Abstract
Herein, we present dicarboxylate platinum(II) complexes of the general formula [Pt(mal)(DMSO)(L)] and [Pt(CBDC)(DMSO)(L)], where L is dbtp 5,7-ditertbutyl-1,2,4-triazolo[1,5-a]pyrimidine) or ibmtp (7-isobutyl-5-methyl-1,2,4- triazolo[1,5-a]pyrimidine), as prospective prodrugs. The platinum(II) complexes were synthesized in a one-pot reaction between cis-[PtCl2(DMSO)2], silver malonate or silver cyclobutane-1,1-dicarboxylate and triazolopyrimidines. All platinum(II) compounds were characterized by FT-IR, and 1H, 13C, 15N and 195Pt NMR; and their square planar geometries with one monodentate N(3)-bonded 5,7-disubstituted-1,2,4-triazolo[1,5-a]pyrimidine, one S-bonded molecule of dimethyl sulfoxide and one O,O-chelating malonato (1, 2) or O,O-chelating cyclobutane-1,1-dicarboxylato (3, 4) was determined. Additionally, [Pt(CBDC)(dbtp)(DMSO)] (3) exhibited (i) substantial in vitro cytotoxicity against the lung adenocarcinoma epithelial cell line (A549) (IC50 = 5.00 µM) and the cisplatin-resistant human ductal breast epithelial tumor cell line (T47D) (IC50 = 6.60 µM); and (ii) definitely exhibited low toxicity against normal murine embryonic fibroblast cells (BALB/3T3).
Highlights
Inert square planar Pt(II) drugs currently used in the chemotherapy of some cancers suffer from lack of selectivity, toxicity and poor aqueous solubility, and in many cases acquired or inherent resistance develops during treatments [1,2,3,4,5,6,7]
It is well known that the presence of the dicarboxylato moiety in the coordination sphere enhances the aqueous solubility of platinum(II) complexes [15], reduces side effects and increases the efficiency of platinum(II) anticancer drugs [16,17,18], and does not Materials 2020, 13, 5312; doi:10.3390/ma13235312
The new dicarboxylato platinum(II) complexes were characterized in depth using multinuclear (1 H, 13 C, 15 N, 195 Pt) NMR spectroscopy, and all coordination shifts were computed in comparison to the spectra of the corresponding free ligands (∆coord = δcomplex − δligand )
Summary
Inert square planar Pt(II) drugs currently used in the chemotherapy of some cancers suffer from lack of selectivity, toxicity and poor aqueous solubility, and in many cases acquired or inherent resistance develops during treatments [1,2,3,4,5,6,7]. In vitro antiproliferative studies showed that symmetrical [Pt(mal)(ibmtp)2 ] (3.44 μM) and [Pt(mal)(dbtp)2 ] (2.66 μM) complexes exhibit higher in vitro activity against T47D and A549 cell lines than cisplatin [22]. We found that the lipophilic platinum(II) complex with the bulky 5,7-diphenyl-1,2,4-triazolo[1,5-a]pyrimidine ligand, i.e., ([Pt(mal)(DMSO)(dptp)], displayed 10-times lower in vitro toxicity than that of cisplatin against a normal cell line (BALB/3T3). To continue our investigation of dicarboxylato platinum(II) compounds as potential anticancer agents, especially novel mixed platinum(II) complexes containing aromatic N-donor molecules and S-donor ligands as carrier groups (vide supra), we applied 7-isobutyl-5-methyl1,2,4-triazolo[1,5-a]pyrimidine (ibmtp) and 5,7-ditertbutyl-1,2,4-triazolo-[1,5-a]pyrimidine (dbtp) to prepare two new malonato platinum(II) complexes with one S-donor DMSO ligand as a non-leaving group, namely, [Pt(mal)(dbtp)(DMSO)] and [Pt(mal)(DMSO)(ibmtp)]. We determined the in vitro antiproliferative activity and estimated the structure–lipophilicity relationship
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