New Water-Soluble Copper(II) Complexes with Morpholine-Thiosemicarbazone Hybrids: Insights into the Anticancer and Antibacterial Mode of Action

Six morpholine-(iso)­thiosemicarbazone hybrids HL1–HL6 and their Cu­(II) complexes with good-to-moderate solubility and stability in water were synthesized and characterized. Cu­(II) complexes [Cu­(L1–6)­Cl] (1–6) formed weak dimeric associates in the solid state, which did not remain intact in solution as evidenced by ESI-MS. The lead proligands and Cu­(II) complexes displayed higher antiproliferative activity in cancer cells than triapine. In addition, complexes 2–5 were found to specifically inhibit the growth of Gram-positive bacteria Staphylococcus aureus with MIC50 values at 2–5 μg/mL. Insights into the processes controlling intracellular accumulation and mechanism of action were investigated for 2 and 5, including the role of ribonucleotide reductase (RNR) inhibition, endoplasmic reticulum stress induction, and regulation of other cancer signaling pathways. Their ability to moderately inhibit R2 RNR protein in the presence of dithiothreitol is likely related to Fe chelating properties of the proligands liberated upon reduction

New Water-Soluble Copper(II) Complexes with Morpholine-Thiosemicarbazone Hybrids: Insights into the Anticancer and Antibacterial Mode of Action

Six morpholine-(iso)thiosemicarbazone hybrids HL1-HL6 and their Cu(II) complexes with good-to-moderate solubility and stability in water were synthesized and characterized. Cu(II) complexes [Cu(L1-6)Cl] (1-6) formed weak dimeric associates in the solid state, which did not remain intact in solution as evidenced by ESI-MS. The lead proligands and Cu(II) complexes displayed higher antiproliferative activity in cancer cells than triapine. In addition, complexes 2-5 were found to specifically inhibit the growth of Gram-positive bacteria Staphylococcus aureus with MIC50 values at 2-5 μg/mL. Insights into the processes controlling intracellular accumulation and mechanism of action were investigated for 2 and 5, including the role of ribonucleotide reductase (RNR) inhibition, endoplasmic reticulum stress induction, and regulation of other cancer signaling pathways. Their ability to moderately inhibit R2 RNR protein in the presence of dithiothreitol is likely related to Fe chelating properties of the proligands liberated upon reduction

Mono-, di- and polynucleating thiosemicarbazones, amidrazones and aminoguanisones, as well as their metal complexes as potential anticancer drugs

Diese Doktorarbeit handelt von der Synthese von Thiosemicarbazonen, Amidrazonen und Aminoguanizonen, welche ein-, zwei- und mehrkernige Metallkomplexe bilden. Diese neuen Moleküle zeigen sowohl antikrebs als auch bacterizide und antivirale Aktivität und wirken als duale Pharmazeutika. Sechs neue, wasserlösliche Morpholin-(iso)thiosemicarbazon Hybride und ihre Kupfer(II) Komplexe wurden synthetisiert. Diese Verbindungen zeigen bemerkenswerte Aktivität in cisplatinsensitiven und cisplatinresistenten Eierstockkrebszellen. Studien mit R2 RNR zeigten, dass die Kupfer(II) Komplexe mit den neuen Liganden das tyrosil Radical in Maus R2 RNR moderat inhibieren. Zusätzlich wurde gezeigt, dass Komplexierung der neuen Liganden zu einer Steigerung der bakteriziden Aktivität gegen S. aureus führt. Amidrazone besitzen ein breites Spektrum an biologischen Aktivitäten und sind gute Metall-Chelatoren. In der vorgestellten Arbeit wurden neue redoxaktive einkernige Cu(II), heterozweikernige Cu(II)-Ru(II) und Cu(II)-Os(II) Komplexe mit [CuCl2]- als Gegenion syntetisiert. Im Falle des Kupfer(II)amidrazon Komplexes war die Aldimin-Bindung stark polarisiert, was zu einer Substitution von H durch eine MeO Gruppe führte. Alle drei Komplexe zeigten moderate Aktivität in Eierstockkrebszellen und Gehirnkrebszellen im mikromolaren Konzentrationsbereich. Spin-Fallen Experimente in zellfreien Medien zeigten, dass die Verbindungen dazu in der Lage sind ROS zu generieren, was eine Erklärung für ihre antiproliferative Aktivität sein könnte. Triapin (3-Aminopyridin-2-carboxaldehydthiosemicarbazon, 3-AP) ist eines der potentesten Antikrebswirkstoffe und ein Inhibitor von R2 RNR. Der Wirkstoff wurde bereits in über 30 klinischen Phase I und II Studien getestet. Zwei neue Derivate mit S-methyl und Pyridin Subsituenten und ihre Kupfer(II) und Eisen(III) Komplexe wurden syntetisiert und in Eierstockkrebszellen und nichtkarzinogenen embryonischen Nierenzellen getestet. Die Komplexe zeigten ein signifikante Cytotoxizität im Vergleich mit den Proliganden, bedauerlicherweise zeigten sie aber keine Selektivität für Krebszellen. Zusätzlich wurden Versuche unternommen mehrkernige Thiosemicarbazonkomplexe zu erhalten, was zur Synthese eines neuen morpholinsubstituierten tris-Thiosemicarbazon und dessen tris-Kupfer(II)komplex führte. Diese Verbindungsklasse wird weiterhin untersucht.This PhD thesis is focused on the synthesis of novel mono-, di- and polynucleating thiosemicarbazones, amidrazones and/or aminoguanizones as well as their metal complexes, which could possess anticancer activity and additionally antibacterial/antiviral activity and act dual pharmaceutical agents. Six novel water-soluble morpholine-(iso)thiosemicarbazone hybrids with their copper(II) complexes were synthesized. Compounds displayed remarkable activity against cisplatin-sensitive and cisplatin-resistant ovarian carcinoma cells. Studies with R2 RNR showed that copper(II) complexes with new hybrid ligands moderately inhibit the tyrosil radical in mouse R2 RNR. Additionally it was discovered that complex formation with new hybrid ligands results in enhancement of antibacterial activity against S. aureus. Amidrazones possess a broad spectrum of biological activity and are good metal chelators. In the presented work new redox-active mono- Cu(II) and heterodinuclear Cu(II)-Ru(II) and Cu(II)-Os(II) complexes with [CuCl2]- as counteranion were synthesized. In case of copper(II)-amidrazone complex aldimine bond was highly polarized which resulted in substitution of H by MeO group. All three complexes have demonstrated moderate activity against ovarian carcinoma and cervical carcinoma cells in micromolar concentration range. Spin trapping experiment in cell-free media and confocal microscopic imaging in ovarian carcinoma cells showed that compounds are able to generate ROS, which could explain their antiproliferative activity. Triapine (3-aminopyridine-2-carboxaldehyde thiosemicarbazone , 3-AP) is one of the most potent antitumor drug and inhibitor of R2 RNR. The drug has already entered more than 30 phase I and II clinical trials. Two new derivatives with S-methyl and pyridine substituents and their Cu(II) and Fe(III) complexes were synthesized and tested against ovarian cancer cells and non-cancerous embryonic kidney cells. Complexes showed significant cytotoxicity in comparison to proligands but unfortunately were not selective to cancer cells. Additionally, attempts to obtain polynucleating thiosemicarbazone-derivatives were undertaken and resulted in synthesis of novel tris-thiosemicarbazone with morpholine moiety and its tricopper(II) complex. The investigation of this class of compounds is going on

