Some physicochemical properties of the antitumor drug thiotepa and its metabolite tepa as obtained by density functional theory (DFT) calculations

Abstract

Density functional theory (DFT) using the B3LYP functional was applied to elucidate the molecular properties of the antitumor drug thiotepa and its main metabolite tepa. Aqueous solvent effects were introduced using the conductor-like polarizable continuum model (CPCM). The protocol for calculating the pK (a) values obtained with different cavity models was tested on a series of aziridine and phosphoramide compounds. An efficient computational scheme has been identified that uses the CPCM model of solvation with a universal force field (UFF) cavity. The method has been used to evaluate the basicities of thiotepa and its metabolite. Our calculations show that the basicities of the aziridine moiety of thiotepa and tepa are dramatically reduced compared to free aziridine, indicating that highly acidic media are needed to produce substantial yields of the N-protonated form of the drug. Finally, the mechanisms of reaction of the drug and its metabolite are discussed based on our theoretical results. The calculations reproduce the experimental trends very satisfactorily.

The Complexation of the Anticancer Drug ThioTEPA with Methylated DNA Base Guanine: Combined Ab Initio and QTAIM Investigation

“…ThioTEPA (the IUPAC name: 1,1′,1′′‐phosphorothioyltriaziridine) is the anti‐cancer drug invented over 60 years ago3 which still remains important for practical application in medicine4–8 and physiology 9. Although this pharmaceutical compound is widely used, not only the physical properties of its molecule have not been studied carefully until recently,10,11 but even the mechanism of its action remains vague enough 5,8,12–15. The researchers assume that the drug acts basically by cross‐linking the cancer cell DNA double helix via chemical bond between two strands, thus preventing the DNA replication process 5,14.…”

Density Functional Theory Investigation of the Binding of ThioTEPA to Purine Bases: Thermodynamics and Bond Evolution Theory Analysis

“…Despite the chemical similarity of the N7 binding site of guanine and adenine, it is commonly agreed that, in vivo, the electrophilic aziridines of TT are the primary targets of nucleophilic attack by N7 of guanine and to a lesser extent by the N3 of adenine. 12 This chemical behavior was ascribed to the molecular shape of guanine compared to adenine (and also cytosine), resulting in stronger steric hindrance in the latter. 15 Indeed, the guanine N7 binding site, exposed in the major groove of normal helical DNA, is more reachable and can thus better react with electrophiles than the N3 of adenine oriented to the minor groove.…”

“…Indeed, it is more stable at 22 °C than at 37 °C and at a pH range of 6–7 rather than at a pH range of 4–5.5. Though several investigations , have contributed to understanding the reactivity of thioTEPA toward purine bases, particularly guanine, the alkylation mechanism remains unclear because two pathways are possible, as depicted in Scheme . In pathway 1 , thioTEPA cross-links with DNA molecules.…”

“…According to Miller’s theory, sites that could interact with electrophilic species are the DNA nucleophilic centers such as the nitrogen atoms of the guanine and adenine purine bases. Despite the chemical similarity of the N7 binding site of guanine and adenine, it is commonly agreed that, in vivo , the electrophilic aziridines of TT are the primary targets of nucleophilic attack by N7 of guanine and to a lesser extent by the N3 of adenine . This chemical behavior was ascribed to the molecular shape of guanine compared to adenine (and also cytosine), resulting in stronger steric hindrance in the latter .…”

Analysis of Tandem Repeat Patterns in Nlrc4 using a Motif Model

“…The advancement of computational tools such as databases [1][2][3][4][5], modelling [6][7][8], decision support systems [9], simu lation [10][11][12], v isualization techniques [13][14][15][16], and web servers [17][18][19][20] have revolutionized the field of bioin formatics and mo lecular biology with the breakthrough in data processing and analysis. These computational tools received wide application in various specialized disciplines in mo lecular bio logy, including systems biology [21][22], genome analysis [23][24], population genetics [25], structural bioinformatics [26][27], and phylogenetics [28][29].…”