Current Medicinal Chemistry - Volume 13, Issue 8, 2006

The initiation, growth, and development of new blood vessels through angiogenesis are essential for tumor growth. Tumor masses require access to blood vessels for a sufficient supply of oxygen and nutrients to maintain growth and metastasis. Inhibiting tumor blood vessel formation as proposed by Judah Folkman in the early 1970s, therefore, offers promising therapeutic approaches for treating tumor afflicted patients. The blood vessel growth in normal tissues is regulated though a delicate and complex balance between the collective action of proangiogenic factors (e.g., vascular endothelial growth factor, VEGF) and the collective action of angiogenic inhibitors (e.g., thrombospondin-1). In pathological angiogenesis, the angiogenic switch is shifted toward the proangiogenic factors, and if the imbalance continues, irregular tumor vessel growth is the result. Despite intense research, the mechanism of the angiogenic switch is not fully understood. Many factors, however, have been shown to be involved in regulating the equilibrium between angiogenic stimulants and inhibitors. VEGFR tyrosine kinase, methionine aminopeptidase-2 (MetAP-2), p53, tubulin, cyclooxygenase-2 (COX-2), and matrix metalloproteinases (MMPs) all directly and/or indirectly influence the angiogenic switch. This review will describe some of the advances in inhibitor design and the mechanisms of action for the aforementioned factors (targets) involved in angiogenesis regulation. Our discussion reveals that a diaryl group separated by various connecting modules is one of the most common features for antiangiogenesis drug design. This idea has been a working pharmacophore hypothesis for our own antiangiogenic drug design endeavors over the years. The recent advances of combination therapy (angiogenesis inhibitors with other chemotherapy/radiation) are also discussed.

The ability to target RNA, mRNA and viral RNA in particular, for degradation is a powerful approach in molecular biology and pharmacology. Such approaches can be used in the study of gene function as in functional genomics, in the identification of disease-associated genes, and for the treatment of human diseases. This review provides a comprehensive up-to-date look at all the current available technologies used for the destruction of RNA, with a focus on their therapeutic potential. This includes approaches that utilize the activity of protein ribonucleases such as antisense oligonucleotide, small interfering RNA, RNase P-associated external guide sequence, onconase and bovine seminal RNase. Sequence-specific approaches that do not utilize activity of protein ribonucleases, such as ribozyme and DNazyme, are also reviewed and discussed. This review should provide a useful starting framework for researchers interested in using the RNA-destruction methodologies on the bench and in the clinic, and serves as a stimulus for further development of novel and more potent RNA degradation technologies. This is particularly critical, given the anticipation of discoveries of new cellular RNA degradation machineries and human diseases that are associated with dysfunctional RNA molecules.

Nicotinamide, the amide form of niacin (vitamin B3), is the precursor for the coenzyme β-nicotinamide adenine dinucleotide (NAD+) and plays a significant role during the enhancement of cell survival as well as cell longevity. Yet, these abilities of nicotinamide appear to be diametrically opposed. Here we describe the development of nicotinamide as a novel agent that is critical for modulating cellular metabolism, plasticity, longevity, and inflammatory microglial function as well as for influencing cellular life span. The capacity of nicotinamide to govern not only intrinsic cellular integrity, but also extrinsic cellular inflammation rests with the modulation of a host of cellular targets that involve mitochondrial membrane potential, poly(ADP-ribose) polymerase, protein kinase B (Akt), Forkhead transcription factors, Bad, caspases, and microglial activation. Further knowledge acquired in regards to the ability of nicotinamide to foster cellular survival and regulate cellular lifespan should significantly promote the development of therapies against a host of disorders, such as aging, Alzheimer's disease, diabetes, cerebral ischemia, Parkinson's disease, and cancer.

Luminescent semiconductor nanocrystals, also known as quantum dots (QDs), are generally composed of II-VI and III-V elements. Due to their quantum confinement of charge carriers in tiny spaces, QDs show some unique and fascinating optical properties, and are characterized as sharp and symmetrical emission spectra, high quantum yields, broad absorption spectra, good chemical and photo-stability and size dependent emission wavelength tunability. Recently, QDs have been successfully used as new fluorescent tags in many biological and biomedical fields, and will become a new promising tool in biomedical studies, clinical diagnostics, drug delivery and photodynamic therapy. In this review, firstly, the methodology of QDs preparation was introduced, which included organic synthesis, aqueous synthesis and microwave assisted aqueous synthesis. Secondly, some procedures for the QDs bio-conjugation with biomarkers were described. And then, some key applications of QDs were summarized, which mainly covered biomedical imaging, immunoassay, DNA hybridization, and photodynamic therapy. Finally, future prospects were discussed.

