Synthesis, Characterization, and Cytotoxicity of the First Oxaliplatin Pt(IV) Derivative Having a TSPO Ligand in the Axial Position

Salvatore Savino,Amalia Azzariti,Nunzio Denora,Letizia Porcelli,Giovanni Natile,Nicola Margiotta,Rosa Iacobazzi

doi:10.3390/ijms17071010

Abstract

The first Pt(IV) derivative of oxaliplatin carrying a ligand for TSPO (the 18-kDa mitochondrial translocator protein) has been developed. The expression of the translocator protein in the brain and liver of healthy humans is usually low, oppositely to steroid-synthesizing and rapidly proliferating tissues, where TSPO is much more abundant. The novel Pt(IV) complex, cis,trans,cis-[Pt(ethanedioato)Cl{2-(2-(4-(6,8-dichloro-3-(2-(dipropylamino)-2-oxoethyl)imidazo[1,2-a]pyridin-2-yl)phenoxy)acetate)-ethanolato}(1R,2R-DACH)] (DACH = diaminocyclohexane), has been fully characterized by spectroscopic and spectrometric techniques and tested in vitro against human MCF7 breast carcinoma, U87 glioblastoma, and LoVo colon adenocarcinoma cell lines. In addition, affinity for TSPO (IC50 = 18.64 nM), cellular uptake (ca. 2 times greater than that of oxaliplatin in LoVo cancer cells, after 24 h treatment), and perturbation of cell cycle progression were investigated. Although the new compound was less active than oxaliplatin and did not exploit a synergistic proapoptotic effect due to the presence of the TSPO ligand, it appears to be promising in a receptor-mediated drug targeting context towards TSPO-overexpressing tumors, in particular colorectal cancer (IC50 = 2.31 μM after 72 h treatment).

Highlights

ASASrrtyytiicclnnlee tthheessiiss, CChhaarraacctteerriizzaattiioonn, aanndd CCyyttoottooxxiicciittyy ooff tthhee FFiirrsstt OOxxaalliippllaattiinn PPtt((IIVV)) DDeerriivvaattiivvee HHaavviinngg aa TTSSPPOO LLiiggaanndd iinn tthhee AAxxiiaall PPoossiittiioonn
Oxaliplatin produces the same type of lesions on DNA as cisplatin, its spectrum of activity is different from that of the first-generation drug and the occurrence of resistance to oxaliplatin is different from that of cisplatin and carboplatin
The free ligand 2, in turn, was more affine than the reference ligand PK 11195 (IC50 of 4.27 nM). These results indicate that the choice of a terminal carboxylic residue on the free ligand 2 for conjugation to a Pt(IV) complex was correct and does not significantly alter the affinity of 2 for the translocator protein (TSPO)

Summary

Introduction

ASASrrtyytiicclnnlee tthheessiiss,, CChhaarraacctteerriizzaattiioonn,, aanndd CCyyttoottooxxiicciittyy ooff tthhee FFiirrsstt OOxxaalliippllaattiinn PPtt((IIVV)) DDeerriivvaattiivvee HHaavviinngg aa TTSSPPOO LLiiggaanndd iinn tthhee AAxxiiaall PPoossiittiioonn. AAbbssttrraacctt:: TThhee ffiirrsstt PPtt((IIVV)) ddeerriivvaattiivvee ooff ooxxaalliippllaattiinn ccaarrrryyiinngg aa lliiggaanndd ffoorr TTSSPPOO ((tthhee 1188--kkDDaa mmiittoocchhoonnddrriiaall ttrraannssllooccaattoorr pprrootteeiinn)) hhaass bbeeeenn ddeevveellooppeedd. The second generation platinum drug carboplatin, cis-diammine(1,1-cyclobutanedicarboxylato) platinum(II), contains a more stable leaving group (1,1-cyclobutanedicarboxylato) with respect to the chlorides present in cisplatin. This modification was introduced to lower the toxicity without affecting the spectrum of antitumor activity. Neurotoxicity is the major dose-limiting feature associated with the use of oxaliplatin [9] Due to their scarce water solubility, platinum(II) complexes are administered by intravenous infusion in the clinics, with low compliance in treated patients [10]. Hambley and colleagues showed that in a series of ethylenediamine-based Pt(IV) complexes the cathodic potential for the reduction of Pt(IV) to Pt(II) depends upon the nature of the axial ligands and decreases in the order Cl > OCOR > OH [13]

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