Molecular Reactivity of Busulfan Through Its Experimental Electrostatic Properties in the Solid State

Ghermani, Nour‐Eddine; Biré, Anne Spasojević-de; Bouhmaida, Nouzha; Ouharzoune, Souad; Bouligand, Jérôme; Layre, Anne; Gref, Ruxandra; Couvreur, Patrick

doi:10.1023/b:pham.0000022406.04888.f1

Cited by 26 publications

(18 citation statements)

References 19 publications

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“…Even detailed information about the reactivity, the reaction mechanisms, and the reaction rates may be possible. Here, the proof of principle was given already by the electron-density analysis of busulfan, [7] and penicillin derivatives. [8] Our efforts direct to the development of cysteine [9] and aspartic protease inhibitors [10] consisting of an electrophilic building block (aziridine, [11,12,15] epoxide [13,14] or acceptorsubstituted olefin [15,16] ) which can covalently block the nucleophilic amino acids of the enzymes' active sites (Cys in cysteine proteases or Asp in aspartate proteases).…”

Section: Introductionmentioning

confidence: 98%

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Electron‐Density Determination of Electrophilic Building Blocks as Model Compounds for Protease Inhibitors

et al. 2007

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Three types of synthesised compounds, the aziridine 1, the epoxide 2 and the acceptor‐substituted olefin 3, were chosen as model compounds for electrophilic building blocks, which can covalently block the nucleophilic amino acids of the active sites of proteases (Cys in cysteine proteases or Asp in aspartate proteases). In order to rationally design optimised inhibitors and to understand the differences in inhibition properties of the scrutinised building blocks their structural and electronic properties were studied by ultra‐high resolution X‐ray diffraction and ab initio calculations to yield the experimental electron‐density distribution. It could be shown that the carbon atom C1 of the three‐membered heterocycle is the preferred electrophilic centre for attack of the nucleophiles, which is consistent with the results of corresponding chemical experiments with sulfur and oxygen nucleophiles.(© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2007)

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Section: Introductionmentioning

confidence: 98%

“…This has already been shown for the antithrombotic drug terbogrel, [5] the neurotransmitter taurine, [6] and the anti-leukemia drug busulfan. [7] For the latter the topological electron-density descriptors were also used to explain its chemical reactivity, namely its alkylating property.…”

Section: Introductionmentioning

confidence: 99%

Electron‐Density Determination of Electrophilic Building Blocks as Model Compounds for Protease Inhibitors

et al. 2007

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“…The main problems related to the poor loadings and uncontrolled drug release were recently identified as: the high tendency of busulfan to crystallize in aqueous media and its low affinity for the biodegradable polymer matrices [23]. Indeed, for safe administration, the NP suspensions should not contain free busulfan crystals, which is another important challenge [24].Busulfan is an alkylating agent widely used in chemotherapy, but with severe side effects. Many attempts have been made to entrap busulfan in nanocarriers to avoid liver accumulation and to protect it against rapid degradation in aqueous media.…”

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confidence: 99%

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Porous Metal Organic Framework Nanoparticles to Address The Challenges Related to Busulfan Encapsulation

et al. 2011

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Busulfan is an alkylating agent widely used in chemotherapy, but with severe side effects. Many attempts have been made to entrap busulfan in nanocarriers to avoid liver accumulation and to protect it against rapid degradation in aqueous media. However, poor loadings (≤ 5 wt%) and fast release were generally obtained due to the low affinity of busulfan towards the nanocarriers. Moreover, drug crystallization often occurred during nanoparticle preparation. To circumvent these drawbacks, metal organic framework (MOF) nanoparticles, based on crystalline porous iron (III) carboxylates, have shown an unprecedented loading (up to 25 wt%) of busulfan. This was attributed to the high porosity of nanoMOFs as well as to their hydrophilic-hydrophobic internal microenvironment well adapted to the amphiphilic character of busulfan. NanoMOFs formulations have kept busulfan in molecular form, preventing its crystallization and degradation. Indeed, busulfan was released intact, as proved by the maintenance of its pharmacological activity.

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“…19 In this study, we have investigated the loading of busulfan in five poly(alkyl cyanoacrylate) (PACA) polymers, using the nanoprecipitation process. Since busulfan has a high dipole moment, 20 it was suspected that there might be specific dipole-dipole interactions between busulfan and some PACA polymers. Thus, this study succeeded in efficiently encapsulating busulfan by choosing the best PACA polymer for the highest busulfan loading efficiency.…”

Section: Introductionmentioning

confidence: 99%

Busulfan loading into poly(alkyl cyanoacrylate) nanoparticles: Physico‐chemistry and molecular modeling

et al. 2006

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The busulfan is an alkylating agent widely used for the treatment of haematological malignancies and nonmalignant disorders. For a long time, it has been available only in an oral form. This treatment leads to a wide variability in bioavailability and side effects such as the veino-occlusive disease. Thus, an intravenous formulation of busulfan-loaded nanoparticles may be considered as a major progress. This study deals with busulfan entrapment by nanoprecipitation into five different types of poly(alkyl cyanoacrylate) polymers. The polymers leading to the highest busulfan loading efficiencies were poly(isobutyl cyanoacrylate) (PIBCA) and poly(ethyl cyanoacrylate). Molecular modeling along with energy minimization process was employed to identify the nature of the interactions occurring between busulfan and PIBCA. Further, optimization studies enabled to obtain PIBCA nanoparticles displaying busulfan loading ratios equal to 5.9% (w/w) together with nanoparticle yields of 71% (w/w). Since busulfan is a highly reactive molecule, we performed (1)H-NMR spectroscopy experiments showing that chemical integrity of the drug was preserved after loading into nanoparticles. The in vitro release studies under sink conditions, in water, or in rat plasma showed a fast release in the first 10 min followed by a slower one over 6 h. This phenomenon could be explained by the semi-polar characteristics of busulfan.

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Molecular Reactivity of Busulfan Through Its Experimental Electrostatic Properties in the Solid State

Cited by 26 publications

References 19 publications

Electron‐Density Determination of Electrophilic Building Blocks as Model Compounds for Protease Inhibitors

Electron‐Density Determination of Electrophilic Building Blocks as Model Compounds for Protease Inhibitors

Porous Metal Organic Framework Nanoparticles to Address The Challenges Related to Busulfan Encapsulation

Busulfan loading into poly(alkyl cyanoacrylate) nanoparticles: Physico‐chemistry and molecular modeling

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