Influence of (Hydroxymethyl)pyridine and Pyridine‐carboxylic Acids, in trans‐Position to the Isopropylamine and Ammine Ligands, on the Cytotoxicity of Platinum Complexes

Abstract

trans-Pt(II) Complexes with aliphatic amines and planar amines such as (hydroxymethyl)pyridines, and pyridine-3- and pyridine-4-carboxylic acids were synthesized and screened for their potential cytotoxic activity in different cancer cell lines used at the NCI for in vitro screens, i.e., MCF7, NCIH460, and SF268. The complexes studied were designed to differ in geometrical parameters such as the position of the phenyl-group substituents and the nature of the substituents themselves for gathering information about the structure-activity relationships in the trans-complexes. The variation of the substituents turns to be crucial for their biological activity, as both pyridine-3- and pyridine-4-carboxylic acids in trans-position to both amine and isopropylamine ligands provided complexes which displayed no specificity toward any type of cell tested, while (hydroxymethyl)pyridine in trans-position to isopropylamine ligands led to complexes that were clearly more effective against the cell lines tested.

Platinum(IV) Complexes of 3‐ and 4‐Picolinic Acids Containing Ammine or Isopropylamine Ligands – Synthesis, Characteri­zation, X‐ray Structures, and Evaluation of Their Cytotoxic Activity against Cancer Cell Lines

“…The Pt-N (amine), Pt-N (picolinic acid) and Pt-Cl bond lengths are in agreement with published data [20,21] for Pt IV complexes and are similar to those in the Pt II counterparts. [15] The N-Pt-N-C(pyridine ring) torsion angles in ammine complexes 1 and 3 are 133(26)°and 166(6)°, respectively, and the carboxyl group deviations from the pyridine ring are about 25°. In the isopropylamine derivatives 2 and 4, the torsion angles are smaller, 65(3)°and 46(3)°, respectively, and the carboxyl group deviations, about 18.5°, are slightly lower.…”

“…We additionally compare their activity with that of the precursor Pt II complexes, which were published in a previous work. [15] Platinum(IV) complex 4, in which isopropylamine and 4-picolinic acid act as ligands, showed activity against MCF7 and SF268 but no response against NCI H460. The platinum(IV) complex 2, in which isopropylamine and 3-pico-linic acid act as ligands, showed only significant activity against MCF7 (Table 3).…”

“…In addition, the crystal structures have been determined. The assignment of NMR spectra was carried out in accordance with published data [15,18,19] and 1 H-195 Pt HMBC and 1 H- 13 C HMQC experiments (see Experimental Section and Scheme 2). Perhaps, the 1 H NMR spectra of 1 and 2 are noteworthy, because of their unusual couplings.…”

“…These results are interesting, especially with regard to the cytotoxic values of the precursor platinum(II) complexes which are not active. [15] The lipophilicity of platinum(IV) complexes has been accepted as one of the main reasons of their activation. In fact, the high cellular uptake of analogues of JM216 in vitro correlates with the high lipophilicity of the platinum(IV) complexes.…”

“…[15] The 4-picolinic acid complexes were isolated by following the known procedure, in which the difference between the trans effects of halide and amine ligands is used (i.e., Cl -Ͼ amine) to achieve control of stereochemistry. The complexes with 3-picolinic acid afforded a complicated mixture, where the desired complexes were a minor product.…”