Unsymmetric Mono- and Dinuclear Platinum(IV) Complexes Featuring an Ethylene Glycol Moiety: Synthesis, Characterization, and Biological Activity

Abstract

Eight novel mononuclear and two dinuclear platinum(IV) complexes were synthesized and characterized by elemental analysis, one-and two-dimensional NMR spectroscopy, mass spectrometry, and reversed-phase HPLC (log k w ) and in one case by X-ray diffraction. Cytotoxicity of the compounds was studied in three human cancer cell lines (CH1, SW480, and A549) by means of the MTT assay, featuring IC 50 values to the low micromolar range. Furthermore a selected set of compounds was investigated in additional cancer cell lines (P31 and P31/cis, A2780 and A2780/cis, SW1573, 2R120, and 2R160) with regard to their resistance patterns, offering a distinctly different scheme compared to cisplatin. To gain further insights into the mode of action, drug uptake, DNA synthesis inhibition, cell cycle effects, and induction of apoptosis were determined for two characteristic substances.

Synthetic Methods for the Preparation of Platinum Anticancer Complexes

“…For example, oxidation of platinum(II) in alcohols with H 2 O 2 gives trans hydroxo-alkoxo complexes (Scheme 18). 273–275,282–284 An optimized protocol for the synthesis of cisplatin analogues of these species, cis,cis,trans -[Pt(NH 3 ) 2 Cl 2 (OH)(OR)], utilizes high dilution conditions in neat alcohol and oxidation with 50% aqueous H 2 O 2 . 274,284 The use of 50% rather than 30% H 2 O 2 presumably minimizes the amount of water in solution, which can compete with the alcohol for coordination to platinum.…”

“…274,342–348 Additionally, a wide variety of amines and alcohols have been coupled to such platinum(IV) complexes in order to systematically adjust their lipophilicities. 284,329,349–354 For coupling reactions carried out in DMF, N, N '-diisopropylcarbodiimide (DIPC), 328 O -(7-azabenzotriazol-1-yl)- N, N, N ', N '-tetramethyluronium hexafluorophosphate (HATU), 342 and 1,1'-carbonyldiimidazole (CDI) 329 were all used with success, whereas for aqueous coupling reactions the combination of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide) (EDC) and N -hydroxysuccinimide (NHS) works well. 336,338,341 …”

Development and Validation of Liquid Chromatography-Based Methods to Assess the Lipophilicity of Cytotoxic Platinum(IV) Complexes

“…A complete list of the complexes, together with their structures and determined lipophilicity parameters can be found in Tables 1, S1 and S2. The complexes 1-15, 17-19 [24,26,30,33,35,[40][41][42], the ionisable complexes 20-24 [24,43], and the extended set of platinum(IV) complexes 25-26, 28, 30, and 32-58 [24,26,32,33,35,[40][41][42][44][45][46][47] were synthesised according to procedures in the literature. ICP-MS.…”

Monofunctional and Higher-Valent Platinum Anticancer Agents

“…106 The use of alcohols and carboxylic acids as solvents for the oxidation of platinum(II) complexes by hydrogen peroxide usually affords mixed trans hydroxo-alkoxo or hydroxo-carboxylato complexes (Scheme 2). 107–112 …”