Preparation of bis(5-phenyltetrazolato) Pt(II) and Pt(IV) analogues of transplatin and in vitro evaluation for antitumor activity

TY - JOUR

T1 - Preparation of bis(5-phenyltetrazolato) Pt(II) and Pt(IV) analogues of transplatin and in vitro evaluation for antitumor activity

AU - Perfahl, Stefanie

AU - Bodtke, Anja

AU - Pracharova, Jitka

AU - Kasparkova, Jana

AU - Brabec, Viktor

AU - Cuadrado, Juan

AU - Stürup, Stefan

AU - Schulzke, Carola

AU - Bednarski, Patrick J.

PY - 2017

Y1 - 2017

N2 - To evaluate the 5-substituted tetrazolate (5R-tetrazolate) ligand for the development of novel antitumor active Pt(II) and Pt(IV) diamines, eight analogues of transplatin bearing 5-phenyltetrazolato and 5-(phenol)tetrazolato ligands were prepared by reacting transplatin with the 5-substituted tetrazolate in DMF in the presence of trimethylamine. Coordination to platinum was through the N2 position of the tetrazolato ligand, as evidenced by a X-ray crystal structure of trans-diamminobis[5-(phenyl-4-ol)tetrazolato-κN2]platinum(II). Attempts to synthesize the corresponding cis-coordinated analogues from cisplatin were unsuccessful due to isomerization to the more stable trans isomers. Hydrogen peroxide was used to oxidize trans-diamminobis(5-phenyltetrazolato) and trans-diamminobis(5-phenoltetrazolato)platinum(II) complexes to the trans-dihydroxo-Pt(IV) analogues; the hydroxo ligands were then further acylated. The binding of Pt to calf thymus DNA for trans,trans,trans-diamminodihydroxidobis(5-phenyltetrazolato-κN2)platinum(IV) was dependent on the presence of ascorbate; however, the Pt(II) analogue trans-diamminobis(5-phenyltetrazolato-κN2)platinum(II) itself bond only very weakly to DNA, indicating that this is not the product of the ascorbate induced reduction of the Pt(IV) complex. Evaluation of the antiproliferative activity on eight human cancer cells in vitro showed the Pt(IV) complexes to be more potent than the Pt(II) analogues but all complexes were still much less active than cisplatin. No cross resistance to cisplatin was observed in the A2870 ovarian cancer cell line.

AB - To evaluate the 5-substituted tetrazolate (5R-tetrazolate) ligand for the development of novel antitumor active Pt(II) and Pt(IV) diamines, eight analogues of transplatin bearing 5-phenyltetrazolato and 5-(phenol)tetrazolato ligands were prepared by reacting transplatin with the 5-substituted tetrazolate in DMF in the presence of trimethylamine. Coordination to platinum was through the N2 position of the tetrazolato ligand, as evidenced by a X-ray crystal structure of trans-diamminobis[5-(phenyl-4-ol)tetrazolato-κN2]platinum(II). Attempts to synthesize the corresponding cis-coordinated analogues from cisplatin were unsuccessful due to isomerization to the more stable trans isomers. Hydrogen peroxide was used to oxidize trans-diamminobis(5-phenyltetrazolato) and trans-diamminobis(5-phenoltetrazolato)platinum(II) complexes to the trans-dihydroxo-Pt(IV) analogues; the hydroxo ligands were then further acylated. The binding of Pt to calf thymus DNA for trans,trans,trans-diamminodihydroxidobis(5-phenyltetrazolato-κN2)platinum(IV) was dependent on the presence of ascorbate; however, the Pt(II) analogue trans-diamminobis(5-phenyltetrazolato-κN2)platinum(II) itself bond only very weakly to DNA, indicating that this is not the product of the ascorbate induced reduction of the Pt(IV) complex. Evaluation of the antiproliferative activity on eight human cancer cells in vitro showed the Pt(IV) complexes to be more potent than the Pt(II) analogues but all complexes were still much less active than cisplatin. No cross resistance to cisplatin was observed in the A2870 ovarian cancer cell line.

U2 - 10.1016/j.ica.2016.11.017

DO - 10.1016/j.ica.2016.11.017

M3 - Journal article

SN - 0020-1693

VL - 456

SP - 86

EP - 94

JO - Inorganica Chimica Acta

JF - Inorganica Chimica Acta

ER -