Potent galloyl-based selective modulators targeting multidrug resistance associated protein 1 and P-glycoprotein.

The multifactorial nature of chemotherapy failure in controlling cancer is often associated with the occurrence of multidrug resistance (MDR), a phenomenon likely related to the increased expression of members of the ATP binding cassette (ABC) transporter superfamily. In this respect, the most extensively characterized MDR transporters include ABCB1 (also known as MDR1 or P-glycoprotein) and ABCC1 (also known as MRP1) whose inhibition remains a priority to circumvent drug resistance. Herein, we report how the simple galloyl benzamide scaffold can be easily and properly decorated for the preparation of either MRP1 or P-gp highly selective inhibitors.

Solution behavior of amidine complexes: an unexpected cis/trans isomerization and formation of di- and trinuclear platinum(III) and platinum(II) species.

Platinum bis-amidine complexes (both the cis and trans isomers) are stable in acetone and chlorinated solvents but are unstable in protic solvents such as methanol or water. In the latter solvents an initial cis/trans isomerization leads to formation of an equilibrium mixture with a cis/trans ratio of about 1:4; subsequently a dinuclear platinum(III) complex (1) is formed under aerobic conditions while, under anaerobic conditions, a trinuclear platinum(II) compound (2) is obtained. We hypothesize that the process of isomerization and formation of polynuclear compounds (1 and 2) have a common precursor: a dinuclear platinum(II) species supported by two bridging amidinato ligands (3), formed in small yield, which can either dissociate back to monomers of cis/trans configuration or evolve in two different polynuclear species depending upon the aerobic/anaerobic conditions.

Insights into the molecular mechanisms of protein platination from a case study: the reaction of anticancer platinum(II) iminoethers with horse heart cytochrome c.

The interactions of anticancer metallodrugs with proteins are attracting a growing interest in the current literature because of their relevant pharmacological and toxicological consequences. To understand in more depth the nature of those interactions, we have investigated the reactions of four anticancer platinum(II) iminoether complexes, namely, trans- and cis-EE (trans- and cis-[PtCl2{(E)-HN=C(OCH3)CH3}2], respectively) and trans- and cis-Z (trans- and cis-[PtCl2(NH3){(Z)-HN=C(OCH3)CH3}], respectively), with horse heart cytochrome c (cyt c). Our investigation was performed using mainly electrospray ionization mass spectrometry (ESI MS) but was also supported by NMR, inductively coupled plasma optical emission spectroscopy (ICP OES), and absorption electronic spectroscopy.