Current Medicinal Chemistry (v.18, #29)

Squalene Synthase Inhibitors: An Update on the Search for New Antihyperlipidemic and Antiatherosclerotic Agents by A.P. Kourounakis, M.G. Katselou, A.N. Matralis, E.M. Ladopoulou, E. Bavavea (4418-4439).
Atherosclerosis and related heart disease is strongly associated with elevated blood levels of total (and LDL) cholesterol. Dueto the widespread incidence as well as severity of this pathological condition, major efforts have been made for the discovery and developmentof hypocholesteroleamic agents. In the past few decades, HMG-CoA reductase inhibitors (statins) are being extensively used aslipid lowering drugs. These agents act predominantly by inhibiting the enzyme 3-hydroxy-3-methylglutaryl coenzyme A reductase(HMGR) that is the rate limiting step of cholesterol biosynthesis. Both the success as well as drawbacks of HMGRIs, have led to the investigationand design of inhibitors of other (downstream) enzymes involved in the multistep cholesterol biosynthetic pathway. One suchclass of agents consists of the squalene sythase inhibitors which act at the first and solely committed step towards the biosynthesis of thecholesterol nucleus. This target is considered not to interfere with the biosynthesis of other biologically important molecules and thus abetter side-effect profile is expected for these inhibitors. Several classes of squalene synthase inhibitors (SQSIs), such as substrate or transition-state analogues, zaragozic acids or 2,8-dioxabicyclo[3.2.1]octane derivatives, dicarboxylic acid and quinuclidine derivatives, 4,1-benzoxazepine as well as substituted morpholinederivatives, have been studied as potent inhibitors of squalene synthase. So far only one benzoxazepine derivative (TAK-475) hasbeen evaluated in advanced clinical trials. In this article we review the up to date research and literature on the therapeutic potential ofthis relatively new class of compounds, the drug discovery efforts towards the development of active squalene synthase inhibitors, theiractivity profile and effectiveness, as well as their structure-activity relationships.

Clinical Trial Update and Novel Therapeutic Approaches for Metastatic Prostate Cancer by R. Larsson, N.P. Mongan, M. Johansson, L. Shcherbina, P.-A. Abrahamsson, L.J. Gudas, O. Sterner, J.L. Persson (4440-4453).
Recurrent prostate cancer (PCa) remains a major clinical challenge. Invasive and metastatic PCa lesions often exhibit a partialand time-limited response to therapy before the cancer progresses and the patient succumbs to the disease. Despite recent advances inearly diagnosis and treatment, approximately one-third of treated patients will relapse and become resistant to currently availabletreatments. In this review we evaluate current treatment practices and recent advances in therapy for localized prostate malignancy andadvanced, metastatic prostate cancer. Some of the promising new drugs for PCa treatment include MDV3100, an androgen receptor (AR)antagonist that prevents androgens from binding to the AR and nuclear translocation and co-activator recruitment of the ligand-receptorcomplex; abiraterone, an orally administered drug that irreversibly inhibits a rate-limiting enzyme in androgen biosynthesis, CYP17; andseveral newer cytotoxic drugs (epothilones, satraplatin). Key new insights are that cancer stem cells play a role in PCa and that PCa cellsare dependent on the AR for proliferation, even in the hormone refractory state of the disease. We also discuss potential molecular targetsfor new drug candidates for the treatment of metastatic PCa.

This review summarizes the current knowledge of the regulatory role of pure anthocyans in cellular signaling pathways andgene expression. The molecular basis for anthocyans pharmacological activity includes the regulation of plethora of mechanisms mainlyinvolved in: (1) suppression of the inflammatory response through targeting the phospholipase A2 and PI3K/Akt and NF-κB pathways,(2) protection from cardiovascular disease by exerting (i) antihypertensive and endothelium-protective activity through targeting theAkt/eNOS and ACE pathways (ii) antiatherogenic activity through targeting NF-κB mediated VCAM and ICAM expression, (3)growth/differentiation control and tumor suppression by exerting (i) anticancerogenic activity through targeting the EGF and HGFsignaling pathways (ii) tumor anti-invasive activity through targeting the VEGF signaling pathway and ECM degrading enzymes (iii) cellcycle arrest and induction of apoptosis through the JNK/p38 MAPK mediated caspase activation (iv) modulation of chemotherapeuticefficacy by affecting resistance to anticancer drugs, (4) reduction of diabetes incidence through modulation of insulin sensitivity andglucose utilization, (5) neuroprotection through amelioration of oxidative stress and Aβ deposition, and (6) hepatoprotective activitythrough interference with TNF-α and TGF-β in the liver. The estrogen-like activity of anthocyans could be utilized in cancer andhormone-replacement therapy. These data provide a concise insight into molecular mechanisms of protective and therapeutic activity ofanthocyans in various pathological conditions, which may not be attributed solely to their antioxidant activity but also to direct blockageof signaling pathways. Structure-activity analysis reveals that the number of hydroxyl groups and presence of sugar moiety are crucial fortheir specific modulatory actions.

