Current Medicinal Chemistry - Volume 18, Issue 29, 2011

Atherosclerosis and related heart disease is strongly associated with elevated blood levels of total (and LDL) cholesterol. Due to the widespread incidence as well as severity of this pathological condition, major efforts have been made for the discovery and development of hypocholesteroleamic agents. In the past few decades, HMG-CoA reductase inhibitors (statins) are being extensively used as lipid 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 investigation and design of inhibitors of other (downstream) enzymes involved in the multistep cholesterol biosynthetic pathway. One such class of agents consists of the squalene sythase inhibitors which act at the first and solely committed step towards the biosynthesis of the cholesterol nucleus. This target is considered not to interfere with the biosynthesis of other biologically important molecules and thus a better 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 morpholine derivatives, have been studied as potent inhibitors of squalene synthase. So far only one benzoxazepine derivative (TAK-475) has been evaluated in advanced clinical trials. In this article we review the up to date research and literature on the therapeutic potential of this relatively new class of compounds, the drug discovery efforts towards the development of active squalene synthase inhibitors, their activity profile and effectiveness, as well as their structure-activity relationships.

Recurrent prostate cancer (PCa) remains a major clinical challenge. Invasive and metastatic PCa lesions often exhibit a partial and time-limited response to therapy before the cancer progresses and the patient succumbs to the disease. Despite recent advances in early diagnosis and treatment, approximately one-third of treated patients will relapse and become resistant to currently available treatments. In this review we evaluate current treatment practices and recent advances in therapy for localized prostate malignancy and advanced, 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-receptor complex; abiraterone, an orally administered drug that irreversibly inhibits a rate-limiting enzyme in androgen biosynthesis, CYP17; and several newer cytotoxic drugs (epothilones, satraplatin). Key new insights are that cancer stem cells play a role in PCa and that PCa cells are dependent on the AR for proliferation, even in the hormone refractory state of the disease. We also discuss potential molecular targets for 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 and gene expression. The molecular basis for anthocyans pharmacological activity includes the regulation of plethora of mechanisms mainly involved 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 the Akt/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 HGF signaling pathways (ii) tumor anti-invasive activity through targeting the VEGF signaling pathway and ECM degrading enzymes (iii) cell cycle arrest and induction of apoptosis through the JNK/p38 MAPK mediated caspase activation (iv) modulation of chemotherapeutic efficacy by affecting resistance to anticancer drugs, (4) reduction of diabetes incidence through modulation of insulin sensitivity and glucose utilization, (5) neuroprotection through amelioration of oxidative stress and Aβ deposition, and (6) hepatoprotective activity through interference with TNF-α and TGF-β in the liver. The estrogen-like activity of anthocyans could be utilized in cancer and hormone-replacement therapy. These data provide a concise insight into molecular mechanisms of protective and therapeutic activity of anthocyans in various pathological conditions, which may not be attributed solely to their antioxidant activity but also to direct blockage of signaling pathways. Structure-activity analysis reveals that the number of hydroxyl groups and presence of sugar moiety are crucial for their specific modulatory actions.

Our ongoing search for a fully-effective vaccine against the Plasmodium falciparum parasite (causing the most lethal form of human malaria) has been focused on identifying and characterising proteins' amino acid sequences (high activity binding peptides or HABPs) involved in parasite invasion of red blood cells (RBC) by the merozoite and hepatocytes by the sporozoite. Many such merozoite HABPs have been recognised and molecularly and structurally characterised; however, native HABPs are immunologically silent since they do not induce any immune response or protection against P. falciparum malaria infection and they have to be structurally modified 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 becoming recognised for constructing a logical and rational methodology for a minimal subunit-based, multi-epitope, multi-stage, chemicallysynthesised vaccine. The same in-depth analysis of the most relevant sporozoite proteins involved in sporozoite cell-traversal and hepatocyte invasion 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, longlasting antibody 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 of defence against the malarial parasite, which may indeed be the most effective one. Our results strongly support including some of these modified sporozoite HABPs in combination with the previously-described modified merozoite HABPs for obtaining the aforementioned fully-protective, multiepitope, multi-stage, minimal subunit-based, chemically-synthesized, antimalarial vaccine.

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, ellagic acid (EA). The functionalized GO showed a good aqueous solubility and biocompatibility. This is the first time that the EA was loaded onto 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 colon adenocarcinoma cells (HT29) were then investigated. The release of EA from these nanocarriers was studied in water (neutral pH) and buffer 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. The cytotoxicity of EA loaded onto the functionalized GO was higher than that of free EA dissolved in DMSO. The DPPH assay was used to study 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 GOs are 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 structural and functional proteins essential for viral maturation. Inhibition of HIV-1 protease leads to the production of noninfectious virus particles and hence is an important therapeutic target for antiviral therapy in AIDS patients. Among many strategies to combat this disease, highly active antiretroviral therapy (HAART) with HIV protease inhibitors (PIs) in combination with reverse transcriptase inhibitors and fusion inhibitor continues to be the first line treatment for control of HIV infection. However, the rapid emergence of drug-resistant HIV-1 strains and the appearance of cross-resistance are severely limiting the long-term treatment options. Thus, numerous efforts have been made in the design and synthesis of novel protease inhibitors with broad-spectrum activity against multidrug-resistant HIV-1 variants by medicinal chemists. This review will focus on the substrate-based drug design of novel peptidomimetic PIs in recent years since 2006.

5-Fluorouracil (5-FU) is one of the most potent antimetabolites which have been widely used in the treatment of advanced solid tumors. As an anticancer agent, because of its low efficacy and high toxicity, numerous modifications of 5-FU structure have been performed. A great number of novel 5-FU derivatives have been developed with highly efficient and much less toxic. In this paper, the recent development of novel 5-FU derivatives as potent antitumor agents is reviewed and discussed.

Phytosterols (PSs) are a group of plant derived steroid alcohols, with wide occurrence in vegetables and fruits. They are integral components of plant cell membranes, having stabilizing effects on phospholipids bilayer, just like cholesterol in animal cell membranes. Structural resemblance of PSs with cholesterol enables them to displace low-density lipoprotein (LDL) cholesterol in the human intestine. Protective effects of PSs against cardiovascular diseases (CVDs), colon and breast cancer developments have been widely documented. Several reports have been published on the potential dietary intake of common PSs, such as β-sitosterol, stigmasterol and campesterol, and their safety concerns. Ability of PSs to reduce cholesterol levels and risks associated with heart problems has made them a class of favorite food supplements. Nowadays functional foods supplemented with PSs have become an alternative and healthy tool to lower LDL-cholesterol levels in a natural way. However, excessive use of PSs has been observed to develop premature coronary artery disease in phytosterolemic patients, high risk of atherosclerotic CVDs, myocardial infarction and even impaired endothelial functions. This manuscript will highlight the recent developments in PSs with particular focus on their role as dietary supplements and in treatment of various heart- and cholesterol-related ailments. Recently explored side effects of PSs will also be discussed.