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. In particular, some gallamides and pyrogallol-1-monomethyl ethers showed remarkable affinity and selectivity toward MRP1. On the other hand, trimethyl ether galloyl anilides, with few exceptions, exhibited moderate to very high and selective P-gp inhibition.

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. ESI MS spectra clearly revealed the formation of a variety of platinum-protein adducts predominantly corresponding to monoplatinated cyt c species. From a careful analysis of the major ESI MS peaks, specific information on the nature of the protein-bound metallic fragments and on the underlying metallodrug-cyt c reactions was gained for the various cases. We found that trans-EE produces a major cyt c adduct (12 667 Da) that is different from that produced by either cis-EE or by trans-Z and cis-Z (12 626 Da). In particular, occurrence of extensive hydrolysis/aminolysis (the latter fostered by ammonium carbonate buffer) of the iminoether ligands and formation of the corresponding amides/amidines has been unambiguously documented. The reactivity of the iminoether ligands is greatly enhanced by the presence of cyt c as inferred from comparative NMR solution studies. Additional ESI MS measurements recorded on enzymatically cleaved samples of platinated cyt c adducts, together with NMR investigation of the cyt c/trans-EE adduct, strongly suggest that protein platination primarily occurs at Met 65. The biological and pharmacological implications of the described protein platination processes are discussed.

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. In aerobic conditions, oxidation of platinum(II) to platinum(III) together with formation of two additional amidinato bridges across the two platinum centers takes place leading to compound 1. In contrast, in anaerobic conditions, oxidation of platinum is prevented and the dinuclear platinum(II) precursor remains in solution until it reacts with an extra molecule of the starting mononuclear complex which loses its two amidine ligands and cross-links the two bridging amidinato ligands of 3 to yield compound 2. This latter features two triply bridging amidinato ligands linking the three platinum units to form a pocket. Complexes 1 and 2 have been characterized by means of IR and NMR spectroscopy, mass spectrometry, elemental analysis, and X-ray crystallography.

New cis‐ and trans‐dichloridoplatinum(II) complexes, which contain two amidine ligands or one amidine and one ammine ligand, cis‐ and trans‐[PtCl2{(Z)‐HN=C(NH2)CH3}2] (1) and cis‐ and trans‐[PtCl2(NH3){(Z)‐HN=C(NH2)CH3}] (2), have been prepared from the corresponding nitrile complexes by amminolysis in thf solution. All synthesized compounds were characterized by elemental analysis, ESI‐MS, and IR and NMR spectroscopy. Amidines are isosters of iminoethers and ketimines. The trans isomers of the platinum complexes of the latter are endowed with an unexpectedly high antitumor activity. An important feature of complexes 1 and 2, as compared to iminoethers, is the exclusive preference for the Z configuration of the amidine ligand(s). The tumor cell growth inhibitory potency of the amidine compounds was tested towards a pair of human ovarian tumor cell lines A2780 (cancer cells sensitive to cisplatin) and A2780cisR (cancer cells with acquired resistance to cisplatin), and compared to that of cisplatin. From the obtained results it appears that the resistance factor is lower for cis‐amidine complexes as compared to cisplatin, and for trans compounds it is lower as compared to cis compounds.(© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2008)

The first triply bridged dinuclear platinum(III) compound\ud with acetamidate ligands, X[Pt2Cl4{N(H)C(CH3)O}3] (X = K+\ud or AsPh4\ud +), has been isolated in the solid state and characterized\ud by one- and two-dimensional NMR spectroscopy and\ud X-ray crystallography. Owing to the asymmetry of the bridging\ud acetamidate ligands, three isomers can be formed (HHH,\ud HHT, and HTH), although only two are found in the crude\ud reaction product: HHT and HTH. The HTH species is thermodynamically\ud less stable and slowly (half life of around two\ud days at room temperature) isomerizes into the HHT form.\ud The more stable and less symmetric HHT isomer crystallizes from chloroform/pentane (AsPh4\ud + counter ion). The two\ud [Pt2Cl4{N(H)C(CH3)O}3]– anions of the unit cell are linked by\ud two strong N–H···O H-bonds while contiguous anions of adjacent\ud cells are linked together by two, slightly weaker N–\ud H···Cl H-bonds. The result is a chain of anions running along\ud the a direction. The crystal packing allows for the formation\ud of one-dimensional pore channels, also running along the a\ud direction, which are filled with disordered pentane molecules