Tuning the activity of nitrogen mustards with heterocyclic substituents at nitrogen: A DFT study

Mazumdar, Pradyumna; Choudhury, Diganta

doi:10.1016/j.comptc.2020.113095

Cited by 3 publications

(2 citation statements)

References 28 publications

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“…[32][33][34][35] The mechanistic details of the PM-DNA binding were thoroughly investigated computationally using guanine nucleobase as a DNA model. Previous experimental and theoretical studies have shed light on the mode of action of different nitrogen mustard derivatives, 36,37 such as mechlorethamine, 38,39 which is widely accepted to exhibit potent anticancer activity through a two-step process: (1) formation of the aziridium ion ring and (2) DNA attack, specifically, to guanine N7 nitrogen. This sequence occurs twice, predominantly resulting in the formation of 1-3 inter-strand DNA adducts, which disrupt the alpha-helix structure and trigger cell apoptosis.…”

Section: Aziridinium Cation Formation From Pm and Interaction Of Azir...mentioning

confidence: 99%

Insights on cyclophosphamide metabolism and anticancer mechanism of action: A computational study

Dabbish,

Scoditti,

Shehata

et al. 2023

J Comput Chem

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The oxazaphosphorine cyclophosphamide (CP) is a DNA‐alkylating agent commonly used in cancer chemotherapy. This anticancer agent is administered as a prodrug activated by a liver cytochrome P450‐catalyzed 4‐hydroxylation reaction that yields the active, cytotoxic metabolite. The primary metabolite, 4‐hydroxycyclophosphamide, equilibrates with the ring‐open aldophosphamide that undergoes β‐elimination to yield the therapeutically active DNA cross‐linking phosphoramide mustard and the byproduct acrolein. The present paper presents a DFT investigation of the different metabolic phases and an insight into the mechanism by which CP exerts its cytotoxic action. A detailed computational analysis of the energy profiles describing all the involved transformations and the mechanism of DNA alkylation is given with the aim to contribute to an increase of knowledge that, after more than 60 years of unsuccessful attempts, can lead to the design and development of a new generation of oxazaphosphorines.

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Section: Aziridinium Cation Formation From Pm and Interaction Of Azir...mentioning

confidence: 99%

Insights on cyclophosphamide metabolism and anticancer mechanism of action: A computational study

Dabbish,

Scoditti,

Shehata

et al. 2023

J Comput Chem

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“…To assess pKa values, the following DFT methods were employed-PCM/B3LYP/6-311+G** and SMD/M06-2X/6-311+G**. These methods somewhat based on routine calculations and are still in common usage [31,32], allowing us to estimate pKa values qualitatively well, which is desirable in our work. It is the cheapest way to reproduce the experimental results qualitatively well and a good preliminary study of acid-base properties to estimate the tendency before carrying out an expensive experiment.…”

Section: Rtln10mentioning

confidence: 99%

Low-Molecular Pyrazine-Based DNA Binders: Physicochemical and Antimicrobial Properties

et al. 2022

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Pyrazine and its derivatives are a large group of compounds that exhibit broad biological activity, the changes of which can be easily detected by a substituent effect or a change in the functional group. The present studies combined theoretical research with the density functional theory (DFT) approach (B3LYP/6-311+G**) and experimental (potentiometric and spectrophotometric) analysis for a thorough understanding of the structure of chlorohydrazinopyrazine, its physicochemical and cytotoxic properties, and the site and nature of interaction with DNA. The obtained results indicated that 2-chloro-3-hydrazinopyrazine (2Cl3HP) displayed the highest affinity to DNA. Cytotoxicity studies revealed that the compound did not exhibit toxicity toward human dermal keratinocytes, which supported the potential application of 2Cl3HP in clinical use. The study also attempted to establish the possible equilibria occurring in the aqueous solution and, using both theoretical and experimental methods, clearly showed the hydrophilic nature of the compound. The experimental and theoretical results of the study confirmed the quality of the compound, as well as the appropriateness of the selected set of methods for similar research.

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A DFT and molecular dynamics simulation study of single-walled carbon nanotube as a drug delivery system for few model nitrogen mustard drugs

Mazumdar

Choudhury

Borgohain

2021

Journal of Molecular Structure

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Tuning the activity of nitrogen mustards with heterocyclic substituents at nitrogen: A DFT study

Cited by 3 publications

References 28 publications

Insights on cyclophosphamide metabolism and anticancer mechanism of action: A computational study

Insights on cyclophosphamide metabolism and anticancer mechanism of action: A computational study

Low-Molecular Pyrazine-Based DNA Binders: Physicochemical and Antimicrobial Properties

A DFT and molecular dynamics simulation study of single-walled carbon nanotube as a drug delivery system for few model nitrogen mustard drugs

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