Synthesis and in vitro Antitumor Potency of (Cyclohexane-1,2-Diamine)Platinum(II) Complexes with Aminotris(Methylenephosphonic Acid) as Bone-Seeking Ligand

In order to develop platinum complexes with selective activity in primary and secondary bone malignancies and with the aim to optimize antitumor activity, platinum(II) complexes with aminotris(methylenephosphonic acid) as bone-seeking (osteotropic) ligand have been synthesized, characterized and tested in the cisplatin-sensitive ovarian carcinoma cell line CH1. As non-leaving diamine ligands, which are decisive for the cellular processing of DNA adducts, cis-R,S-cyclohexane-1,2-diamine, trans-S,S-cyclohexane-1,2-diamine and trans-R,R-cyclohexane-1,2-diamine have been used, resulting in complexes 1, 2, and 3, respectively. The cytotoxicity of the complexes under investigation decreases in the order 3 > 2 > 1 which is in accord with structure-activity relationships with other (cyclohexane-1,2- diamine)platinum(II) and platinum(IV) complexes: Both trans complexes (2 and 3) display a higher in vitro potency than the corresponding cis isomer (I), with the trans-R,R isomer (3) being the most active in this series. In comparison to the analogous (cyclohexane-1,2-diamine)platinum(II) complexes with bis(phosphonomethyl)aminoacetic acid as osteotropic carrier ligand, the cytotoxicity of 1-3 was found to be 1.5 – 2 fold higher, which is explainable by a different coordination mode of the phosphonic acid ligands (acetato versus phosphonato)

Oxoplatin‐Based Pt(IV) Lipoate Complexes and Their Biological Activity

α‐Lipoic acid, known for its anti‐inflammatory and antioxidant activity, represents a promising ligand for Pt(IV) prodrugs. Three new Pt(IV) lipoate complexes were synthesized and characterized by NMR spectroscopy ( 1 H, 13 C, 195 Pt), mass spectrometry and elemental analysis. Due to the low solubility of the complex containing two axial lipoate ligands, further experiments to examine the biological activity were performed with two Pt(IV) complexes containing just one axial lipoate ligand. Both complexes exhibit anticancer activity and produce reactive oxygen species (ROS) in the cell lines tested. Especially, the monosubstituted complex can be reduced by ascorbic acid and forms adducts with 9‐methylguanine (9MeG), which is favorable for the formation of DNA‐crosslinks in the cells

Supplementary data for article: Mészáros, J. P.; Geisler, H.; Poljarević, J. M.; Roller, A.; Legina, M. S.; Hejl, M.; Jakupec, M. A.; Keppler, B. K.; Kandioller, W.; Enyedy, É. A. Naphthoquinones of Natural Origin: Aqueous Chemistry and Coordination to Half-Sandwich Organometallic Cations. Journal of Organometallic Chemistry 2020, 907. https://doi.org/10.1016/j.jorganchem.2019.121070

Supplementary material for: [https://doi.org/10.1016/j.jorganchem.2019.121070]Related to published version: [http://cherry.chem.bg.ac.rs/handle/123456789/3804

Supplementary data for article: Mészáros, J. P.; Geisler, H.; Poljarević, J. M.; Roller, A.; Legina, M. S.; Hejl, M.; Jakupec, M. A.; Keppler, B. K.; Kandioller, W.; Enyedy, É. A. Naphthoquinones of Natural Origin: Aqueous Chemistry and Coordination to Half-Sandwich Organometallic Cations. Journal of Organometallic Chemistry 2020, 907. https://doi.org/10.1016/j.jorganchem.2019.121070

Supplementary material for: [https://doi.org/10.1016/j.jorganchem.2019.121070]Related to published version: [http://cherry.chem.bg.ac.rs/handle/123456789/3804

Platinum(IV)-Loaded Degraded Glycol Chitosan as Efficient Platinum(IV) Drug Delivery Platform

A new class of anticancer prodrugs was designed by combining the cytotoxicity of platinum(IV) complexes and the drug carrier properties of glycol chitosan polymers: Unsymmetrically carboxylated platinum(IV) analogues of cisplatin, carboplatin and oxaliplatin, namely (OC-6-44)-acetatodiammine(3-carboxypropanoato)dichloridoplatinum(IV), (OC-6-44)-acetaodiammine(3-carboxypropanoato)(cyclobutane-1,1-dicarboxylato)platinum(IV) and (OC-6-44)-acetato(3-carboxypropanoato)(1R,2R-cyclohexane-1,2-diamine)oxalatoplatinum(IV) were synthesised and conjugated via amide bonding to degraded glycol chitosan (dGC) polymers with different chain lengths (5, 10, 18 kDa). The 15 conjugates were investigated with 1H and 195Pt NMR spectroscopy, and average amounts of platinum(IV) units per dGC polymer molecule with ICP-MS, revealing a range of 1.3–22.8 platinum(IV) units per dGC molecule. Cytotoxicity was tested with MTT assays in the cancer cell lines A549, CH1/PA-1, SW480 (human) and 4T1 (murine). IC50 values in the low micromolar to nanomolar range were obtained, and higher antiproliferative activity (up to 72 times) was detected with dGC-platinum(IV) conjugates in comparison to platinum(IV) counterparts. The highest cytotoxicity (IC50 of 0.036 ± 0.005 µM) was determined in CH1/PA-1 ovarian teratocarcinoma cells with a cisplatin(IV)–dGC conjugate, which is hence 33 times more potent than the corresponding platinum(IV) complex and twice more potent than cisplatin. Biodistribution studies of an oxaliplatin(IV)–dGC conjugate in non-tumour-bearing Balb/C mice showed an increased accumulation in the lung compared to the unloaded oxaliplatin(IV) analogue, arguing for further activity studies