Affinities to Oxaliplatin: Vitamins from B Group vs. Nucleobases

Abstract

Oxaliplatin, similar to Cisplatin, exhibits anticancer activity by interacting with DNA and inducing programmed cell death. It is biotransformed through a number of spontaneous and non-enzymatic processes. In this way, several transient reactive species are formed, including dichloro-, monochloro-, and diaqua-DACH platin, which can complex with DNA and other macromolecules. The molecular level suggests that such interactions can also take place with vitamins containing aromatic rings with lone pair orbitals. Theoretical and experimental studies were performed to investigate interactions of vitamins from the B group with Oxaliplatin, and the results were compared with values characterizing native purines. Quantum-chemical simulations were carried out at the B3LYP/6-31G(d,p) level, with the LANL2DZ basis set representing atomic orbitals of platinum atom, and at the MN15/def2-TZVP levels of theory with the use of Polarizable Continuum Model (IEF-PCM formulation) and water as a solvent. Additionally, time-dependent density functional theory (TD-DFT) was employed to study molecular properties in the electronic excited state. Interactions of vitamins and Oxaliplatin were investigated using UV-Vis spectroscopy. Values of the free energy (ΔGr) indicate spontaneous reactions with monoaqua [PtH2OClDACH]+ and diaqua [Pt(H2O)2DACH]2+ derivatives of Oxaliplatin. However, diaqua derivatives were found to be preferable. The free energy (ΔGr) values obtained for vitamins from the B group indicate lower affinity of Oxaliplatin compared with values characterizing complexes formed by guanine, adenine, and cytosine. The exception is the monoaqua form of vitamin B1 (thiamine) at the MN15/def2-TZVP levels of calculations. An application of atoms in molecules (AIM) theory revealed non-covalent interactions present in the complexes studied. The comparison of computed and experimental spectroscopic properties showed a good agreement.

Will the Interactions of Some Platinum (II)-Based Drugs with B-Vitamins Reduce Their Therapeutic Effect in Cancer Patients? Comparison of Chemotherapeutic Agents such as Cisplatin, Carboplatin and Oxaliplatin—A Review

“…Thiamine (vitamin B1) has the second addition center for interaction such as the nitrogen atom N 1 . The affinities of all vitamins to cis-platinum were analyzed for the first time [ 49 , 50 , 51 , 52 ]. The estimated values of Gibbs free energy (ΔG r ) of reaction for mono- and diaqua platinum complexes of the studied vitamins were compared with the results for guanine in this review ( Figure 7 , Figure 8 , Figure 9 and Figure 10 , Table 1 , Table 2 , Table 3 and Table 4 ).…”

“… Gibbs free energy (ΔG r ) values in kcal/mol of complexes of monoaqua derivatives of oxaliplatin (Pt-DACH-Chloroaqua) with B vitamins and guanine at B3LYP/6-31G(d,p)/LANL2DZ and MN15/def2-TZVP level of theory [ 52 ]. …”

“… Comparison of Gibbs free energy (ΔG r ) values in kcal/mol of complexes of diaqua derivatives of cisplatin and oxaliplatin (cis-Pt-diaqua and Pt-DACH-diaqua) at B3LYP/6-31G(d,p)/LANL2DZ level of theory [ 49 , 52 ]. …”

“…Cisplatin and oxaliplatin have a similar mechanism of action where for the activation of the relatively inert platinum (II) complexes, the hydrolysis of non-active drugs to diaqua complexes via the monoaqua form is necessary [ 47 , 48 , 49 , 50 , 51 , 52 ] ( Figure 2 , Figure 3 and Figure 4 ).…”

“…During the study, the reactivity of hydrolysis products such as monoaqua and diaqua derivatives of three platinum (II)-based drugs, cisplatin, carboplatin and oxaliplatin, was analyzed [ 47 , 48 , 49 , 50 , 51 , 52 ]. Such products as [(cis~[Pt(NH 3 ) 2 Cl(H 2 O)] + ) and (cis~[Pt(NH 3 ) 2 (H 2 O) 2 ] 2+ )] in the case of cisplatin, [Pt(H 2 O)ClDACH] + and [Pt(H 2 O) 2 DACH] 2+ in the case of oxaliplatin and Pt(NH 3 ) 2 H 2 O(OH) + plus Pt(NH 3 ) 2 (OH) 2 in the case of carboplatin can interact not only with nucleobases ( Figure 3 and Figure 4 ), which is the basis of their therapeutic action, but also with all compounds which have aromatic rings in their structures with lone-pair orbitals analogous to N 7 in purine ( Figure 5 and Figure 6 ).…”