Mini Reviews in Medicinal Chemistry - Volume 5, Issue 2, 2005

The problem of multidrug resistance has gained increasing importance in the fields of tumour therapy and treatment of bacterial and fungal infections. One of the major mechanisms responsible for development of multiple drug resistance is overexpression of drug efflux pumps. These membrane bound, ATP driven transport proteins efflux a wide variety of natural product toxins and chemotherapeutic drugs out of cells and give rise to decreased intracellular accumulation of these compounds. Thus, inhibition of efflux pumps is a versatile approach for overcoming multiple drug resistance, and several compounds are in clinical phase III studies. The main target is P-glycoprotein, which is responsible for MDR in tumour cells, and transport systems in S. aureus, P. aerugiosa and E. coli. Due to the fact, that 3D-structures of the proteins at atomic resolution were not available, drug development was performed solely on basis of ligand based design. However, electron microscopy studies as well as X-ray structures of three bacterial efflux pumps may open the door to target based drug design in the near future. The hot topic issue will deal with the topic of drug efflux pumps from different perspectives. The article of Klopman and Zhu present new methodologies for estimating lipophilicity and their impact on prediction of membrane transport properties of drugs. Seelig and Gatlik-Landwojtowicz highlight the biophysical characterisation of inhibitors of efflux pumps and their membrane and protein interactions. An overview on the approaches used for lead identification and optimisation for inhibitors of P-glycoprotein is given by Pleban and Ecker. Peer et al. focus in their article on recent progress in identifying substrate binding domains of P-glycoprotein by means of photoaffinity labeling. Analogous multidrug transport systems in lactic acid bacteria are dealt by Mazurkiewicz et al. Last but not least Fischer et al. give an overview on the clinical relevance of efflux transporter. These articles will demonstrate, that, although much progress has been made in the development of EPIs, we are far away from understanding the basic principle of drug recognition and transport mechanism of this class of pumps. These issues will continue to be one of the major tasks in the field of modulation of drug resistance!

The lipophilicity of drug molecules (represented as the logarithm of the n-octanol / water partition coefficient) often strongly correlates with their pharmacological and toxic activities. It is therefore, not surprising that there is considerable interest in developing mathematical models capable to accurately predict their value for new drug candidates. In this review, current major approaches for estimating partition coefficients are described and some of their advantages and disadvantages are discussed. Recent uses of these partition coefficient algorithms in the development of membrane transport models are also discussed.

Modulators and inhibitors of multidrug efflux transporters, like P-glycoprotein, are used to reduce or inhibit multidrug resistance, MDR, which leads to a failure of the chemotherapy of e.g. cancers, epilepsy, bacterial, parasitic, and fungal diseases. Binding and transport of first-, second-, and third-generation modulators and inhibitors of P-glycoprotein are discussed, taking into account the properties of the drug (Hbonding potential, dimensions, and pKα values) as well as the properties of the membrane.

The membrane bound drug efflux pump P-glycoprotein (P-gp) transports a wide variety of functionally and structurally diverse cytotoxic drugs out of tumour cells. Overexpression of P-glycoprotein is one of the predominant mechanisms responsible for development of multiple drug resistance in tumour therapy. Thus, inhibition of P-gp represents a promising approach for treatment of multidrug resistant tumours. This review highlights concepts for identification and optimization of new inhibitors of Pglycoprotein.

The aim of the present review is to summarize recent progress in identifying substrate binding domains of P-glycoprotein by photoaffinity labeling. Preferred substrate binding regions have been identified using a number of photoaffinity ligands, including anthracyclines, the quinazoline iodoarylazidoprazosine (IAAP), dihydropyridines, taxanes and propafenones. These studies allowed identification of protein regions, which are involved in ligand interaction.

Gram-positive lactic acid bacteria possess several Multi-Drug Resistance systems (MDRs) that excrete out of the cell a wide variety of mainly cationic lipophilic cytotoxic compounds as well as many clinically relevant antibiotics. These MDRs are either proton / drug antiporters belonging to the major facilitator superfamily of secondary transporters or ATP-dependent primary transporters belonging to the ATPbinding cassette superfamily of transport proteins. Here we summarize the existing data on these MDRs and discuss recent observations that suggest the use of new strategies in the ongoing battle against drug-resistant microbial pathogens.

It is increasingly recognized that efflux transporters play an important role, not only in chemo protection e.g. multi-drug resistance, but also in the absorption, distribution, and elimination of drugs. The modulation of drug transporters through inhibition or induction can lead to significant drug-drug interactions by affecting intestinal absorption, renal secretion, and biliary excretion, thereby changing the systemic or target tissue exposure of the drug. Few clinically significant drug interactions that affect efficacy and safety are due to a single mechanism and there is considerable overlap of substrates, inhibitors, and inducers of efflux transporters and drug metabolizing enzymes, such as CYP3A. As well, genetic polymorphisms of efflux transporters have been correlated with human disease and variability of drug exposure. Accordingly, this review will discuss drug interactions and suitable probe substrates, as well as, the clinical relevance of the variability and modulation of efflux transporters and the exploitation of substrates as diagnostic tools. An update is given on inhibitors, which clinically reverse drug resistance and minimize the risk of metabolic interactions.

The key importance of lipophilicity in bio-studies is discussed for ß-blockers. Examples of their lipophilicity-dependent pharmacological properties including pharmacokinetic, pharmacodynamic and clinical aspects are reviewed. Comprehensive lipophilicity compilations of ß-blockers are lacking so far. LogP calculations with 10 programs for 30 clinically relevant ß-blockers are presented for the first time in this review.

Okadaic acid is the main toxin responsible for the natural phenomena known as diarrheic shellfish poisoning (DSP). This toxin is a tumor promoter C38 polyether fatty acid that contains acidic and hydrophobic moieties and is cyclic. Okadaic acid is a potent inhibitor of important classes of protein serine / threonine phosphatases such as protein phosphatase 1 and 2A. The toxin binds in a hydrophobic groove adjacent to the active site of the protein phosphatases and interacts with basic residues within the active site. Therefore okadaic acid causes increases in phosphorylation of proteins that affect a diverse array of cellular processes. For instance, this toxin modulates metabolic parameters in intact cells. In this sense it stimulates lipolysis, and inhibits fatty acid synthesis in adipocytes however increases glucose output and gluconeogenesis in hepatocytes. Additionally, okadaic acid reaches cytotoxic concentrations in the intestinal tissues in accordance with the diarrhea. Recent studies suggested that toxic effects of okadaic acid might be related to modification of nutrients, ionic and water absorption across the small intestine presumably by altering the transporter system. The subject of this review is limited to the effect of okadaic acid on glucose regulation and its cellular as well as clinical implications.

Recent research developments in the field of NO-donor compounds have concerned conjugation of NO-donor moieties with antioxidant groups, NO-donor targeting, design of NO-donor hybrid drugs and of NOdelivery systems. These new approaches are illustrated and discussed through selected examples.