No abstract

Novel 3,9-diazatetraasteranes have been synthesized with varied aromatic substitution patterns and evaluated as P-glycoprotein (P-gp) inhibitors. Structure-activity relationships (SAR) are discussed in relation to determined physicochemical properties. The potential to induce P-gp expression has been evaluated in cancer cell lines. The bioanalytical results indicate favorable noninducing properties compared to P-gp inducing drug standard.

HIV‐1 protease inhibitor binding. Inhibitor binding towards HIV‐1 protease subsites was investigated by the introduction of hydrogen bond acceptor and donor functions into the phenylic substituents of cage dimeric 1,4‐dihydropyridines. Determined affinity constants Ki are discussed and suggested binding modes towards enzyme′s subsites are confirmed by docking studies.

Multidrug resistance (MDR) is an increasingly common problem in the treatment of infectious diseases and cancer. [1][2][3] Transmembrane efflux pumps play a role in the MDR of bacteria, viruses, fungi and cancer. The MDR efflux pumps mainly found in cancer cells belong to the ABC-transporter family. Pglycoprotein (P-gp) causes the highest incidence of resistance, followed by multidrug resistance-associated protein (MRP) subtypes, such as MRP1 and MRP2.[3, 4] P-gp was also discovered to be causative agent for viral resistance to AIDS treatment, because peptidic inhibitors of HIV protease as a therapeutic target in AIDS treatment were found to be P-gp substrates. [2] While recent results of the X-ray crystal-structure analysis of the bacterial efflux transporter AcrB have given insight into the functional aspects of substrate transport, [5] there are, currently, only models for the structure and function of P-gp. While bacterial efflux systems are thought to collect all substrates in a central cavity from which they are actively transported through a pore tunnel, [5] P-gp is assumed to bind substrates first. [6,7] This binding can cause conformational changes in neighboring transmembrane a-helical subunits, and then lead to the entrance of the substrate into the transporter channel.[6]The binding affinities of various P-gp substrates have been determined in a radioligand-binding assay.[8] These results correlate well with the P-gp-inhibitory properties of the compounds and proved that verapamil was one of the best inhibitors of P-gp function. So far, nothing certain is known about the P-gp-substrate-binding region. We present here structureactivity studies of symmetric and asymmetric modulators of Pgp function that strongly support a C 2 -symmetric structure for the P-gp binding region. Activity data suggest, however, that this binding region has a conserved conformational structure than the more flexible one of the second enzymatic target of the molecules, HIV-1 protease, which likewise has a C 2 -symmetric structure. Such a conserved binding region might come as a surprise, considering that the P-gp transporter is a model of high flexibility acting as flippase [9] or "vacuum cleaner". [7] A series of exclusively C 2 -symmetric cage compounds 3 (Scheme 1) has been prepared by a primary solution dimerization reaction of monomeric 1,4-dihydropyridines 1 (see Experimental Section). They have been evaluated in a fluorescenceuptake assay in mouse T-lymphoma parental cells and the MDR-1-transfected resistant subline by using rhodamine-123 as a fluorescent P-gp substrate with two inhibitor concentrations ( Table 1). As is evident from the calculated inhibitory activity ratios R by directly comparing fluorescence-uptake data in relation to an untreated control, an increase in fluorescence uptake unequivocally corresponds to P-gp inhibition. The activity data of all compounds prove that almost all of them are active at a low concentration (1 mm); the exceptions being 3 a[10] and b, both of which show activity at 10 mm. Com...

Physicochemical characteristics of two structurally different cage dimeric 1,4-dihydropyridines HX (1) and CC (2) have been determined and compared to their P-glycoprotein inhibiting properties. While the weakly basic compound (1) showed pH-dependent apparent partition coefficients (log D), the neutral compound (2) proved to have almost identical log D values at varying pH-values. The subsequent determination of partition coefficients (log P) resulted in comparably low log P values revealing a less lipophilic compound character. Determined significantly differing P-glycoprotein (P-gp) inhibitory properties indicated that the lipophilicity of the compounds does not play a decisive role for the P-gp activity.