Multiaction Pt(IV) prodrugs can overcome resistance associated with the FDA approved Pt(II) drugs like cisplatin. Intracellular reduction of the octahedral Pt(IV) derivatives of cisplatin releases cisplatin and the two axial ligands. When the released axial ligands act synergistically with cisplatin to kill the cancer cells, we have multiaction prodrugs. Most Pt(IV) multiaction prodrugs have bioactive ligands possessing a carboxylate that is conjugated to the Pt(IV) because breaking the Pt(IV)−ligand bond releases the active moiety. As many drugs that act synergistically with cisplatin do not have carboxylates, a major challenge is to prepare multiaction Pt(IV) complexes with drugs that have amino groups or hydroxyl groups such that following reduction, the drugs are released in their active form. Our objective was to prepare multiaction Pt(IV) prodrugs that release bioactive molecules having amino groups. Because we cannot conjugate amino groups to the axial position of Pt(IV), we developed a novel and efficient approach for the synthesis of Pt(IV)−carbamato complexes and demonstrated that following reduction of the Pt(IV), the released carbamates undergo rapid decarboxylation, releasing the free amine, as in the case of the PARP-1 inhibitor 3aminobenzamide and the amino derivative of the HDAC inhibitor SAHA. Pt(IV)−carbamato complexes are stable in cell culture medium and are reduced by ascorbate. They are reduced slower than their carboxylato and carbonato analogues. We believe that this approach paves the way for preparing novel classes of multiaction Pt(IV) prodrugs with amino containing bioactive molecules that up to now were not accessible.
Iodo coordinated half-sandwich RuII-anthraimidazoldione shows stability and low cytotoxicity even under hypoxia in metastatic cancer MDA-MB-231 cells (1–2 μM), induces apoptosis without ROS, and prevents migration at IC20 dose.
Anthraquinone based anion receptors have gained importance due to their colorimetric response on sensing a specific anion and the possibility of tuning this property by varying the conjugated moiety (the donor) to the diamine. In this work, we have synthesized and characterized four anthraimidazoledione compounds having 2,5-dihydroxy benzene, 4-(bis(2-chloroethyl)amino)benzene, imidazole and 4-methylthiazole moieties respectively (1-4). All of them were probed for their potential as anion sensors to study the effect of changes in the hydrogen bond donor-acceptor. The p-hydroquinone bound anthraimidazoledione (1) and thioimidazole bound anthraimidazoledione (4) were able to detect both F(-) and CN(-) in the presence of other anions Cl(-), Br(-), I(-), H2PO4(-), OAc(-), NO3(-)and ClO4(-). Both 1 and 4 could not differentiate F(-) from CN(-) and provided a similar response to both. The 1H NMR studies of 1 and 4 with F(-) showed the formation of [HF2](-) at 16.3 ppm and the 19F NMR showed a sharp peak at -145 ppm in both cases. However, although there may be NMR evidence of [HF2](-) formation F(-) may not be detected colorimetrically if the CT band remains almost unchanged, as found for 3. The results emphasize that the change of a hetero atom in the donor moiety of an anthraimidazoledione may render a large difference in sensitivity. In the case of 4 selective detection of F(-) was possible in the presence of 0.5 equivalent of Cu2+ with the exhibition of a distinct green colour with a Δλ shift of ca. 50 nm in contrast to CN(-) which showed orange colouration with a Δλ shift of only 15 nm. In the presence of Cu2+ the F(-) detection limit was 0.038(5) ppm (below the WHO specified level) at a receptor concentration of 25 μM.
