Mini Reviews in Medicinal Chemistry - Volume 9, Issue 14, 2009

POCD describes a decline in cognitive function after surgery with a predominance in the elderly patient. Although there is general agreement that POCD is likely to be multifactorial, it remains unclear whether its occurrence is a result of the effects of surgery or general anesthesia. This review provides a synopsis of the available clinical and preclinical data and summarizes recent research relevant to the occurrence of POCD and possible pharmacologic algorithms for its prevention and treatment.

The endothelin (ET) axis plays a major role in cardiovascular diseases and a number of human cancers. This review summarizes the work that has been published in the past ten years using labeled endothelin receptor ligands for the visualization of endothelin receptor expression in vivo.

Proteins of Bcl-2(B-cell lymphoma-2) family are key regulators of programmed cell death. Scientist found that some members of this family are over-expressed in malignant tumors and influence the sensitivity of tumor cells to chemotherapy and radiotherapy. This report reviews the recent progress of structures, functions and inhibition of Bcl-2 family proteins, especially the development of Bcl-2 inhibitors in past decades as anticancer agents.

CXCR4 and CCR5 constitute the two major coreceptors for HIV-1 entry into host cells. In the course of an HIV-infection, a coreceptor switch takes place in approximately half of the patients - from R5 HIV-1 (CCR5 utilizing) strains to X4 HIV-1 (CXCR4 utilizing) strains. Treatment of HIV-infected individuals with CXCR4 antagonists delays the onset of AIDS by preventing the CCR5 to CXCR4 coreceptor switch. In addition to the endogenous CXCR4 and CCR5 ligands, other chemokines, for example the human herpesvirus 8 encoded CC-vCCL2, and modifications hereof, have proven efficient HIV-1 cell-entry inhibition through chemokine receptor interaction. However, pharmacokinetic and immunogenic drawbacks of chemokines and peptidic/peptoid compounds have brought the attention towards small-molecule antagonists, such as AMD3100, that displays high specificity and affinity towards CXCR4, but unfortunately no oral bioavailability. The hunt for orally active small-molecule CXCR4 antagonists led to the development of monocyclambased compounds, and recently to the non-cyclam antagonist AMD070, which is orally active and currently in Phase II clinical trial as anti-HIV treatment. Current review provides an overview of the drug discovery within the field of anti- HIV treatment targeting CXCR4 spanning from natural occurring and modified chemokines, to HIV-mimicking peptides and peptoids ending at the non-peptide antagonists.

The search for telomerase inhibitors has been widely explored in the last few years, since telomerase activity in somatic cells can be considered as a general cancer mark. One of the possible strategies is the capping of telomere 3'-end (the enzyme subs trate) in a conformation not available to the recognition of telomerase, with particular attention to Gquadruplex structures. Small organic molecules, able to induce and/or stabilize G-quadruplexes, have been synthesized and studied in many different research groups. Here, we mean to critically analyze the class of hydrosoluble perylene diimides (HPDIs), which offers the intriguing possibility to fix the hydrophobic molecule moiety (perylene) able to bind to the terminal G-quartet of telomeric G-quadruplex, while widely varying the number and features of the hydrophilic side chains, which interact with the DNA grooves. We will show that, using this strategy, it is possible to significantly improve HPDIs efficiency in inhibiting telomerase and their selectivity for telomeric G-quadruplex with respect to duplex genomic DNA.

Recombinant antibodies are therapeutic molecules of choice regarding their efficacy, pharmacokinetics and tolerance - all the more if they are human. The efficacy of antibodies generally depends on their affinity for their antigens. The most straightforward approach to isolate human antibodies with high affinities is the construction and screening of human immune libraries, but Humans cannot be immunized with all antigens of interest, for ethical and practical reasons. We circumvented that difficulty by utilizing non-human primates (NHP) instead of Humans and, in the course of our different studies, we have obtained several antibody fragments with high or very high affinities (from 3 nM to 50 pM) and neutralizing properties. The framework regions (FR) - the regions most implicated in tolerance - of these NHP antibody fragments were shown to be very similar to FR encoded by human germline genes. In one case, in a process called “germline humanization” (or “super-humanization”), we have increased that level of similarity and managed to go even beyond the level observed for human antibodies, without any loss of affinity. Here, the methodological peculiarities of our approach, in comparison with immune libraries built from immunised Humans, and the rationales behind these peculiarities, will be reviewed. The isolation of NHP antibody fragments from immune libraries, followed by the “super-humanization” process, opens a new and highly efficient approach for the production of high-quality recombinant antibodies for therapeutic uses.

From the past few decades, tremendous awareness has been laid on the use of natural polymers in ocular drug delivery. Chitosan, a modified natural carbohydrate polymer, has number of applications in the field of ophthalmics and attracted a great deal of attention of scientific community, academicians and environmentalists due to its unique features. Chitosan has been explored for the delivery of drugs, genes, biotechnological products, proteins and peptides to the target site within ocular tissues. Chitosan being a polycationic in nature interacts with the polyanionic surface of ocular mucosa through hydrogen bonding /ionic interactions and enhance the mucoadhesive effect of formulation. Sustained and controlled ocular delivery can be achieved with chitosan based formulations like chitosan gels, inserts, chitosan coated liposome/niosome and chitosan nanoparticles. This review discussed various aspects related to chitosan and chitosan based formulations particularly developed for ocular therapeutics. The fate and toxicological consideration related to chitosan, resulting with its interaction to ocular tissues, has also been summed up in addition.

Quinoline and its fused heterocyclic derivatives tested with diverse pharmacological activity constitute an important class of compounds for new drug development. Therefore, many researchers have synthesized these compounds as target structures and evaluated their biological activities. The present review provides an in depth view of work done so far on quinolines and its biological activities covering anticancer, antimycobacterial, antimicrobial, anticonvulsant, antiinflamatory and cardiovascular activities.

New drugs are introduced to the market every year and each individual drug represents a privileged structure for its biological target. These new chemical entities (NCEs) provide insights into molecular recognition and also serve as leads for designing future new drugs. This review covers the syntheses of 18 NCEs marketed in 2008.

Werner Heisenberg (1901-1976) is one of the most controversial, most ambivalent and most important figures in the history of modern science. The debate surrounding him with respect to nuclear weapons and National Socialism appears unending. Even though Heisenberg's uncertainty principle of the quantum system and his involvement in the Nazi atomic bomb project have been thoroughly discussed in various journals over the past decades, no communication has ever been published at a holistic level of his greatest Nobel-prize winning achievement in theoretical physics. In order to fill up this hole, this piece explicitly communicates the Heisenberg's paradox at all levels of science.