Stephanie D Dannen1, Lauren Cornelison2, Paul Durham2, John E Morley3, Kiana Shahverdi4, Junwei Du5, Haiying Zhou4, Leland C Sudlow4, Daniel Hunter6, Matthew D Wood6, Mikhail Y Berezin7, Nikolay Gerasimchuk8. 1. Department of Chemistry, Temple Hall 431, Missouri State University, 901 S. National, Springfield, MO 65897, USA. 2. Department of Biology, Missouri State University, MC/Center for Biomedical & Life Sciences, Springfield, MO 65897, USA. 3. Division of Geriatric Medicine, Saint Louis University, St. Louis, MO 63110, USA. 4. Department of Radiology, Washington University School of Medicine, St. Louis, MO 63110, USA. 5. Institute of Materials Science and Engineering, Washington University in St. Louis, St. Louis, MO 63130, USA. 6. Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA. 7. Department of Radiology, Washington University School of Medicine, St. Louis, MO 63110, USA; Institute of Materials Science and Engineering, Washington University in St. Louis, St. Louis, MO 63130, USA. Electronic address: berezinm@wustl.edu. 8. Department of Chemistry, Temple Hall 431, Missouri State University, 901 S. National, Springfield, MO 65897, USA. Electronic address: NNGerasimchuk@MissouriState.edu.
Abstract
Several biologically active bivalent Pd and Pt complexes with two structurally similar cyanoxime ligands abbreviated as H(DECO): 2-oximino-2-cyano-N,N'-diethylacetamide, and H(PyrCO): 2-oximino-2-cyan-N-pyrrolidine acetamide were synthesized and characterized using spectroscopic methods, thermal analysis and X-ray crystallography. Structures revealed planar cis-geometry of studied complexes. Freshly obtained Pt(DECO)2, Pd(DECO)2, Pt(PyrCO)2 and Pd(PyrCO)2 complexes were used in for in vitro cytotoxicity assays using two different etiology human cancer cell lines HeLa and WiDr cells. Investigated compounds showed cytotoxicity levels at or above cisplatin. Pt(DECO)2 was also tested in vivo in healthy C57BL/6 mice. The complex was administered at three different dosage (0, 7.5, 15 mg/kg, i.p. once/week), over a total period of 8 weeks. No changes were observed in the animal weight in the treated mice compared to the control dextrose-treated group. The levels of erythrocytes, leukocytes, and hemoglobin were within the normal level suggesting low myelotoxicity. Negligible cardiotoxicity was observed from the histological evaluation of the hearts from the treated animals. Results from the tail nerve conduction velocity (NCV) and nerve histomorphometry suggested no impact of Pt(DECO)2 on peripheral nerves. The complex, however, induced certain hepatotoxicity and lead to the elevation of IL-6, a pro-inflammatory cytokine. Overall, Pt(DECO)2 showed minimal in vivo toxicity, thus presenting a promising candidate for future testing in animal models of cancer.
Several biologically active bivalent class="Chemical">Pd and n class="Chemical">Pt complexes with two structurally similar cyanoxime ligands abbreviated as H(DECO): 2-oximino-2-cyano-N,N'-diethylacetamide, and H(PyrCO): 2-oximino-2-cyan-N-pyrrolidine acetamide were synthesized and characterized using spectroscopic methods, thermal analysis and X-ray crystallography. Structures revealed planar cis-geometry of studied complexes. Freshly obtained Pt(DECO)2, Pd(DECO)2, Pt(PyrCO)2 and Pd(PyrCO)2 complexes were used in for in vitro cytotoxicity assays using two different etiology humancancer cell lines HeLa and WiDr cells. Investigated compounds showed cytotoxicity levels at or above cisplatin. Pt(DECO)2 was also tested in vivo in healthy C57BL/6 mice. The complex was administered at three different dosage (0, 7.5, 15 mg/kg, i.p. once/week), over a total period of 8 weeks. No changes were observed in the animal weight in the treated mice compared to the control dextrose-treated group. The levels of erythrocytes, leukocytes, and hemoglobin were within the normal level suggesting low myelotoxicity. Negligible cardiotoxicity was observed from the histological evaluation of the hearts from the treated animals. Results from the tail nerve conduction velocity (NCV) and nerve histomorphometry suggested no impact of Pt(DECO)2 on peripheral nerves. The complex, however, induced certain hepatotoxicity and lead to the elevation of IL-6, a pro-inflammatory cytokine. Overall, Pt(DECO)2 showed minimal in vivo toxicity, thus presenting a promising candidate for future testing in animal models of cancer.
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