This work presents a deeper pharmacological evaluation of two formerly prepared and characterized, and highly in vitro cytotoxic platinum(II) oxalato complexes [Pt(ox)(L1)2] (1) and [Pt(ox)(L2)2] (2), containing the derivatives of cyclin-dependent kinase inhibitor (CDKi) seliciclib ((R)-roscovitine, CYC202) coordinating as N-donor carrier ligands, i.e., 2-(1-ethyl-2-hydroxyethylamino)-N6-(4-methoxybenzyl)-9-isopropyladenine (L1) and 2-chloro-N6-(2,4-dimethoxybenzyl)-9-isopropyladenine (L2). The positive results of in vitro cytotoxicity screening on human cancer cell lines (HeLa, HOS, A2780, A2780R, G361 and MCF7 with IC50 at low micromolar levels) published previously, motivated us to perform extended preclinical in vitro experiments to reveal the mechanisms associated with the induction of cancer cell death. In addition, the in vivo antitumor activity was evaluated using the mouse lymphocytic leukaemia L1210 model. The obtained results revealed that complex 1 exceeds the antitumor effect of cisplatin (as for the extension of life-span of mice) and shows far less adverse effects as compared to reference drug cisplatin. The in vitro and ex vivo studies of cellular effects and molecular mechanisms of cell death induction showed that the mechanism of action of complex 1 is essentially different from that of cisplatin. The obtained results showed a possible way how to obtain antitumor active platinum(II) oxalato complexes with better therapeutic profile than contemporary used platinum-based therapeutics.

• Keywords
• Antitumor activity, Ex vivo, In vivo, Platinum(II) complexes, Seliciclib derivatives,
• MeSH
• Apoptosis drug effects   MeSH
• Cisplatin adverse effects   MeSH
• Humans MeSH
• Lymphoma pathology   MeSH
• Mice, Inbred DBA MeSH
• Mice MeSH
• Cell Line, Tumor MeSH
• Organoplatinum Compounds chemistry   MeSH
• Oxalates chemistry   MeSH
• Antineoplastic Agents chemistry   pharmacology   MeSH
• Roscovitine chemistry   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Male MeSH
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Cisplatin MeSH
• Organoplatinum Compounds MeSH
• Oxalates MeSH
• Antineoplastic Agents MeSH
• Roscovitine MeSH

The platinum(II) oxalato complexes [Pt(ox)(naza)2] (1-3) were synthesized and characterized by elemental analysis (C, H, N), multinuclear NMR spectroscopy ((1)H, (13)C, (15)N, (195)Pt) and electrospray ionization mass spectrometry (ESI-MS); naza = 4-chloro-7-azaindole (4Claza; 1), 3-bromo-7-azaindole (3Braza; 2) or 4-bromo-7-azaindole (4Braza; 3). The prepared substances were screened for their in vitro antitumor activity on the osteosarcoma (HOS) and breast adenocarcinoma (MCF7) human cancer cell lines, where 2 showed moderate antitumor effect (IC50 = 27.5 μM, and 18.3 μM, respectively). The complex 2 was further tested on a panel of six others human cancer cell lines, including the malignant melanoma (G361), cervix carcinoma (HeLa), ovarian carcinoma (A2780), cisplatin-resistant ovarian carcinoma (A2780R), lung carcinoma (A549) and prostate adenocarcinoma (LNCaP). This substance was found to be moderate antitumor effective against G361 (IC50 = 17.3 μM), HeLa (IC50 = 31.8 μM) and A2780 (IC50 = 19.2 μM) cell lines. The complex 2 was also studied by NMR for its solution stability and by ESI-MS experiments for its ability to interact with biomolecules, such as cysteine, glutathione or guanosine 5'-monophosphate.

• MeSH
• Indoles chemistry   MeSH
• Humans MeSH
• Molecular Structure MeSH
• Cell Line, Tumor MeSH
• Nuclear Magnetic Resonance, Biomolecular MeSH
• Organoplatinum Compounds chemical synthesis   chemistry   pharmacology   MeSH
• Oxalates chemistry   MeSH
• Antineoplastic Agents chemistry   pharmacology   MeSH
• Cell Survival drug effects   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• 7-azaindole dimer MeSH Browser
• Indoles MeSH
• Organoplatinum Compounds MeSH
• Oxalates MeSH
• Antineoplastic Agents MeSH

A one-step synthetic procedure using the reaction of potassium bis(oxalato)platinate(II) with the corresponding N6-benzyladenosine derivative (nL) provided the [Pt(ox)(nL)₂]∙1.5H₂O oxalato (ox) complexes 1-5, involving the nL molecules as monodentate coordinated N-donor ligands. The complexes were thoroughly characterized by elemental analysis, multinuclear (¹H, ¹³C, ¹⁵N, 1¹⁹⁵Pt) and two dimensional NMR, infrared and Raman spectroscopy, and mass spectrometry, proving their composition and purity as well as coordination of nL through the N7 atom of the purine moiety. Geometry of [Pt(ox)(4FL)₂] (5) was optimized at the B3LYP/LANLTZ/6-311G** level of theory. The complexes were screened for their in vitro cytotoxicity against two human cancer cell lines (HOS osteosarcoma and MCF7 breast adenocarcinoma), but they did not show any effect up to the concentration of 50.0 µM (compounds 1, 2) or 20.0 µM (compounds 3-5).

• MeSH
• Adenosine chemistry   MeSH
• Humans MeSH
• Ligands * MeSH
• Molecular Structure MeSH
• Cell Line, Tumor MeSH
• Organoplatinum Compounds chemical synthesis   chemistry   toxicity   MeSH
• Oxalates chemistry   MeSH
• Antineoplastic Agents chemical synthesis   chemistry   pharmacology   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Adenosine MeSH
• Ligands * MeSH
• Organoplatinum Compounds MeSH
• Oxalates MeSH
• Antineoplastic Agents MeSH

In the title compound, C17H20ClN5O2, the benzene ring and the purine ring system make a dihedral angle of 78.56 (4)°. In the crystal, mol-ecules are linked by pairs of N-H⋯N hydrogen bonds, forming inversion dimers. C-H⋯O and C-H⋯Cl contacts further link the mol-ecules, forming a three-dimensional network.

• Publication type
• Journal Article MeSH