Oxamusplatin: a cytotoxic Pt(ii ) complex of a nitrogen mustard with resistance to thiol based sequestration displays enhanced selectivity towards cancer
| Autor: | Arindam Mukherjee, Moumita Maji, Subhendu Karmakar, Ruturaj, Arnab Gupta |
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| Rok vydání: | 2020 |
| Předmět: |
Organoplatinum Compounds
Antineoplastic Agents Apoptosis 010402 general chemistry 01 natural sciences Medicinal chemistry Article Inorganic Chemistry chemistry.chemical_compound Neoplasms Tumor Cells Cultured medicine Humans Chelation Cell Proliferation Cisplatin chemistry.chemical_classification 010405 organic chemistry Cell Cycle Leaving group Glutathione Nitrogen mustard 0104 chemical sciences chemistry Copper-Transporting ATPases Drug Resistance Neoplasm Cancer cell Thiol Selectivity Copper medicine.drug |
| Zdroj: | Dalton Transactions. 49:2547-2558 |
| ISSN: | 1477-9234 1477-9226 |
| DOI: | 10.1039/c9dt04269e |
| Popis: | Pt(II) drugs and nitrogen mustards display severe side effects, poor tumour selectivity and face growing resistance by cancer cells due to sequestration by the thiol-containing molecules (viz. glutathione (GSH) and the copper ATPases like ATP7A/7B). ATP7A and ATP7B sequester Pt(II) complexes which contribute to the dose inefficacy and resistance. Incorporation of bulky ligands and chelating leaving groups may prevent deactivation by thiols. In this work, we have synthesised four new Pt(II) complexes (3-6) of two carrier ligands, bis(2-hydroxyethyl)pyridylmethylamine (L1) and bis(2-chloroethyl)pyridylmethylamine (L2) with oxalato and cyclobutanedicarboxylato leaving groups. Among the four new complexes (3-6) the Pt(II) complex of L2 with oxalato leaving group (5, termed as, “oxamusplatin”) is cytotoxic. 'Oxamusplatin' is more resistant than cisplatin or oxaliplatin towards hydrolysis, thiol binding and sequestration by ATP7B. It targets cellular DNA and is capable of disrupting the microtubule network in the cytoskeleton. Oxamusplatin demonstrates better selectivity than oxaliplatin towards cancerous cells. It is ca. 4-10 times greater cytotoxic towards metastatic prostate carcinoma (DU-145, IC(50) = 21 ± 1 µM) and ca. 10-24 times greater cytotoxic towards breast adenocarcinoma (MCF-7, IC(50) = 8.1 ± 0.8 µM) compared to the three noncancerous cells investigated. |
| Databáze: | OpenAIRE |
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