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Angewandte Chemie (International Ed. in... Jun 2016Understanding how small molecules interact with DNA is essential since it underlies a multitude of pathological conditions and therapeutic interventions. Many different...
Understanding how small molecules interact with DNA is essential since it underlies a multitude of pathological conditions and therapeutic interventions. Many different intercalator compounds have been studied because of their activity as mutagens or drugs, but little is known regarding their interaction with nucleosomes, the protein-packaged form of DNA in cells. Here, using crystallographic methods and molecular dynamics simulations, we discovered that adducts formed by [(η(6) -THA)Ru(ethylenediamine)Cl][PF6 ] (THA=5,8,9,10-tetrahydroanthracene; RAED-THA-Cl[PF6 ]) in the nucleosome comprise a novel one-stranded intercalation and DNA distortion mode. Conversely, the THA group in fact remains solvent exposed and does not disrupt base stacking in RAED-THA adducts on B-form DNA. This newly observed DNA binding mode and topology dependence may actually be prevalent and should be considered when studying covalently binding intercalating compounds.
Topics: Anthracenes; Binding Sites; DNA; Ethylenediamines; Intercalating Agents; Molecular Dynamics Simulation; Organometallic Compounds
PubMed: 27184539
DOI: 10.1002/anie.201602145 -
Journal of Medicinal Chemistry Jul 2018Metal based therapeutics are a precious class of drugs in oncology research that include examples of theranostic drugs, which are active in both diagnostic, specifically... (Review)
Review
Metal based therapeutics are a precious class of drugs in oncology research that include examples of theranostic drugs, which are active in both diagnostic, specifically imaging, and therapeutics applications. Ruthenium compounds have shown selective bioactivity and the ability to overcome the resistance that platinum-based therapeutics face, making them effective oncotherapeutic competitors in rational drug invention approaches. The development of antineoplastic ruthenium therapeutics is of particular interest because ruthenium containing complexes NAMI-A, KP1019, and KP1339 entered clinical trials and DW1/2 is in preclinical levels. The very robust, conformationally rigid organometallic Ru(II) compound DW1/2 is a protein kinase inhibitor and presents new Ru(II) compound designs as anticancer agents. Over the recent years, numerous strategies have been used to encapsulate Ru(II) derived compounds in a nanomaterial system, improving their targeting and delivery into neoplastic cells. A new photodynamic therapy based Ru(II) therapeutic, TLD-1433, has also entered clinical trials. Ru(II)-based compounds can also be photosensitizers for photodynamic therapy, which has proven to be an effective new, alternative, and noninvasive oncotherapy modality.
Topics: Animals; Antineoplastic Agents; Biological Transport; Drug Discovery; Humans; Organometallic Compounds; Ruthenium
PubMed: 29446940
DOI: 10.1021/acs.jmedchem.7b01689 -
Molecules (Basel, Switzerland) Jan 2021Reactions of cyclometalated compounds are numerous. This account is focused on one of such reactions, the exchange of cyclometalated ligands, a reaction between a... (Review)
Review
Reactions of cyclometalated compounds are numerous. This account is focused on one of such reactions, the exchange of cyclometalated ligands, a reaction between a cyclometalated compound and an incoming ligand that replaces a previously cyclometalated ligand to form a new metalacycle: + H-C*~Z ⇄ + H-C~Y. Originally discovered for Pd complexes with Y/Z = N, P, S, the exchange appeared to be a mechanistically challenging, simple, and convenient routine for the synthesis of cyclopalladated complexes. Over four decades it was expanded to cyclometalated derivatives of platinum, ruthenium, manganese, rhodium, and iridium. The exchange, which is also questionably referred to as transcyclometalation, offers attractive synthetic possibilities and assists in disclosing key mechanistic pathways associated with the C-H bond activation by transition metal complexes and C-M bond cleavage. Both synthetic and mechanistic aspects of the exchange are reviewed and discussed.
