Multiaction Pt(IV) Carbamate Complexes Can Codeliver Pt(II) Drugs and Amine Containing Bioactive Molecules.

Abstract

Multiaction Pt(IV) prodrugs can overcome resistance associated with the FDA approved Pt(II) drugs like cisplatin. Intracellular reduction of the octahedral Pt(IV) derivatives of cisplatin releases cisplatin and the two axial ligands. When the released axial ligands act synergistically with cisplatin to kill the cancer cells, we have multiaction prodrugs. Most Pt(IV) multiaction prodrugs have bioactive ligands possessing a carboxylate that is conjugated to the Pt(IV) because breaking the Pt(IV)-ligand bond releases the active moiety. As many drugs that act synergistically with cisplatin do not have carboxylates, a major challenge is to prepare multiaction Pt(IV) complexes with drugs that have amino groups or hydroxyl groups such that following reduction, the drugs are released in their active form. Our objective was to prepare multiaction Pt(IV) prodrugs that release bioactive molecules having amino groups. Because we cannot conjugate amino groups to the axial position of Pt(IV), we developed a novel and efficient approach for the synthesis of Pt(IV)-carbamato complexes and demonstrated that following reduction of the Pt(IV), the released carbamates undergo rapid decarboxylation, releasing the free amine, as in the case of the PARP-1 inhibitor 3-aminobenzamide and the amino derivative of the HDAC inhibitor SAHA. Pt(IV)-carbamato complexes are stable in cell culture medium and are reduced by ascorbate. They are reduced slower than their carboxylato and carbonato analogues. We believe that this approach paves the way for preparing novel classes of multiaction Pt(IV) prodrugs with amino containing bioactive molecules that up to now were not accessible.

• Authors: Tomer Babu, Amrita Sarkar, Subhendu Karmakar, Claudia Schmidt, Dan Gibson
• Journal: Inorganic chemistry (Inorg Chem) Vol. 59 Issue 7 Pg. 5182-5193 (Apr 06 2020) ISSN: 1520-510X [Electronic] United States
• PMID: 32207294 (Publication Type: Journal Article)

Chemical References

• Antineoplastic Agents
• Benzamides
• Carbamates
• Coordination Complexes
• Ligands
• Prodrugs
• Platinum
• 3-aminobenzamide
• Cisplatin

Topics

• Antineoplastic Agents (chemical synthesis, pharmacology)
• Benzamides (pharmacology)
• Carbamates (chemical synthesis, pharmacology)
• Cell Line, Tumor
• Cisplatin (pharmacology)
• Coordination Complexes (chemical synthesis, pharmacology)
• Drug Screening Assays, Antitumor
• Humans
• Ligands
• Oxidation-Reduction
• Platinum (chemistry)
• Prodrugs (chemical synthesis, pharmacology)