ABSTRACT
New metal-based anticancer chemotherapeutic drug candidates [Cu(phen)L](NO3)2 (1) and [Zn(phen)L](NO3)2 (2) were synthesized from ligand L (derived from pharmacophore scaffold barbituric acid and pyrazole). In vitro DNA binding studies of the L, 1 and 2 were carried out by various biophysical techniques revealing electrostatic mode. Complex 1 cleaves pBR322 DNA via oxidative pathway and recognizes major groove of DNA double helix. The molecular docking study was carried out to ascertain the mode of action towards the molecular target DNA and enzymes. The complex 1 exhibited remarkably good anticancer activity on a panel of human cancer cell lines (GI50 values < 10 µg/ml), and to elucidate the mechanism of cancer inhibition, Topo-I enzymatic activity was carried out.
Subject(s)
Antineoplastic Agents/pharmacology , Copper/chemistry , DNA Topoisomerases, Type I/adverse effects , Plasmids , Topoisomerase I Inhibitors/pharmacology , Antineoplastic Agents/chemistry , Cell Line, Tumor , DNA/drug effects , Electrophoresis, Agar Gel , Humans , Molecular Docking Simulation , Reactive Oxygen Species/metabolism , Spectrum Analysis/methods , Topoisomerase I Inhibitors/chemistry , X-Ray DiffractionABSTRACT
BACKGROUND: The Sucrose Breath Test (SBT) is a simple noninvasive technique for the detection of small intestinal mucositis. AIM: We utilised rat models of intestinal mucositis induced by different classes of chemotherapeutic agents to broaden application of the SBT. METHODS: Mucositis was induced in rats by injection of Doxorubicin (Dox), Etoposide (Etop), Irinotecan (Irin), or Cyclophosphamide (Cy) and Etop in combination (Cy+Etop). The SBT was carried out following sucrose gavage, 72 h after chemotherapy. At kill, intestinal tissues were collected for mucositis assessments. RESULTS: SBT for controls was 16.0 +/- 0.6% (mean +/- SEM) cumulative dose at 90 min. Irin, Doxo, Etop, and Cy+Etop significantly decreased the SBT to 53%, 43%, 32% and 30% of saline control values, respectively (p < 0.01) whilst sucrase activity was correspondingly decreased to 60%, 36%, 14% and 2%. There was good concordance with histological mucositis severity in the jejunum, with median scores of 11, 19, 28 and 27. Correlations between SBT, sucrase activity, and histological severity score yielded r(2) values of 0.82. CONCLUSIONS: The SBT detected mucositis induced by the alkylating agent, anthracycline and DNA-topoisomerase inhibitor classes, facilitating the detection of small intestinal dysfunction, providing a further means to screen newly-developed drugs for intestinal side-effects.