Topics: Ligands; Metals; Molecular Structure; Organometallic Compounds
PubMed: 33401624
DOI: 10.3390/molecules26010210 -
Journal of Toxicology. Clinical... 1999Manganese is a very hard, brittle metal, which is used to increase the strength of steel alloys. Absorption from the gastrointestinal tract occurs in the divalent and... (Review)
Review
Manganese is a very hard, brittle metal, which is used to increase the strength of steel alloys. Absorption from the gastrointestinal tract occurs in the divalent and tetravalent forms. Permanganates, which are strong oxidizing agents, have a +7 valence. The principal organomanganese compound is the anti-knock additive, methylcyclopentadienyl manganese tricarbonyl. Manganese is a ubiquitous constituent of the environment comprising about 0.1% of the earth's crust. For the general population, food is the most important source of manganese with daily intake ranging from 2-9 mg Mn. Combustion of gasoline containing methylcyclopentadienyl manganese tricarbonyl releases submicron particles of Mn3O4 that are potentially respirable. Biomagnification of manganese in the food chain probably does not occur. The lungs and gastrointestinal tract absorb some manganese, but the relative amounts absorbed from each site are not known. Homeostatic mechanisms limit the absorption of manganese from the gastrointestinal tract. Elimination of manganese occurs primarily by excretion into the bile. Animal studies indicate that manganese is an essential co-factor for enzymes, such as hexokinase, superoxide dismutase, and xanthine oxidase. However, no case of manganese deficiency in humans has been identified. Manganism is a central nervous system disease first described in the 1800s following exposure to high concentrations of manganese oxides. Manganese madness was the term used to describe the initial psychiatric syndrome (compulsive behavior, emotional lability, hallucinations). More commonly, these workers developed a Parkinson's-like syndrome. Currently, the risks of exposure to low concentrations of manganese in the industrial and in the environmental settings (e.g., methylcyclopentadienyl manganese tricarbonyl in gasoline) are being evaluated with regards to the development of subclinical neuropsychological changes. The American Conference of Governmental and Industrial Hygienists recently lowered the TLV-TWA for manganese compounds and inorganic manganese compounds to 0.2 mg Mn/m3.
Topics: Animals; Environmental Pollutants; Humans; Manganese; Manganese Compounds; Manganese Poisoning; Occupational Exposure; Organometallic Compounds
PubMed: 10382563
DOI: 10.1081/clt-100102427 -
ACS Applied Materials & Interfaces Dec 2018Tip-enhanced Raman spectroscopy (TERS) is capable of probing specific molecular information with high sensitivity, but dual chemical sensing remains a challenge. Another...
Tip-enhanced Raman spectroscopy (TERS) is capable of probing specific molecular information with high sensitivity, but dual chemical sensing remains a challenge. Another major hindrance to TERS chemical detection in biosamples such as blood is the interference from the strong absorptions of biomolecules. Herein, we report the preparation of an organometallic-conjugated TERS tip. We demonstrate that organometallic chemistry can be perfectly coupled with TERS for dual-molecule sensing. The unique Raman signals generated by the organometallic compound circumvent signal interference from the biomolecules in blood, allowing the rapid analysis of two important molecules (glucose and thiol) in ultralow volume (50 nL) samples. This enabled a correlation between the thiol and glucose levels in the blood of nondiabetic and diabetic patients to be drawn.
Topics: Blood Glucose; Diabetes Mellitus; Humans; Organometallic Compounds; Spectrum Analysis, Raman; Sulfhydryl Compounds
PubMed: 30387600
DOI: 10.1021/acsami.8b11950 -
Scientific Reports Aug 2017Arterial thrombosis plays a key role in cardiovascular diseases. Hence, developing more effective antithrombotic agents is necessary. We designed a ruthenium...
