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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. 相似文献
2.
Djaffar Jureidini I Chamseddine N Keleshian S Naoufal R Zahed L Hakime N 《Molecular biology reports》2011,38(8):5449-5452
Clopidogrel is one of the most commonly prescribed drugs, as its combination with low-dose aspirin is the recommended oral
anti-platelet therapy, to prevent ischaemic events following coronary syndromes or stent placement. Numerous recent studies
have shown that polymorphisms in the gene encoding the cytochrome P450 (CYP450) 2C19 enzyme (CYP2C19) contribute to variability
in response to clopidogrel; patients with certain common genetic variants of CYP2C19 (*2, *3) have a reduced metabolism of
clopidogrel and have a higher rate of cardiovascular events or stent thrombosis compared to patients with the CYP2C19 (*1)
allele. CYP2C19*2 is most common in Caucasians, Africans and Asians while CYP2C19*3 has been found mostly in Asians. Since
the prevalence of these variants in the Lebanese population has not yet been reported, our aim was to determine the genotypes
of CYP2C19 in our population. CYP2C19 (*1/*2/*3) variants were assessed by Polymerase Chain Reaction-Restriction Length Polymorphism
(PCR–RFLP) assays in a representative sample of 161 unrelated healthy Lebanese volunteers. The allele frequencies of CYP2C19
*2 and *3 were 0.13 and 0.03. Carriers of the CYP2C19 *2 or *3 represented 24.2% of the subjects. Our data show no significant
difference in the frequency of CYP2C19 allelic variants when compared to Caucasian populations and demonstrate that the application
of the recent FDA recommendations would also be beneficial in Lebanon, allowing physicians to identify patients at high risk
for atherothrombotic events, and eventually advising them to consider other antiplatelet medications or alternative dosing
strategies in poor metabolizers. 相似文献
3.
Djaffar Kheffache Hind Guemmour Azzedine Dekhira Ahmed Benaboura Ourida Ouamerali 《Journal of molecular modeling》2013,19(11):4837-4847
In the present work, we carried out a conformational analysis of cis-3-aminoindan-1-ol and evaluated the role of the intramolecular hydrogen bond in the stabilization of various conformers using quantum mechanical DFT (B3LYP) and MP2 methods. On the basis of relative energies, we have found nine conformational minima, which can interchange through the ring-puckering and the internal rotation of the OH and NH2 groups on the five-membered ring. The intramolecular hydrogen bonds such as OH????π, NH????π, NH????OH and HN????HO are expected to be of critical importance for the conformational stabilities. The intramolecular interactions of the minima have been analyzed by calculation of electron density (ρ) and Laplacian (ρ) at the bond critical points (BCPs) using atoms-in-molecule (AIM) theory. The existence or absence of OH????π and NH????π in cis-3-aminoindan-1-ol remains unclear since the geometrical investigation has not been confirmed by topological criteria. The results of theoretical calculations demonstrate that this compound exists predominantly in one ring-puckering form stabilized by strong hydrogen bond HN????HO Interaction. 相似文献
4.
D B Taichman M I Cybulsky I Djaffar B M Longenecker J Teixidó G E Rice A Aruffo M P Bevilacqua 《Molecular biology of the cell》1991,2(5):347-355
Hematogenous metastasis involves adhesive interactions between blood-borne tumor cells and the vessel wall. By the use of in vitro assays, the adhesion of human melanoma, osteosarcoma, and kidney carcinoma (but not colon carcinoma) cell lines was shown to involve the cytokine-inducible endothelial cell surface protein inducible cell adhesion molecule 110 (INCAM-110) and the alpha 4 beta 1 integrin, molecules normally involved in endothelial-leukocyte interactions. Tumor adhesion to human endothelial cell monolayers was increased 1.9- to 8.2-fold by endothelial activation with the cytokine tumor necrosis factor (TNF) and inhibited by the anti-INCAM-110 monoclonal antibody (mAb) E1/6. Each of these tumor cells expressed members of the beta 1 integrin family of adhesion molecules, and antibodies to the alpha 4 and beta 1 integrin subunits inhibited tumor-endothelial adhesion (48-87% inhibition). A cDNA encompassing the three N-terminal Ig-like domains of vascular cell adhesion molecule 1 (VCAM-1) encoded a protein recognized by the anti-INCAM-110 mAb E1/6 and, when captured onto plastic, supported melanoma cell adhesion by an alpha 4 integrin-dependent mechanism. In contrast to mAb E1/6, a second anti-INCAM-110 mAb Hu8/4 neither inhibited adhesion to activated endothelium nor bound the first three Ig-like domains of INCAM-110/VCAM-1. These data indicate that the adherence of several human tumors to activated endothelium is mediated by an interaction of alpha 4 beta 1 integrin and the N-terminal Ig-like domains of endothelial INCAM-110/VCAM-1. Tumor acquisition of the alpha 4 integrin subunit and endothelial expression of INCAM-110 may affect the frequency and distribution of metastasis. 相似文献
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