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 3aminobenzamide 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.

Recent Advances in the Chemistry of Metal Carbamates

“…number of Pt(IV) carbamato derivatives, including some related to secondary amines, thus extending the scope provided by the hydroxide/isocyanate coupling [272]. A peculiar ligand-assisted addition of CO2 was reported for a Fe(II) compound containing a pyridyl-amine ligand.…”

“…Following optimization [260], allowing the reaction to be conducted in dimethylformamide and not in neat isocyanate, more than 60 different Pt(IV) species were thus prepared, arousing interest as possible anticancer agents (see Reaction of an amine with a metal carboxyl complex (Scheme 18e). Another type of synthesis comprises the reactions of amines (or N-donors in general) with a metal carboxyl complex, i.e., bicarbonate [269], formate [270,271], carbonate ester [272] or a CO2 adduct directly [273]. As an example, the intramolecular attack of an amine group belonging to a tetradentate pyridylamine ligand onto a Zn(II)-HCO3 species resulted in carbamate generation [269] (Scheme 26a).…”

“…Ligand transfer routes (Scheme 18f). Over the years, the trans-metalation reaction has been extensively employed for the targeted synthesis of various metal carbamates, especially number of Pt(IV) carbamato derivatives, including some related to secondary amines, thus extending the scope provided by the hydroxide/isocyanate coupling [272]. A peculiar ligand-assisted addition of CO2 was reported for a Fe(II) compound containing a pyridyl-amine ligand.…”

“…Following a different approach, the incorporation of a maleimide fragment enabled specific interactions with proteins (e.g., addition to thiol residues) for compounds showing a promising anticancer activity in vivo [261,268,369]. The conjugation with suitable targeting groups, to enhance the pharmacological performance, can be achieved via modification of either the axial carboxylato co-ligand [367,370] or the carbamato ligand itself [272,371,372]. Remarkably, all of these Pt(IV) complexes are stable for several hours or even days in physiological aqueous solutions [260,261,263,272].…”

“…Reaction of an amine with a metal carboxyl complex ( Scheme 18 e). Another type of synthesis comprises the reactions of amines (or N -donors in general) with a metal carboxyl complex, i.e., bicarbonate [ 269 ], formate [ 270 , 271 ], carbonate ester [ 272 ] or a CO 2 adduct directly [ 273 ]. As an example, the intramolecular attack of an amine group belonging to a tetradentate pyridylamine ligand onto a Zn(II)-HCO 3 species resulted in carbamate generation [ 269 ] ( Scheme 26 a).…”