Arterial thrombosis plays a key role in cardiovascular diseases. Hence, developing more effective antithrombotic agents is necessary. We designed a ruthenium (II)-derived complex, [Ru(η-cymene)2-(1H-benzoimidazol-2-yl)-quinoline Cl]BF (TQ-6), as a new antiplatelet drug. TQ-6 (0.3 µM) exhibited extremely strong inhibitory activity against platelet aggregation, Src, and Syk phosphorylation stimulated by agonists in human platelets. In collagen-activated platelets, TQ-6 also inhibited ATP-release, [Ca]i, P-selectin expression, FITC-PAC-1 binding, and hydroxyl radical formation, as well as the phosphorylation of phospholipase Cγ2, protein kinase C, mitogen-activated protein kinases, and Akt. Neither FITC-JAQ1 nor FITC-triflavin binding or integrin β phosphorylation stimulated by immobilized fibrinogen were diminished by TQ-6. Furthermore, TQ-6 had no effects in cyclic nucleotide formation. Moreover, TQ-6 substantially prolonged the closure time in whole blood, increased the occlusion time of thrombotic platelet plug formation and bleeding time in mice. In conclusion, TQ-6 has a novel role in inhibiting platelet activation through the inhibition of the agonist receptors-mediated inside-out signaling such as Src-Syk-PLCγ2 cascade and subsequent suppression of granule secretion, leading to disturb integrin αβ-mediated outside-in signaling, and ultimately inhibiting platelet aggregation. Therefore, TQ-6 has potential to develop as a therapeutic agent for preventing or treating thromboembolic disorders.
Topics: Animals; Biomarkers; Blood Coagulation; Blood Coagulation Tests; Blood Platelets; Cell Survival; Humans; Male; Mice; Molecular Structure; Organometallic Compounds; Phosphorylation; Platelet Activation; Platelet Aggregation; Platelet Aggregation Inhibitors; Platelet Membrane Glycoproteins; Ruthenium; Signal Transduction
PubMed: 28842683
DOI: 10.1038/s41598-017-09695-z -
International Journal of Molecular... Dec 2017Platelet activation plays a major role in cardio and cerebrovascular diseases, and cancer progression. Disruption of platelet activation represents an attractive...
Platelet activation plays a major role in cardio and cerebrovascular diseases, and cancer progression. Disruption of platelet activation represents an attractive therapeutic target for reducing the bidirectional cross talk between platelets and tumor cells. Platinum (Pt) compounds have been used for treating cancer. Hence, replacing Pt with iridium (Ir) is considered a potential alternative. We recently developed an Ir(III)-derived complex, [Ir(Cp*)1-(2-pyridyl)-3-(2-hydroxyphenyl)imidazo[1,5-a]pyridine Cl]BF₄ (Ir-11), which exhibited strong antiplatelet activity; hence, we assessed the therapeutic potential of Ir-11 against arterial thrombosis. In collagen-activated platelets, Ir-11 inhibited platelet aggregation, adenosine triphosphate (ATP) release, intracellular Ca mobilization, P-selectin expression, and OH formation, as well as the phosphorylation of phospholipase Cγ2 (PLCγ2), protein kinase C (PKC), mitogen-activated protein kinases (MAPKs), and Akt. Neither the adenylate cyclase inhibitor nor the guanylate cyclase inhibitor reversed the Ir-11-mediated antiplatelet effects. In experimental mice, Ir-11 prolonged the bleeding time and reduced mortality associated with acute pulmonary thromboembolism. Ir-11 plays a crucial role by inhibiting platelet activation through the inhibition of the PLCγ2-PKC cascade, and the subsequent suppression of Akt and MAPK activation, ultimately inhibiting platelet aggregation. Therefore, Ir-11 can be considered a new therapeutic agent against either arterial thrombosis or the bidirectional cross talk between platelets and tumor cells.
Topics: Humans; Iridium; Mitogen-Activated Protein Kinases; Organometallic Compounds; Phospholipase C gamma; Platelet Activation; Platelet Aggregation; Platelet Aggregation Inhibitors; Protein Kinase C; Thrombosis
PubMed: 29206177
DOI: 10.3390/ijms18122616 -
Pharmacological Research May 2016Ruthenium compounds have become promising alternatives to platinum drugs by displaying specific activities against different cancers and favorable toxicity and clearance...