Our ongoing search for a fully-effective vaccine against the Plasmodium falciparum parasite (causing the most lethal form ofhuman malaria) has been focused on identifying and characterising proteins’ amino acid sequences (high activity binding peptides orHABPs) involved in parasite invasion of red blood cells (RBC) by the merozoite and hepatocytes by the sporozoite. Many such merozoiteHABPs have been recognised and molecularly and structurally characterised; however, native HABPs are immunologically silentsince they do not induce any immune response or protection against P. falciparum malaria infection and they have to be structurallymodified to allow them to fit perfectly into immune system molecules. A deeply structural analysis of these conserved merozoite HABPs and their modified analogues has led to rules or principles becomingrecognised for constructing a logical and rational methodology for a minimal subunit-based, multi-epitope, multi-stage, chemicallysynthesisedvaccine. The same in-depth analysis of the most relevant sporozoite proteins involved in sporozoite cell-traversal and hepatocyteinvasion as well as the hepatic stage is shown here. Specifically modifying these HABPs has resulted in a new set of potential pre-erythrocyte targets which are able to induce high, longlastingantibody titres in Aotus monkeys, against their corresponding recombinant proteins and the complete parasite native molecules.This review shows how these rules may be applied against the first stage of parasite invasion (i.e. the sporozoite) to mount the first line ofdefence against the malarial parasite, which may indeed be the most effective one. Our results strongly support including some of thesemodified sporozoite HABPs in combination with the previously-described modified merozoite HABPs for obtaining the aforementionedfully-protective, multiepitope, multi-stage, minimal subunit-based, chemically-synthesized, antimalarial vaccine.

Functionalized Graphene Oxide as Nanocarrier for Loading and Delivery of Ellagic Acid by M. Kakran, N.G. Sahoo, H. Bao, Y. Pan, L. Li (4503-4512).
In this research, we have covalently functionalized graphene oxide (GO) with hydrophilic and biocompatible Pluronic F38(F38), Tween 80 (T80) and maltodextrin (MD) for loading and delivery of a poorly water soluble antioxidant and anticancer drug, ellagicacid (EA). The functionalized GO showed a good aqueous solubility and biocompatibility. This is the first time that the EA was loadedonto GO-F38, GO-T80 and GO-MD through Π-Π interactions, yielding a loading capacity of 1 g, 1.22 g and 1.14 g of EA per gram of..GO-F38, GO-T80, and GO-MD respectively. Their capabilities to kill human breast carcinoma cells (MCF7) and human colonadenocarcinoma cells (HT29) were then investigated. The release of EA from these nanocarriers was studied in water (neutral pH) andbuffer solutions of pH 4 and 10 at 37 °C. The GO-F38, GO-T80 and GO-MD released ~36-38% drug within 3 days at pH 10. Thecytotoxicity of EA loaded onto the functionalized GO was higher than that of free EA dissolved in DMSO. The DPPH assay was used tostudy the antioxidant activity, and the very similar antioxidant activities were obtained for three EA-loaded nanocarriers and the free EA,indicating that loading of EA onto the functionalized GO did not hamper its antioxidant activity. Therefore, all three functionalized GOsare suitable nanocarriers for drug delivery because of their non-toxicity and high drug loading capacity.

HIV protease plays a crucial role in the viral life cycle by processing the viral Gag and Gag-Pol polyproteins into structuraland functional proteins essential for viral maturation. Inhibition of HIV-1 protease leads to the production of noninfectious virus particlesand hence is an important therapeutic target for antiviral therapy in AIDS patients. Among many strategies to combat this disease, highlyactive antiretroviral therapy (HAART) with HIV protease inhibitors (PIs) in combination with reverse transcriptase inhibitors and fusioninhibitor continues to be the first line treatment for control of HIV infection. However, the rapid emergence of drug-resistant HIV-1strains and the appearance of cross-resistance are severely limiting the long-term treatment options. Thus, numerous efforts have beenmade in the design and synthesis of novel protease inhibitors with broad-spectrum activity against multidrug-resistant HIV-1 variants bymedicinal chemists. This review will focus on the substrate-based drug design of novel peptidomimetic PIs in recent years since 2006.

Development of 5-Fluorouracil Derivatives as Anticancer Agents by Xiaoyan Pan, Chen Wang, Fang Wang, Pengfei Li, Zhigang Hu, Yuanyuan Shan, Jie Zhang (4538-4556).
5-Fluorouracil (5-FU) is one of the most potent antimetabolites which have been widely used in the treatment of advancedsolid tumors. As an anticancer agent, because of its low efficacy and high toxicity, numerous modifications of 5-FU structure have beenperformed. A great number of novel 5-FU derivatives have been developed with highly efficient and much less toxic. In this paper, therecent development of novel 5-FU derivatives as potent antitumor agents is reviewed and discussed.

Phytosterols: Perspectives in Human Nutrition and Clinical Therapy by S.P. Choudhary, L.S. Tran (4557-4567).
Phytosterols (PSs) are a group of plant derived steroid alcohols, with wide occurrence in vegetables and fruits. They areintegral components of plant cell membranes, having stabilizing effects on phospholipids bilayer, just like cholesterol in animal cellmembranes. Structural resemblance of PSs with cholesterol enables them to displace low-density lipoprotein (LDL) cholesterol in thehuman intestine. Protective effects of PSs against cardiovascular diseases (CVDs), colon and breast cancer developments have beenwidely documented. Several reports have been published on the potential dietary intake of common PSs, such as β-sitosterol, stigmasteroland campesterol, and their safety concerns. Ability of PSs to reduce cholesterol levels and risks associated with heart problems has madethem a class of favorite food supplements. Nowadays functional foods supplemented with PSs have become an alternative and healthytool to lower LDL-cholesterol levels in a natural way. However, excessive use of PSs has been observed to develop premature coronaryartery disease in phytosterolemic patients, high risk of atherosclerotic CVDs, myocardial infarction and even impaired endothelialfunctions. This manuscript will highlight the recent developments in PSs with particular focus on their role as dietary supplements and intreatment of various heart- and cholesterol-related ailments. Recently explored side effects of PSs will also be discussed.