Expanding the Arsenal of Pt^IV Anticancer Agents: Multi‐action Pt^IV Anticancer Agents with Bioactive Ligands Possessing a Hydroxy Functional Group

Abstract

Dedicated to the late Prof.J .Katzhendler for his mentorship,inspiration and friendship.Abstract: Most multi-action Pt IV prodrugs have bioactive ligands containing carboxylates.T his is probably due to the ease of carboxylating the OH axial ligands and because following reduction, the active drug is released. Am ajor challenge is to expand the arsenal of bioactive ligands to include those without carboxylates.W ed escribe ag eneral approach for synthesis of Pt IV prodrugs that release drugs with OH groups.W elinked the OH groups of gemcitabine (Gem), paclitaxel (Tax), and estramustine (EM) to the Pt IV derivative of cisplatin by ac arbonate bridge.F ollowing reduction, the axial ligands lost CO 2 ,r apidly generating the active drugs.I n contrast, succinate-linked drugs did not readily release the free drugs.T he carbonate-bridged ctc-[Pt(NH 3 ) 2 (PhB)(Gem-Carb)Cl 2 ]w as significantly more cytotoxic than the succinate-bridged ctc-[Pt(NH 3 ) 2 (PhB)(Gem-Suc)Cl 2 ], and more potent and less toxic than gemcitabine,c isplatin, and coadministration of cisplatin and gemcitabine.

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

“…We only observed the peaks of the free PhB (4-phenyl butyrate) and diethylamine, suggesting that the carbamate underwent rapid decarboxylation, releasing the free amine (Figure C). This is reminiscent of the rapid decarboxylation we observed when the monoester of carbonic acids are released following reduction of Pt­(IV) …”

“…This is reminiscent of the rapid decarboxylation we observed when the monoester of carbonic acids are released following reduction of Pt(IV). 17 Pastorin and Ang described a study of ratiometric delivery of cisplatin and doxorubicin (Figure 4A) using tumor-targeting carbon nanotubes. Because doxorubicin has no carboxylates, they used its only amino groups to tether the doxorubicin to the Pt(IV).…”

“…Stability in Cell Culture Medium and Rates of Reduction. After having demonstrated that carbonate linkages can release OH-containing molecules 17 and that carbamate linkages can release amine-containing molecules, we thought it worthwhile to compare the stability and rates of reduction of carboxylate vs carbonate vs carbamate linkers. Toward this end, we synthesized the symmetric bis-carbonates, biscarboxylates, and bis-carbamates (Figure 5) and compared their rates of reduction and their stability in cell culture medium.…”

“…do not possess carboxylates. Recently, we described a method for conjugating molecules with an OH group to Pt­(IV) via a carbonate linkage, such that following reduction, the native form of the molecule is released . Herein, we demonstrate that when amino groups are conjugated to the Pt­(IV) via a carbamate linkage, reduction of these complexes is followed by rapid decarboxylation of the carbamate, leading to the release of the free amines.…”

Stability, Reduction, and Cytotoxicity of Platinum(IV) Anticancer Prodrugs Bearing Carbamate Axial Ligands: Comparison with Their Carboxylate Analogues

“…In addition to their increased stability, another attractive character of Pt­(IV) complexes is the introduction of two extra axial ligands to Pt­(II) species, which opens up the possibility to impart and fine-tune the pharmacological properties of platinum prodrugs. , By modifying the chemical structures of the two axial ligands, researchers can predictably alter solubility, lipophilicity, and reduction rate of Pt­(IV) complexes while permitting the cytotoxicity of Pt­(II) congeners to remain unchanged. − Bioactive axial ligands of Pt­(IV) prodrugs have been extensively explored and can be either cancer-cell-targeting moieties to improve cancer-cell-selectivity or enzyme inhibitors with the aim of overcoming drug resistance. − Obviously, axial ligands play an imperative role in developing promising Pt­(IV) drug candidates.…”