Comparative chemical and biological studies of four prototype phosphoraziridine antineoplastic agents

Dunn, Joseph A.; Bardos, Thomas J.

doi:10.1016/0006-2952(91)90192-8

Cited by 3 publications

(2 citation statements)

References 33 publications

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“…Design of the alkylating agents. As explained in the "Introduction" section, the reactivity of thioTEPA depends on cross link formation with DNA which takes place by the nucleophilic opening of aziridine groups [13,15] regardless of the differences between the two possible pathways. Since it has been verified that presence of two aziridinyl arms is necessary in formation of the required cross links [14], it was decided to insert two aziridine moieties in some template structures.…”

Section: Alkylating Activitymentioning

confidence: 99%

“…These cross-links cause the direct nucleophilic ring opening of two aziridinyl groups [14]; and 2) hydrolysis of thioTEPA to aziridine can happen due to a nucleophilic attack of water at the phosphorus atom and the N-P bond cleavage. In both of the pathways, the ring opening reaction of aziridine is initiated by its protonation, which makes aziridine the main target of nucleophilic attack [15]. Musser et al have shown that thioTEPA leads to depurination and formation of aminoethyl adducts of guanine and adenine [16], so the nucleophilic attack should be advanced by guanine and adenine bases.…”

Section: Introductionmentioning

confidence: 99%

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Farnesyltransferase as a target for anticancer drug design

1997

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This study aims to design some dual-target anticancer candidates, capable to act as an alkylating agent as well as a thymidylate synthase (TS) inhibitor. The designed scaffold is a combination of nucleobase, amino acid and aziridine structures. The candidates are docked into TS and three DNA double strand structures and evaluated based on their binding interaction energies and ligand efficiencies, compared to several reference drugs. The ADME properties of the alkylating agents are also predicted. The designed ligands exhibit improved interaction energies and lower ligand efficiencies with respect to the reference drugs. Among the ligands, L4 is the best DNA binding agent and L2, L5 and L6 are the best TS inhibitors. In addition, the thioTEPA based Ser and Met analogues are the strongest and poorest alkylating agents, respectively. Further, molecular dynamics simulations on the best ligand-target complexes, i.e. L4-4AWL and L6-TS systems, provide evidences for the potential L6 and L4 anti-proliferation activities.

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Section: Alkylating Activitymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Farnesyltransferase as a target for anticancer drug design

1997

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

Kheffache

Ouamerali

2010

J Mol Model

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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.

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Mechanisms and kinetics of thiotepa and tepa hydrolysis: DFT study

Torabifard

Fattahi

2012

J Mol Model

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N,N',N″-triethylenethiophosphoramide (Thiotepa) and its oxo analogue (Tepa) as the major metabolite are trifunctional alkylating agents with a broad spectrum of antitumor activity. In vivo and vitro studies show alkylation of DNA by Thiotepa and Tepa can follow two pathways, but it remains unclear which pathway represents the precise mechanism of action. In pathway 1, these agents are capable of forming cross-links with DNA molecules via two different mechanisms. In the first mechanism, the ring opening reaction is initiated by protonating the aziridine, which then becomes the primary target of nucleophilic attack by the N7-Guanine. The second one is a direct nucleophilic ring opening of aziridyl group. Thiotepa and Tepa in pathway 2, act as a cell penetrating carrier for aziridine, which is released via hydrolysis. The released aziridine can form a cross-link with N7-Guanine. In this study, we calculated the activation free energy and kinetic rate constant for hydrolysis of these agents and explored interaction of aziridine with Guanine to predict the most probable mechanism by applying density functional theory (DFT) using B3LYP method. In addition, solvent effect was introduced using the conductor-like polarizable continuum model (CPCM) in water, THF and diethylether. Hyperconjugation stabilization factors that have an effect on stability of generated transition state were investigated by natural bond order (NBO) analysis. Furthermore, quantum theory of atoms in molecules (QTAIM) analysis was performed to extract the bond critical points (BCP) properties, because the electron densities can be considered as a good description of the strength of different types of interactions.

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Comparative chemical and biological studies of four prototype phosphoraziridine antineoplastic agents

Cited by 3 publications

References 33 publications

Farnesyltransferase as a target for anticancer drug design

Farnesyltransferase as a target for anticancer drug design

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

Mechanisms and kinetics of thiotepa and tepa hydrolysis: DFT study

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