Current Drug Discovery Technologies - Volume 1, Issue 2, 2004

New tumor targeting agents are required to advance cancer diagnosis and treatment. Bacteriophage (phage) display technology, a molecular genetic means of combinatorial drug discovery, is an emerging approach to identify and improve peptide molecules as pharmaceuticals. Peptides are thought to have clinically desirable benefits over currently used biomolecules, such as antibodies, because of their rapid blood clearance, increased diffusion and tissue penetration, non-immunogenic nature and ease of synthesis. Using phage display, one can rapidly and simultaneously survey billionclone peptide libraries, resulting in large numbers of “hits”. However, only a few lead compounds resulting from the hits historically reach the drug market. Hence determining which peptide may best translate into a useful drug is of particular importance. Examination of successfully marketed drugs has highlighted key features of a winning agent, including low molecular weight, high affinity, stability, solubility, lipophilicity and conformational rigidity. Although peptide modulators of tumor cell function and cancer targeting agents have been developed, the majority of peptide-based drugs reported thus far are immune and cardiac regulators. In this review, we will highlight how phage display has been employed to isolate peptides that target key steps in cancer progression - from tumor growth to metastasis - and how phage display technology can be harnessed to select a priori peptides with inherent features essential for anti-cancer drug efficacy. In 2003, phage display provided us with several novel peptides not only in clinical trials but approved by the FDA for use as therapeutics in a variety of diseases - suggesting that the future looks bright for phage display in anticancer drug development.

Pharmacological and pharmacodynamic properties of biologically active natural and synthetic compounds are crucially determined via their binding to proteins of the human body. Several spectroscopic techniques are available to study these mainly non-covalent interactions. Circular dichroism (CD) spectroscopy, being sensitive to the chirality of ligand molecules induced by the asymmetric protein environment, has widely and successfully been applied for many decades. Chiral conformation of the ligand due to conformational adaptation to its binding site, or interaction between ligand molecules held in chiral arrangement relative to each other by the protein sites, results in one or more induced CD bands with different shape, sign and intensity. These extrinsic Cotton effects present in light absorbing region of the optically active or inactive ligand molecules give qualitative and quantitative information of the binding process. It can provide valuable data on the stereochemistry, number, location and nature of the binding sites. This paper is aimed to survey briefly the literature and the results of recent investigations undertaken in this field.

A variety of endo-3,6-tricyclo[6.2.1.02,7]undeca-4,9-diene-3,6-endo-diol depsipeptide or bis-amino acid derivatives containing the same parallel strands were synthesised and examined for conformational preferences by NMR. The study indicates that this novel class of constrained peptides displays β-turn-like and β-sheet-like conformations. Evidences are supported by observation of the rates of proton-deuterium exchange, nuclear Overhauser effects and further by dynamic simulations, semi-empirical and ab initio calculations. The chemical shifts were measured in CDCl3 and CDCl3 with 15% DMSO-d6 solutions. It was carried out a van't Hoff analysis, which is in agreement with the theoretical studies. In chloroform-d, for the derivatives 3-6 the hydrogen-bonded species are enthalpically preferred but entropically disfavoured.

Microemulsions, being thermodynamically stable systems, with low viscosity and elegant in appearance have attracted interest not only for the delivery of single drug substances with low water solubility but for the stabilization of drugs in combination due to their preferential solubility in either the water or oil phases. Microemulsion design involves the solubilisation of an optimum amount of the dispersed phase in the continuous phase, utilizing the minimum amount of surfactant / mixture of surfactants / cosurfactants. It is the choice of the surfactant / surfactant mixture and / or cosurfactants, which poses the greatest challenge in the design of a thermodynamically stable microemulsion formulation. This paper will present a strategy for choosing surfactants to achieve a stable, dilutable microemulsion formulation for oral administration. Ternary and pseudo-ternary phase diagrams were constructed by titrating a series of mixtures [lipid (miglyol 812): cosurfactant and / or surfactant (cremophor RH, imwitor 308 / 742, sorbitol, brij 97, crillet 3)] with water at room temperature, the phases formed visually assessed after each addition and classified as isotropic (ME), liquid crystalline (LC) or coarse emulsions (EM). Results indicate that the surfactant combination of imwitor 308 and crillet 3 proved most successful in incorporating 25 to 30% miglyol 812 into a microemulsion formulation utilizing an intermediate quantity of surfactant and maintaining homogeneity on dilution.

Cyclic voltammetry (CV) is a unique technique for the electrochemical characterization of compounds by providing their oxidation / reduction potentials. This technique is widely used in evaluating antioxidants in the oil, food, diagnostic and agricultural industries; however, CV is rarely used in the development of pharmaceutical formulations. This review briefly describes the basic principles of CV and its application in other industries along with the potential and limitations of CV in the rapid evaluation of antioxidants in pharmaceutical formulations. An extensive survey of the literature shows that there is a good correlation between the oxidation potentials of various antioxidants and their antioxidant efficiency. In conclusion, CV should be useful in the development of pharmaceutical formulations where a small group of the preferred antioxidants is rapidly identified. This small group of the most preferred antioxidants can then be employed in a conventional drug stability study thereby providing a rapid approach for the selection of the most suitable antioxidant for a pharmaceutical formulation.