Three Cu(II) complexes of bis-pyrazole based ligands have been synthesized and structurally characterized by X-ray crystallography. One of the ligand (L2) contains a methionine ester conjugated to a bis-pyrazole carboxylate through an amide linkage. The binding constant for complexes 1-3 with CT DNA are of the order of 10(4) M(-1). The crystal structure suggests that the axial Cu-O bonds (ca. 2.31(4) Å) are relatively labile and hence during the redox cycle with ascorbic acid and oxygen one or both the axial Cu-O bonds might open to promote copper oxygen reaction and generate ROS. The chemical nuclease activity of complexes 1-3 in dark, show complete relaxation of supercoiled DNA at 100 μM concentration in presence of ascorbic acid (H2A). The mechanistic investigation suggests that the complexes 1 and 2 show involvement of peroxo species whereas 3 shows involvement of both singlet oxygen and peroxo species in DNA cleavage. The singlet oxygen formation in dark is otherwise unfavourable but the presence of methionine as pendant arm in L2 might activate the generation of singlet oxygen from the metal generated peroxo species. The results of DNA cleavage studies suggest that methionine based copper(II) complexes can promote dual pathway for DNA cleavage. Probing the cytotoxic activity of these complexes on MCF-7, human breast cancer cell line shows that 3 is the most effective one with an IC50 of 70(2) μM.
Our work shows that NO release is a feasible pathway of action for aromatic and heterocyclic N-(2-chloroethyl)-N-nitrosoureas and faster NO release may not lead to higher cytotoxicity.
Copper, platinum and palladium complexes of an oxazolidinone ligand show potential in catalysis or cytotoxicity, depending on the metal incorporated.
A hydroquinone based palladium complex [Pd(H 2 L)(Cl) 2 ] (1), acts as an efficient room temperature catalyst for reduction of nitroarenes in water as solvent. 1 also acts as a tandem catalyst for Suzuki-Miyaura cross coupling in ethanol followed by reduction of nitroarenes in one pot with a loading of 0.25 mol% catalyst. Palladium based catalysts are well known in the literature for their efficiency in a wide spectrum of coupling reactions and reduction of various functionalities. 1 Such catalytic reactions are of importance for their use in industrial applications spanning from pharmaceuticals to polymers or syntheses of natural products, dyes. 2 Aryl amine derivatives are very important intermediates in syntheses of many of the above using nitroarene precursors. 3 Room temperature reduction of nitroarenes is advantageous since there are compounds which are susceptible to degradation when heated during reduction. Several transition metal based catalysts are known to perform reduction of nitroarenes. 4 Most metal catalyzed nitro reduction reactions require higher temperatures, 4f,5 hydrogen gas, 3b,6 or use of expensive hydride source like silanes. 4b,5e,g,7 Among the most recent ones the work of Beller and co-workers used a Fephenanthroline catalyst (1.0 mol%) at 100 C in THF with four molar equivalent hydrazine as the hydrogen source for efficient and very selective reduction of nitroarenes. 5b However, metal complexes that reduces nitroarenes at room temperature are scarce ( Table 1). Most of such catalysts are nano particles (Table 1). Hence performing the nitroarene reduction in a green solvent like water at room temperature with a discrete metal complex is challenging. Very few catalysts perform the reduction of nitroarenes at room temperature with water as the solvent (Table 1) viz. Zn-dust (10 eq.) in surfactant (TPGS-750 M) water mixture 8 and the ionic liquid based PVDF-[C 6 (mpy) 2 ] [NiCl 4 ] 22 (5 mol%) catalyst 9 are needed in less amounts, are less toxic to environment are of high interest for their potential applications. 10 Such catalysts are air stable, efficient, economically viable and hence greener. The hydroquinone ligand used in this work is synthesized in a single step and is stable. The Palladium catalyst is active in lesser mol% without a phosphine or carbene ligand. To the best of our knowledge the use of hydroquinone in nitroarene reduction is not known.The reaction between a pyrazole derivatized hydroquinone ligand H 2 L and Pd II (MeCN) 2 Cl 2 in acetonitrile under reux condition led to formation of complex 1 which was further puried by crystallization from acetonitrile solution (Scheme 1). The single crystal X-ray diffraction showed the complex crystallizes in orthorhombic, space group Cmc2(1). The N atoms from the two pyrazoles chelate to the Pd II forming a seven membered ring and the remaining two coordination sites of the Pd II are satised by two chloride ions. The two Pd-N bond distances are ca. 2.024Å with an angle of ca. 85.5 . 1 H NMR of the complex indicate that the co...
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