ABSTRACT
Inhaltliche Richtigstellung zu folgendem Beitrag in der Chemical Education-Reihe: C. A. Vock, Chimia 2021, 75, 443-445, https://doi.org/10.2533/chimia.2021.443.
ABSTRACT
Im Rahmen einer didaktischen Einordnung der bedeutenden nicht-proteinogenen Aminosäure Norleucin in die Familie der konstitutionsisomeren Leucine werden Vorkommen in Naturstoffen und Pharmaka sowie insbesondere die komplizierte historische Namensfindung der Verbindung dargestellt.
ABSTRACT
L-tert-Leucin wird mit wichtigen Zusatzinformationen zu Herstellung, Vorkommen und Verwendung als Konstitutionsisomer der proteinogenen Aminosäuren L-Leucin und L-Isoleucin vorgestellt.
ABSTRACT
Upon the screening of 16 antiproliferative compounds against Toxoplasma gondii and Neospora caninum, two hydrolytically stable ruthenium complexes (compounds 16 and 18) exhibited 50% inhibitory concentrations of 18.7 and 41.1 nM (T. gondii) and 6.7 and 11.3 nM (N. caninum). To achieve parasiticidal activity with compound 16, long-term treatment (22 to 27 days at 80 to 160 nM) was required. Transmission electron microscopy demonstrated the rapid impact on and ultrastructural alterations in both parasites. These preliminary findings suggest that the potential of ruthenium-based compounds should thus be further exploited.
Subject(s)
Coordination Complexes/pharmacology , Life Cycle Stages/drug effects , Neospora/drug effects , Ruthenium/chemistry , Toxoplasma/drug effects , Animals , Chlorocebus aethiops , Coordination Complexes/chemical synthesis , Fibroblasts/drug effects , Fibroblasts/parasitology , Humans , Inhibitory Concentration 50 , Microscopy, Electron, Transmission , Neospora/growth & development , Neospora/ultrastructure , Toxoplasma/growth & development , Toxoplasma/ultrastructure , Vero CellsABSTRACT
Two series of η(6)-areneruthenium(II) phosphite complexes were prepared, characterized, and evaluated in vitro for their toxic potential against Echinococcus multilocularis metacestodes. Neutral complexes of general formula [(η(6)-p-cymene)RuCl(2){P(OR)(3)}] (R = Et, (i)Pr, Ph) with two easily exchangable chloride ligands showed only minor toxicity, whereas the substitution of these moieties against a ß-diketonate (2,2,6,6-tetramethylheptanedionate) ligand led to hydrolytically stable complex salts of type [(η(6)-p-cymene)Ru(ß-diketonate){P(OR)(3)}][BF(4)] (R = Et, (i)Pr, Ph) with comparable in vitro toxicity (50% PGI release at c = 1.4 - 4.7 µM) to the reference drug nitazoxanide (50% PGI release at c = 1.2 µM). In addition, the latter complexes were highly toxic against rat hepatoma cells (IC(50) = 0.40-2.0 µM) and less toxic against human foreskin fibroblasts (IC(50) = 1.1-2.9 µM) and Vero cells (IC(50) = 1.2-8.9 µM). The measured cytotoxicities against mammalian cells are, to the best of our knowledge, among the highest ever observed for ruthenium-based complexes. In conclusion, complex salts of type [(η(6)-p-cymene)Ru(ß-diketonate){P(OR)(3)}][BF(4)] might be interesting candidates for further development toward anthelmintic drugs and/or highly cytotoxic metal compounds.
Subject(s)
Anthelmintics/pharmacology , Coordination Complexes/pharmacology , Echinococcosis, Hepatic/drug therapy , Echinococcus multilocularis/drug effects , Phosphites/pharmacology , Ruthenium/chemistry , Animals , Anthelmintics/chemical synthesis , Anthelmintics/chemistry , Cell Line, Tumor , Cell Survival/drug effects , Chlorocebus aethiops , Coordination Complexes/chemical synthesis , Coordination Complexes/chemistry , Dose-Response Relationship, Drug , Echinococcosis , Echinococcosis, Hepatic/parasitology , Humans , Magnetic Resonance Spectroscopy , Mass Spectrometry , Molecular Structure , Monoterpenes/chemical synthesis , Monoterpenes/chemistry , Monoterpenes/pharmacology , Phosphites/chemical synthesis , Phosphites/chemistry , Rats , Vero CellsABSTRACT
Outgoing from an etomidate-based design concept, we succeeded in the development of a series of highly active and selective inhibitors of CYP11B1, the key enzyme of cortisol biosynthesis, as potential drugs for the treatment of Cushing's syndrome and related diseases. Thus, compound 33 (IC50 = 152 nM) is the first CYP11B1 inhibitor showing a rather good selectivity toward the most important steroidogenic CYP enzymes aldosterone synthase (CYP11B2), the androgen-forming CYP17, and aromatase (estrogen synthase, CYP19).