The new generation of antiviral drugs intended to counter HIV-1 entry into susceptible cells is emerging swiftly. The antiviral agents that inhibit HIV entry to the target cells (denoted as HIV entry inhibitors) are already in different phases of clinical trials. Operating early in the viral life cycle, they prevent viral entry, and have a novel, highly specific mechanism of action with a low toxicity profile. Entry inhibitors have different toxicity and resistance profiles than the existing reverse transcriptase and protease inhibitors. Some of these compounds demonstrated in vitro synergism with other classes of antivirals, thus offering the rationale for their combination in therapies for HIV-infected individuals. It is worth focusing on recent developments in HIV entry inhibitors, as most of the current drug regimens suffer from the events of developing resistance against existing combination therapies. Recent advances in the understanding of the cellular and molecular mechanisms of HIV-1 entry provide the basis for novel therapeutic strategies that prevent viral penetration of the target cell-membrane, while reducing detrimental virus and treatment effects on cells and prolonging virion exposure to immune defenses. A number of potential sites for therapeutic intervention become accessible during the narrow window between virus attachment and the subsequent fusion of viral envelope with the cell membrane. The HIV-1 coreceptors are particularly attractive from the perspective of identifying new antiviral compounds, since they are seven-transmembrane motif G protein-coupled receptors (GPCRs), a family of proteins that is a well-validated target for drug development. Among the many chemokine receptors that can mediate HIV-1 entry in vitro, only CCR5 and CXCR4 are of frontline pharmacological importance. In particular, CCR5 is essential for viral transmission and replication during the early and clinically latent phase of disease. Several small-molecule antagonists of CCR5 and CXCR4 that block chemokine binding and HIV-1 entry have been identified in recent years. Considerable advances have been made in the last years in the design of derivatives acting as inhibitors of HIV entry. The molecular mechanism involved in viral entry, the structural and functional aspects of entry inhibitors are reviewed here. We have also summarized the recent insights into how small-molecule antagonists interact with CCR5 and CXCR4, focusing on drug development programs that are well documented in the scientific literature. An overview of the entry inhibitors that are in preclinical or early clinical development, and the Quantitative Structure-Activity Relationships (QSAR) studies reported for the coreceptor antagonists are also be presented.

The term "epigenetics" is defined as "heritable changes in gene expression that occur without changes in DNA sequence". Recently, it has been revealed that DNA methylation and histone modifications such as acetylation, methylation and phosphorylation are epigenetic mechanisms according to this definition. In other words, these posttranslational modifications are important factors in determining when and where a gene will be expressed. To date, several enzymes that catalyze DNA or histone modifications have been identified, such as DNA methyltransferases and histone deacetylases. Inhibitors and activators of enzymes controlling epigenetic modifications are considered useful not only as tools for the elucidation of cellular and biological phenomena, but also as therapeutic agents, since disruption of the balance of epigenetic networks is known to cause some disease states such as cancer. In this review, we present natural products and synthetic molecules that inhibit or activate enzymes catalyzing DNA methylation or histone modifications, and discuss the potential of epigenetic therapy.

Since the discovery of artificially produced radioisotopes in the 1930's, an estimated 10-12 million nuclear medicine diagnostic and therapeutic procedures are currently performed each year only in the United States. Gamma emission imaging has been successfully applied to almost every organ of the body (brain, bone, heart, kidney, lung, neuroreceptors) as well as sites of inflammation, atherosclerosis, and thrombosis. FDG-PET has been used in some of the inflammatory diseases as well. On the other hand, both alpha and beta-emitting isotopes have been evaluated for brachytherapy of rheumatoid diseases, each with different radiobiological effectiveness. The current status of radionuclides for imaging, therapy and research studies of inflammatory processes is reviewed here and a look into the future directions is described at the conclusion.

Recently, animal fatty acid synthase (FAS) is reported as a potential therapeutic target for obesity and cancer. Considerable interest has been developed in identifying novel inhibitors of the enzyme. It is found that tea polyphenols inhibit FAS in both reversible and irreversible manners. Epigallocatechin gallate (EGCG) and epicatechin gallate (ECG) inhibit FAS with IC50 values of 52 μM and 42 μM mainly by reacting on the β-ketoacyl reductase (KR) domain of FAS. The inhibitory ability of catechin gallate (CG) is 15 and 12 folds higher than that of EGCG and ECG. Its major reacting site on FAS is not KR. All of these irreversibly inactivate FAS on the KR domain with similar rates. Mulliken population analysis suggests that the positive charge is distributed on the carbon atom of galloyl ester, and this carbon becomes more susceptible for a nucleophilic attack. 12 flavonoids inhibit FAS with IC50 values ranging from 2 to 112 μM. SAR analysis shows that the flavonoids containing two hydroxyl groups in B ring and 5, 7-hydroxyl groups in A ring with C-2, 3 double bond are the most potent inhibitors. The inhibition kinetics shows that they inhibit FAS competitively with acetyl CoA and most likely react mainly on acyl transferase domain. Further studies show that C ring of flavonoids is not necessary for the inhibition. Resveratrol, phlorizin and NDGA contain two phenyl rings connected by 2 to 4 atom chains instead of C ring. Their IC50 values range from 5 μM to 40μM. From these results, a common model for polyphenol inhibitor of FAS is conceived.