The water soluble ruthenium(II) organometallic compound [Ru(p-cymene)(bis(3,5 dimethylpyrazol-1-yl)methane)Cl]Cl suppresses triple negative breast cancer growth by inhibiting tumor infiltration of regulatory T cells.
Ruthenium compounds have become promising alternatives to platinum drugs by displaying specific activities against different cancers and favorable toxicity and clearance properties. Here, we show that the ruthenium(II) complex [Ru(p-cymene)(bis(3,5-dimethylpyrazol-1-yl)methane)Cl]Cl (UNICAM-1) exhibits potent in vivo antitumor effects. When administered as four-dose course, by repeating a single dose (52.4mgkg-1) every three days, UNICAM-1 significantly reduces the growth of A17 triple negative breast cancer cells transplanted into FVB syngeneic mice. Pharmacokinetic studies indicate that UNICAM-1 is rapidly eliminated from kidney, liver and bloodstream thanks to its high hydrosolubility, exerting excellent therapeutic activity with minimal side effects. Immunohistological analysis revealed that the efficacy of UNICAM-1, mainly relies on its capacity to reverse tumor-associated immune suppression by significantly reducing the number of tumor-infiltrating regulatory T cells. Therefore, UNICAM-1 appears very promising for the treatment of TNBC.
Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Female; Humans; Kidney; Liver; Mice; Organometallic Compounds; Ruthenium; T-Lymphocytes, Regulatory; Triple Negative Breast Neoplasms; Tumor Burden
PubMed: 27038531
DOI: 10.1016/j.phrs.2016.03.032 -
European Journal of Medicinal Chemistry Dec 2022In recent years, both metal-based complexes and selenium-containing compounds have been widely explored for their therapeutic properties due to their roles in biological... (Review)
Review
In recent years, both metal-based complexes and selenium-containing compounds have been widely explored for their therapeutic properties due to their roles in biological processes and modulation of diverse molecular targets. However, despite their growing interest, there is no review to date that covers the potential use of the combination of these entities to design new therapeutic derivatives. This review highlights the latest achievements in this particular field, with a focus on compounds with anticancer and/or antimicrobial properties. With this aim, the formation of coordination compounds including several metals bearing selenium either with direct interaction with the metal center or as part of the organic ligand elsewhere is covered. Besides, coordination compounds with a Se(IV) center have been assessed. The biological properties of several selenium-containing organometallic complexes have also been discussed, including metallocenes, half-sandwich complexes, and compounds with N-heterocyclic carbenes, CO, and π-ligands, and other σ-bonded entities. The information compiled in this review may be helpful to design and develop novel, more potent, and safer metal-based compounds for the treatment of several pathologies.
Topics: Selenium; Antineoplastic Agents; Coordination Complexes; Ligands; Metals; Anti-Infective Agents; Biological Phenomena; Organometallic Compounds
PubMed: 36215861
DOI: 10.1016/j.ejmech.2022.114834 -
Acta Crystallographica. Section C,... Apr 2005The title compound, (C6H9N2)[ZnCl3(C6H8N2)], consists of one 2-amino-5-methylpyridinium cation and one (2-amino-5-methylpyridine)trichlorozincate(II) anion, which are...
The title compound, (C6H9N2)[ZnCl3(C6H8N2)], consists of one 2-amino-5-methylpyridinium cation and one (2-amino-5-methylpyridine)trichlorozincate(II) anion, which are held together by N-H...Cl hydrogen bonds and pi-pi interactions. The cation and the pyridine ligand show similar geometric features, except for the N-C bond lengths. Molecules of the title compound are connected by N-H...Cl hydrogen bonds to form chiral chains; these chains are associated further by C-H...Cl hydrogen bonds to form layers, which are in turn linked by pi-pi interactions.
Topics: Crystallography, X-Ray; Hydrogen Bonding; Molecular Conformation; Organometallic Compounds; Pyridinium Compounds; Spectrophotometry, Infrared; Zinc
PubMed: 15805621
DOI: 10.1107/S0108270105006694