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 Read More

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 Read More

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 pot Read More

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 hi Read More

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, whic Read More

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 Read More

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 Read More

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 Read More

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.