ABSTRACT
A series of 23 N-(Pyridin-3-yl)benzamides was synthesized and evaluated for their potential to inhibit human steroid-11ß-hydroxylase (CYP11B1) and human aldosterone synthase (CYP11B2). The most potent and selective CYP11B2 inhibitors (IC(50) values 53-166 nM) were further evaluated for their potential to inhibit human CYP17 and CYP19, and no inhibition was observed. Clear evidence was shown for N-(Pyridin-3-yl)benzamides to be a highly selective class of CYP11B2 inhibitors in vitro.
Subject(s)
Benzamides/chemistry , Cytochrome P-450 CYP11B2/antagonists & inhibitors , Enzyme Inhibitors/chemistry , Aromatase/chemistry , Aromatase/metabolism , Benzamides/chemical synthesis , Benzamides/pharmacology , Cytochrome P-450 CYP11B2/metabolism , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Humans , Steroid 11-beta-Hydroxylase/antagonists & inhibitors , Steroid 11-beta-Hydroxylase/metabolism , Steroid 17-alpha-Hydroxylase/antagonists & inhibitors , Steroid 17-alpha-Hydroxylase/metabolism , Structure-Activity RelationshipABSTRACT
A library of 17 novel estrogen analogues 3 and 4 containing different substituents at rings A and D (steroid nomenclature) was prepared in a five- to seven-step synthesis. The key transformation is a Sonogashira-coupling of cyclic vinyl iodides of type 7 or 8 with phenylacetylenes of type 9. Reduction of the keto function in 3 led to the estradiol analogue 5.
Subject(s)
Estradiol/analogs & derivatives , Estradiol/chemical synthesis , Estrone/analogs & derivatives , Estrone/chemical synthesis , Small Molecule Libraries/chemical synthesis , Estradiol/chemistry , Estrone/chemistry , Molecular Conformation , StereoisomerismABSTRACT
Organometallic ruthenium(II) complexes of the general formula [Ru(eta6-p-cymene)Cl2(L)] and [Ru(eta6-p-cymene)Cl(L)2][BPh4] with modified phenoxazine- and anthracene-based multidrug resistance (MDR) modulator ligands (L) have been synthesized, spectroscopically characterized, and evaluated in vitro for their cytotoxic and MDR reverting properties in comparison with the free ligands. For an anthracene-based ligand, coordination to a ruthenium(II) arene fragment led to significant improvement of cytotoxicity as well as Pgp inhibition activity. A similar, but weaker effect was also observed when using a benzimidazole-phenoxazine derivative as Pgp inhibitor. The most active compound in terms of both Pgp inhibition and cytotoxicity is [Ru(eta6-p-cymene)Cl2(L)], where L is an anthracene-based ligand. Studies show that it induces cell death via inhibition of DNA synthesis. Moreover, because the complex is fluorescent, its uptake in cells was studied, and relative to the free anthracene-based ligand, uptake of the complex is accelerated and accumulation of the complex in the cell nucleus is observed.
Subject(s)
Anthracenes/chemistry , Antineoplastic Agents/chemical synthesis , Drug Resistance, Multiple , Drug Resistance, Neoplasm , Organometallic Compounds/chemical synthesis , Oxazines/chemistry , Ruthenium , Animals , Anthracenes/chemical synthesis , Anthracenes/pharmacology , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Cell Line, Tumor , Cell Nucleus/metabolism , Chelating Agents/chemical synthesis , Chelating Agents/chemistry , Chelating Agents/pharmacology , Crystallography, X-Ray , Cymenes , Drug Screening Assays, Antitumor , Humans , Ligands , Mice , Molecular Structure , Monoterpenes/chemistry , Organometallic Compounds/chemistry , Organometallic Compounds/pharmacology , Oxazines/chemical synthesis , Oxazines/pharmacologyABSTRACT
Ten complexes of general formula [Ru(eta6-arene)Cl2(L)], [Ru(eta6-arene)Cl(L)2][X], and [Ru(eta6-arene)(L)3][X]2 (eta6-arene = benzene, p-cymene; L = imidazole, benzimidazole, N-methylimidazole, N-butylimidazole, N-vinylimidazole, N-benzoylimidazole; X = Cl, BF4, BPh4) have been prepared and characterized by spectroscopy. The structures of five representative compounds have been established in the solid state by single-crystal X-ray diffraction. All the new compounds were assessed by the same in vitro screening assays applied to [imidazole-H][trans-RuCl4(DMSO)(imidazole)] (NAMI-A) and [Ru(eta6-arene)Cl2(1,3,5-triaza-7-phosphaadamantane)] (RAPTA) compounds. It was found that the new compounds show essentially the same order of cytotoxicity as the RAPTA compounds toward cancer cells. Several of the compounds were selective toward cancer cells in that they were less (or not) cytotoxic toward nontumorigenic cells that are used to model healthy human cells. Thus, two of the compounds, [Ru(eta6-p-cymene)Cl(vinylimid)2][Cl] (vinylimid = N-vinylimidazole) and [Ru(eta6-benzene)(mimid)3][BF4]2 (mimid = N-methylimidazole), have been selected for a more detailed in vivo evaluation.