of human immunodeficiency virus type 1 (HIV-1) is a crucial step in the life cycle initiatedby the viral-coded reverse transcriptase (RT), functioning as RNA- and DNA-dependent DNA polymerase (RDDPand DDDP) and the ribonuclease H (RNase H). The RNase H functions to degrade the RNA strand of the RNA:DNA heteroduplex,which makes it an attractive target for rational anti-HIV-1 drug design and development. Although developmentof drugs targeting the DNA polymerase have been highly successful, the discovery of drugable inhibitors of HIVRNase H is still in its infancy and none of RNase H inhibitors has reached the clinical development stage currently. Thisreview describes the recent progress in the HIV-1 RNase H inhibitors, focusing on their chemical feature, mechanism andthe structure-activity relationship (SAR).

Molecular Dynamics Simulation in RNA Interference by Xia Wang, Yonghua Wang, Lei Zheng, Jianxin Chen (1968-1975).
RNA interference (RNAi) is a mechanism that utilizes small RNA molecules to silence gene expression afterthe gene has been transcribed. To understand the mechanisms of small RNA biogenesis, target nucleic acid recognitionand cleavage, and how they are influenced by other regulators, one needs to know the structures and dynamics of the proteinsor/and nucleic acids in these processes. Molecular dynamics (MD) simulation is a powerful tool for understandingmotions and dynamics of macro-biomolecules at an atomic-scale via theoretical and empirical principles in physicalchemistry. With its application to RNAi, an excellent overview of structural and dynamical mechanistic of RNAi processeshas already emerged. In this review, we summarize the recent advances in MD simulations in the study of functionalmodules and their assemblies and target recognition and cleavage in RNAi processes. Additionally, we also present someperspectives on this technique.

Development of HIV-1 Fusion Inhibitors Targeting gp41 by K. Lu, M.R. Asyifah, F. Shao, D. Zhang (1976-1996).
The HIV-1 envelope protein glycoprotein 41 (gp41) is crucial in the HIV-1 infection process, therefore gp41has emerged as an attractive target for drug design against AIDS. During the past few decades, tremendous efforts havebeen made on developing inhibitors that can prevent the HIV-1 entry process via suppressing functional gp41. In this review,the development of HIV-1 fusion inhibitors targeting gp41 including peptide inhibitors, small molecule inhibitors,vaccines and neutralized antibodies will be discussed.

Advances in Non-peptidomimetic HIV Protease Inhibitors by X. Pang, Z. Liu, G. Zhai (1997-2011).
HIV protease plays a crucial role in the viral life cycle. It can cleave a series of heptamers in the viral Gag andGagPol precursor proteins to generate mature infectious virus particles. Successful inhibition of the protease will preventthis maturation step and hence block the spreading of HIV. However, the rapid emergence of drug resistance makes it urgentto develop new HIV protease inhibitors to combat the global disease. Besides, poor oral bioavailability, unacceptableside effects, high treatment cost and pill burden also trouble the application of HIV protease inhibitors. In such situations,non-peptidomimetic HIV protease inhibitors have drawn an increasing interest as a potential therapeutic option due totheir small molecular weight, favorable bioavailability, high stability in vivo, low resistance and cost of production. In thisreview, we present the recent advances in non-peptidomimetic HIV protease inhibitors. Their design strategies, biologicalactivities, resistance profiles, as well as clinical application will also be discussed.

MK-0626, A Dipeptidyl Peptidase-4 Inhibitor, Improves Neovascularization by Increasing Both the Number of Circulating Endothelial Progenitor Cells and Endothelial Nitric Oxide Synthetase Expression by Chun-Ming Shih, Yung-Hsiang Chen, Yi-Wen -Lin, Nai-Wen Tsao, Shinn-Chih Wu, Yung-Ta Kao, Kuang-Hsing Chiang, Chi-Yuan Li, Nen-Chung Chang, Cheng-Yen Lin, Chun-Yao Huang, Feng-Yen Lin (2012-2022).
Current treatment modalities for critical limb ischemia (CLI) are of limited benefit; therefore, advances intherapeutic vasculogenesis may open an important new avenue for the treatment of CLI. This study examines the therapeuticpotential of the DPP-4 inhibitor MK-0626 as a regulator of vasculogenesis in vivo. MK-0626 was administereddaily to C57CL/B6 mice and eGFP-labeled bone marrow-transplanted ICR mice that had undergone hind limb ischemiasurgery. Laser Doppler imaging and flow cytometry were used to evaluate the degree of neo-vasculogenesis and the numberof circulating endothelial progenitor cells (EPCs), respectively. Cell surface markers of EPCs and the level of endothelialnitric oxide synthase (eNOS) were studied in the vessels. Mice that received MK-0626 had an elevated level of glucagon-like peptide-1 (GLP-1) and a decreased level of dipeptidyl peptidase-4 (DPP-4) in their plasma, in addition to anischemia-induced increase in the level of stromal cell-derived factor-1 (SDF-1). In C57CL/B6 mice, blood flow in theischemic limb was significantly improved by treatment with MK-0626. The number of circulating EPCs and both the synthesisand phosphorylation of eNOS were also increased in ischemic thigh muscle after MK-0626 treatment. In contrast,similar effects of MK-0626 were not observed in B6.129P2-Nos3tm1Unc/J mice (an eNOS knockout mouse). Additionally,MK-0626 treatment promoted the mobilization and homing of EPCs to ischemic tissue in eGFP transgenic mouse bonemarrow-transplanted ICR mice. We conclude that both the number of circulating EPCs and neo-vasculogenesis are increasedin response to DPP-4 inhibitor treatment and that this occurs via an eNOS-dependent mechanism. The resultshighlight the therapeutic vasculogenesis potential of the DPP-4 inhibitor MK-0626 using a hind limb ischemia mousemodel.