Modulation of the Biological Properties of Aspirin by Formation of a Bioorganometallic Derivative

Ott, Ingo; Kircher, Brigitte; Bagowski, Christoph P.; Vlecken, Danielle H.; Ott, Elisabeth; Will, Joanna; Bensdorf, Kerstin; Sheldrick, William S.; Gust, Ronald

doi:10.1002/anie.200803347

Cited by 118 publications

(98 citation statements)

References 30 publications

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“…30 However, Ott et al showed that cobalt-aspirin complex leaves the serine residue untouched and acetylates other sites instead that may result in a different activity spectrum for the drug. 31 In summary, our data demonstrate the superiority of zinc complex of ASA to ASA in preventing postischemic myocardial dysfunction. Induction of anti-oxidant enzymes and the anti-inflammatory cytokine TGF-b 1 may play a pivotal role in the mechanism of action of Zn(ASA) 2 .…”

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confidence: 52%

Superiority of zinc complex of acetylsalicylic acid to acetylsalicylic acid in preventing postischemic myocardial dysfunction

Korkmaz

Atmanli

et al. 2015

Exp Biol Med (Maywood)

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The pathophysiology of ischemic myocardial injury involves cellular events, reactive oxygen species, and an inflammatory reaction cascade. The zinc complex of acetylsalicylic acid (Zn(ASA) 2 ) has been found to possess higher anti-inflammatory and lower ulcerogenic activities than acetylsalicylic acid (ASA). Herein, we studied the effects of both ASA and Zn(ASA) 2 against acute myocardial ischemia. Rats were pretreated with ASA (75 mg/kg) or Zn(ASA) 2 (100 mg/kg) orally for five consecutive days. Isoproterenol (85 mg/kg, subcutaneously [s.c.]) was applied to produce myocardial infarction. After 17-22 h, animals were anesthetized with sodium pentobarbital (60 mg/kg, intraperitoneally [i.p.]) and both electrical and mechanical parameters of cardiac function were evaluated in vivo. Myocardial histological and gene expression analyses were performed. In isoproterenoltreated rats, Zn(ASA) 2 treatment normalized significantly impaired left-ventricular contractility index (E max 2.6 AE 0.7 mmHg/mL vs. 4.6 AE 0.5 mmHg/mL, P < 0.05), increased stroke volume (30 AE 3 mL vs. 50 AE 6 mL, P < 0.05), decreased systemic vascular resistance (7.2 AE 0.7 mmHg/min/mL vs. 4.2 AE 0.5 mmHg/min/mL, P < 0.05) and reduced inflammatory infiltrate into the myocardial tissues. ECG revealed a restoration of elevated ST-segment (0.21 AE 0.03 mV vs. 0.09 AE 0.02 mV, P < 0.05) and prolonged QT-interval (79.2 AE 3.2 ms vs. 69.5 AE 2.5 ms, P < 0.05) by Zn(ASA) 2 . ASA treatment did not result in an improvement of these parameters. Additionally, Zn(ASA) 2 significantly increased the mRNA-expression of superoxide dismutase 1 (þ73 AE 15%), glutathione peroxidase 4 (þ44 AE 12%), and transforming growth factor (TGF)-b 1 (þ102 AE 22%). In conclusion, our data demonstrate that oral administration of zinc and ASA in the form of bis(aspirinato)zinc(II) complex is superior to ASA in preventing electrical, mechanical, and histological changes after acute myocardial ischemia. The induction of antioxidant enzymes and the anti-inflammatory cytokine TGF-b 1 may play a pivotal role in the mechanism of action of Zn(ASA) 2 .

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confidence: 52%

Superiority of zinc complex of acetylsalicylic acid to acetylsalicylic acid in preventing postischemic myocardial dysfunction

Korkmaz

Atmanli

et al. 2015

Exp Biol Med (Maywood)

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“…A new approach involves modelling the pharmacological properties of established drugs with organometallic fragments (Ott et al, 2009). The metallocyclic peptide, bacitracin, has an interesting SOD activity.…”

Section: Fig 2 Structures Of Carboplatin (Left) and Oxaliplatin (Rimentioning

confidence: 99%

“…Cobalt-aspirin complexes are investigated as potential cytostatics (Ott et al, 2009). Aspirin (acetylsalicylic acid) belongs to the family of nonsteroidal antirheumatics (NSAR), which have anti-inflammatory and pain-relieving effects The pharmacological effects of NSARs stem from the inhibition of enzymes in the cyclooxygenase family (COX).…”

Section: Fig 2 Structures Of Carboplatin (Left) and Oxaliplatin (Rimentioning

confidence: 99%

“…18. The structure of hexacarbonyldicobalt-aspirin complex (Ott et al, 2009) Sadler and coworkers (Meggers, 2007) investigated the binding of metal complexes of 1,4,8,11-tetraazacyclotetradecane (cyclam) macrocycles to the CXCR4 coreceptor and lysozyme as a model protein. In such metallocyclam complexes, the metal is supposed to function by controlling the conformation and configuration of the macrocycle.…”

Section: Fig 2 Structures Of Carboplatin (Left) and Oxaliplatin (Rimentioning

confidence: 99%

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Therapeutic Organometallic Compounds

Anılanmert¹

2012

Pharmacology

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“…Encouragingly, some metal-NSAID complexes exhibit greater cytotoxicity than cisplatin. A recent comprehensive review It should be noted that several metal-NSAIDs have been previously reported, and their binding to biomolecules such as DNA and human serum albumin (HSA) has been well characterized using spectroscopic methods [48][49][50][51][52]. In general, metal-NSAID complexes display stronger binding to biomolecules than the corresponding free NSAID.…”

Section: Introductionmentioning

confidence: 99%

A Cancer Stem Cell Potent Cobalt(III)–Cyclam Complex Bearing Two Tolfenamic Acid Moieties

2017

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Cancer stem cells (CSCs) are thought to be responsible for cancer relapse. CSCs are a subtype of cancer cells with the ability to differentiate, self-renew, and form secondary or tertiary tumors. Current cancer treatments-including chemotherapy, radiation, and surgery-effectively remove bulk cancer cells but are unable to eliminate CSCs. Here, we present the synthesis, characterization, and anti-CSC properties of a cobalt(III)-cyclam complex bearing two tolfenamic acid moieties, 3. Notably, 3 displays sub-micromolar potency towards breast CSCs and bulk breast cancer cells. Detailed mechanistic studies show that 3 is taken up readily by breast CSCs, enters the nucleus, causes DNA damage, and induces caspase-dependent apoptosis. Furthermore, 3 inhibits cyclooxygenase-2 (COX-2) expression in CSCs. The mechanism of action of 3 is similar to that of a naproxen-appended cobalt(III)-cyclam complex, 1 recently reported by our group. The advantage of 3 over 1 is that it has the potential to remove whole tumor populations (bulk cancer cells and CSCs) with a single dose.

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Modulation of the Biological Properties of Aspirin by Formation of a Bioorganometallic Derivative

Cited by 118 publications

References 30 publications

Superiority of zinc complex of acetylsalicylic acid to acetylsalicylic acid in preventing postischemic myocardial dysfunction

Superiority of zinc complex of acetylsalicylic acid to acetylsalicylic acid in preventing postischemic myocardial dysfunction

Therapeutic Organometallic Compounds

A Cancer Stem Cell Potent Cobalt(III)–Cyclam Complex Bearing Two Tolfenamic Acid Moieties

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