2-[(Pyridin-2-yl)amino]pyridinium 2,4,6-trinitrophenolate

In the cation of the title salt, C10H10N3+·C6H2N3O7−, the pyridine and pyridinium rings are linked by an intramolecular N—H...N hydrogen bond and are approximately coplanar, with a dihedral angle between their planes of 4.24 (6)°. In the crystal, the cations and anions are linked through N—H...O hydrogen bonds, forming supramolecular chains propagating along the c-axis direction. π–π stacking is observed between neighbouring chains, the centroid–centroid distances being 3.7638 (11) (between pyridinium rings) and 3.5331 (11) Å (between benzene rings)

Crystal structure of 2-{[(E)-(4-anilinophenyl)iminiumyl]methyl}-5-(diethylamino)phenolate

The title compound, C23H25N3O, crystallized with one single molecule in the asymmetric unit and is present in the zwitterionic form. There is an intramolecular N—H...O hydrogen bond in the molecule with the phenol ring being inclined to the central benzene ring by 20.67 (14)°. The terminal aminophenyl ring forms a dihedral angle of 54.21 (14)° with the central benzene ring. The two outer aromatic rings are inclined to one another by 74.54 (14)°. In the crystal, the molecules are connected by N—H...O hydrogen bonds, with adjacent molecules related by a 21 screw axis, generating –A–B–A–B– zigzag chains extending along [010]. The chains are linked via C—H...π and π–π interactions [with a centroid–centroid distance of 3.444 (3) Å] between the benzene ring and the imino group of symmetry-related molecules, forming slabs lying parallel to (100)

Crystal structure of bis(μ-N-hydroxypicolinamidato)bis[bis(N-hydroxypicolinamide)sodium]

The title compound, [Na2(C6H5N2O2)2(C6H6N2O2)4], is a centrosymmetric coordination dimer based on the sodium(I) salt of N-hydroxypicolinamide. The molecule has an {Na2O6(μ-O)2} core with two bridging carbonyl O atoms and two hydroxamate O atoms of two mono-deprotonated residues of N-hydroxypicolinamide, while two neutral N-hydroxypicolinamide molecules are coordinated in a monodentate manner to each sodium ion via the carbonyl O atoms [the Na—O distances range from 2.3044 (2) to 2.3716 (2) Å]. The pentacoordinated sodium ion exhibits a distorted trigonal–pyramidal coordination polyhedron. In the crystal, the coordination dimers are linked into chains along the c axis via N—H...O and N—H...N hydrogen bonds; the chains are linked into a two-dimensional framework parallel to (100) via weak C—H...O and π–π stacking interactions