Synthesis, characterization, and biological activity of platinum II, III, and IV pivaloamidine complexes.
Imino ligands have proven to be able to activate the trans geometry of platinum(II) complexes towards antitumor activity. These ligands, like aromatic N-donor heterocycles, have a planar shape but, different from the latter, have still an H atom on the coordinating nitrogen which can be involved in H-bond formation. Three classes of imino ligands have been extensively investigated: iminoethers (HN=C(R)OR'), ketimines (HN=CRR'), and amidines (HN=C(R)NR'R″). The promising efficacy of the platinum compounds with amidines (activity comparable to that of cisplatin for cis complexes and much greater than that of transplatin for trans complexes) prompted us to extend the investigation to amidine complexes with a bulkier organic residue (R = t-Bu). The tert-butyl group can confer greater affinity for lipophilic environments, thus potentiating the cellular uptake of the compound. In the present study we describe the synthesis and characterization of pivaloamidine complexes of platinum(II), (cis and trans-[PtCl2(NH3){Z-HN=C(t-Bu)NH2}] and cis and trans-[PtCl2{Z-HN=C(t-Bu)NH2}2]), platinum(III) ([Pt2Cl4{HN=C(t-Bu)NH}2(NH3)2]), and platinum(IV) (trans-[PtCl4(NH3){Z-HN=C(t-Bu)NH2}] and trans-[PtCl4{Z-HN=C(t-Bu)NH2}2]). The cytotoxicity of all new Pt complexes was tested toward a panel of cultured cancer cell lines, including cisplatin and multidrug resistant variants. In addition, cellular uptake and DNA binding, perturbations of cell cycle progression, induction of apoptosis, and p53 activation were investigated for the most promising compound trans-[PtCl2(NH3){Z-HN=C(t-Bu)NH2}]. Remarkably, the latter complex was able to overcome both acquired and intrinsic cisplatin resistance.
Dipartimento di Chimica, University of Bari "Aldo Moro", via E. Orabona 4, 70125, Bari, Italy.
Marilù
M
Sinisi
Valentina
V
Gandin
Teresa
T
Saltarella
Francesco P
FP
Intini
Concetta
C
Pacifico
Christine
C
Marzano
Giovanni
G
Natile
D000578:Amidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D004247:DNA / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D009944:Organoplatinum Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D000578:Amidines; D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; D016159:Tumor Suppressor Protein p53; D004247:DNA