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Ruthenium Anticancer Drugs
Published in Astrid Sigel, Helmut Sigel, Metal Ions in Biological Systems, 2004
Enzo Alessio, Giovanni Mestroni, Alberta Bergamo, Gianni Sava
In the eighties, Keppler and coworkers reported the exciting news that two isostructural Ru(III) compounds of formula [ImH][trans-RuCl4(Im)2] (ICR) and [IndH][trans-RuCl4(Ind)2] were active against a platinum-resistant colorectal tumor in rats [18]. In that period, while working on the preparation of cis- and trans-RuCl2(dmso-S)4 [19], we isolated and characterized the dmso analog of the above Keppler-type compounds, namely [(dmso)2H][trans-RuCl4(dmso-S)2] (1) [20] (Scheme 1). The cation in 1 can be easily exchanged (e.g., for Na+, , ImH+, tBu4N+), thus making it soluble in a wide range of solvents. Treatment of 1 with AgBF4 in the presence of dmso led to the isolation of the neutral complex mer,trans-RuCl3(dmso-S)2(dmso-O) (2), which is still soluble in water. Compounds 1 and 2 proved to be unsuited for biological testing, because of their rapid hydrolysis at physiological pH, followed by formation of oxo- or hydroxo-bridged polymeric species.
PARACEST Contrast Agents
Published in Michel M. J. Modo, Jeff W. M. Bulte, Molecular and Cellular MR Imaging, 2007
These systems do highlight one further advantage of using lanthanide-based agents for CEST. Because the coordination chemistry of the lanthanides is virtually identical along the series, isostructural complexes can be prepared with any lanthanide ion and any given ligand system. This means that the hyperfine shift characteristics and relaxation properties of a PARACEST agent can be tuned by the choice of lanthanide ion. As can be seen from Table 6.1, both the magnitude and sign of the chemical shift of protons in lanthanide complexes can be altered considerably by lanthanide ion substitution. This means that more than one PARACEST agent could be administered simultaneously, and each could be activated separately by an appropriate choice of CEST frequency. This concept was nicely demonstrated both in phantoms and in living cells by Aime and coworkers.18 A schematic of this experiment is illustrated in Figure 6.5 with four samples: one containing EuDOTA-4AmC− (Δω = 50 ppm downfield), one containing TbDOTA-4AmC− (Δω = 600 ppm upfield), one containing a mixture of both complexes, and a control containing only water. When a presaturation pulse is applied at +50 ppm prior to image acquisition, a change in total water signal intensity is observed only in those samples containing the europium complex. No change in water intensity is observed in samples that do not contain the europium complex. Conversely, a presaturation pulse applied at −600 ppm activates only the terbium complex, and a decrease in water intensity is observed only in those samples containing the terbium complex. As illustrated for the sample containing both complexes, the presence of a second complex does not affect the performance of the first complex as long as the saturation frequencies are well separated from one another. There are many imaging applications where the use of multiple PARACEST agents could be envisioned; for example, cell-tracking experiments might allow more than onetype of cell to be tracked simultaneously, or two types of PARACEST agents could be given at equal concentrations, one for reporting a physiological measure such as pH and another simply acting as a concentration marker.
Antibacterial carbonic anhydrase inhibitors: an update on the recent literature
Published in Expert Opinion on Therapeutic Patents, 2020
Claudiu T. Supuran, Clemente Capasso
Sulfonamides, together with the inorganic anions, are the most investigated CA inhibitors (CAIs) [18,29,47,48]. Domagk discovered the antimicrobial sulfonamides in 1935 [49], and they were the first antimicrobial drugs to be widely used in clinical settings. The first sulfonamide showing effective antibacterial activity was Prontosil, a sulfanilamide prodrug, the last compound being isosteric/isostructural with p-aminobenzoic acid (PABA), the substrate of dihydropteroate synthase (DHPS) [50]. In the following years after sulfanilamide was shown to be an effective antibacterial agent, a range of analogs constituting the so-called sulfa drug class of antibacterials entered into clinical use, and many of these compounds are still widely used, despite significant drug resistance problems. DHPS, as mentioned above, is the target of the sulfa drugs. Several DHPS mutations are responsible for the sulfonamide resistance [5]. However, the presence of primary sulfonamide moieties in sulfanilamide also endows it with CA inhibitory properties [27,29]. Thus, a range of compounds incorporating SO2NH2 groups were investigated as CAIs against bacterial CAs (and of course also against CAs present in other organisms) [27,29].
Biomedical applications of prokaryotic carbonic anhydrases
Published in Expert Opinion on Therapeutic Patents, 2018
Claudiu T. Supuran, Clemente Capasso
CA inhibitors (CAIs) are small molecules capable to bind the catalytic metal ion, the metal coordinated-water molecule, and the occlusion of the active site [45,46]. Following these observations they can be grouped into four different groups: (1) the metal ion binders, such as anion, sulfonamides and their bioisosteres, dithiocarbamates, xanthates, etc.; (2) compounds like phenols, polyamines, thioxocoumarins, sulfocumarins, which anchor to the zinc-coordinated water molecule/hydroxide ion; (3) compounds, such as coumarins and their isosteres, which occlude the active site entrance; and (4) finally, compounds, which inhibit the CA binding out of the active site [46]. The most investigated CAIs are anions and sulfonamides [46–49]. Sulfonamides were discovered by Domagk in 1935 [50], which were the first antimicrobial drugs. The first sulfonamide showing effective antibacterial activity was Prontosil, a sulfanilamide prodrug isosteric/isostructural with p-aminobenzoic acid (PABA) [51]. In the following years, a range of analogs, the so-called ‘sulfa drug class’ entered into clinical use, and many of them are still widely used. A library of 40 compounds, 39 sulfonamides and one sulfamate, were used as CAIs (Figure 3) [3,7,10,11,28,34,52–61].