Analysis of the Interaction of Dp44mT with Human Serum Albumin and Calf Thymus DNA Using Molecular Docking and Spectroscopic Techniques

Di-2-pyridylketone-4,4,-dimethyl-3-thiosemicarbazone (Dp44mT) exhibits significant antitumor activity. However, the mechanism of its pharmacological interaction with human serum albumin (HSA) and DNA remains poorly understood. Here, we aimed to elucidate the interactions of Dp44mT with HSA and DNA using MTT assays, spectroscopic methods, and molecular docking analysis. Our results indicated that addition of HSA at a ratio of 1:1 did not alter the cytotoxicity of Dp44mT, but did affect the cytotoxicity of the Dp44mT-Cu complex. Data from fluorescence quenching and UV-VIS absorbance measurements demonstrated that Dp44mT could bind to HSA with a moderate affinity (K_a = approximately 10⁴ M⁻¹). CD spectra revealed that Dp44mT could slightly disrupt the secondary structure of HSA. Dp44mT could also interact with Ct-DNA, but had a moderate binding constant (K_EB = approximately 10⁴ M⁻¹). Docking studies indicated that the IB site of HSA, but not the IIA and IIIA sites, could be favorable for Dp44mT and that binding of Dp44mT to HSA involved hydrogen bonds and hydrophobic force, consistent with thermodynamic results from spectral investigations. Thus, the moderate binding affinity of Dp44mT with HSA and DNA partially contributed to its antitumor activity and may be preferable in drug design approaches.     

Synthesis and Study of Multifunctional Cyclodextrin–Deferasirox Hybrids

Metal dyshomeostasis is central to a number of disorders that result from, inter alia, oxidative stress, protein misfolding, and cholesterol dyshomeostasis. In this respect, metal deficiencies are usually readily corrected by treatment with supplements, whereas metal overload can be overcome by the use of metal-selective chelation therapy. Deferasirox, 4-[(3Z,5E)-3,5-bis(6-oxo-1-cyclohexa-2,4-dienylidene)-1,2,4-triazolidin-1-yl]benzoic acid, Exjade, or ICL670, is used clinically to treat hemosiderosis (iron overload), which often results from multiple blood transfusions. Cyclodextrins are cyclic glucose units that are extensively used in the pharmaceutical industry as formulating agents as well as for encapsulating hydrophobic molecules such as in the treatment of Niemann–Pick type C or for hypervitaminosis. We conjugated deferasirox, via an amide coupling reaction, to both 6^A-amino-6^A-deoxy-β-cyclodextrin and 3^A-amino-3^A-deoxy-2^A(S),3^A(S)-β-cyclodextrin, at the upper and lower rim, respectively, creating hybrid molecules with dual properties, capable of both metal chelation and cholesterol encapsulation. Our findings emphasize the importance of the conjugation of β-cyclodextrin with deferasirox to significantly improve the biological properties and to decrease the cytotoxicity of this drug.     

A Double Prodrug with Improved Membrane Permeability over the Parent Chelator HBED Provides Superior Cytoprotection against Hydrogen Peroxide

The clinical use of N,N′‐bis(2‐hydroxybenzyl)ethylenediamine‐N,N′‐diacetic acid (HBED) has been hindered by its lack of bioavailability. N,N′‐bis(2‐boronic pinacol ester benzyl)ethylenediamine‐N,N′‐diacetic acid methyl, ethyl, and isopropyl esters 7 a – c , respectively, and their dimesylate salts 8 a – c , are double prodrugs that mask the two phenolate and two carboxylate donors of HBED as boronic esters and carboxylate esters, respectively. Their activation by chemical hydrolysis and oxidation, their passive diffusivity, and their cytoprotective capabilities have been investigated here. 8 a – c hydrolyzed in minimum essential medium at 37 °C with half‐lives of 0.69, 0.81, and 2.28 h, respectively. The intermediate formed, 9 [N,N′‐bis(2‐boronic acid benzyl)ethylenediamine‐N,N′‐diacetic acid], then underwent oxidative deboronation by H₂O₂ to give HBED (k=1.82 m ^?1 min^?1). Solubility measurements in mineral oil and in phosphate buffer indicated that 7 a had a better balance between lipid and aqueous solubilities than did HBED. 7 a was also able to passively diffuse across a lipid‐like silicone membrane (log flux=?0.36), whereas HBED‐HCl was not. 8 c provided better protection to retinal cells than did HBED against a lethal dose of H₂O₂ (84 % vs. 28 % protection, respectively, at 44 μm ). These results suggest that the double prodrugs have better membrane permeability than does HBED, and therefore could be therapeutically useful for improving the delivery of HBED.     

Kaolin modified with new resin–iron chelate as flame retardant system for polypropylene

Polypropylene's fire‐retardant properties can be improved by using modified kaolin. Modification was done by reaction of kaolin with a prepared resin–iron chelate. Polypropylene samples were loaded with different amounts of kaolin, modified kaolin, and their mixture. Ignition properties of the produced samples were evaluated using cone calorimeter, UL 94, and thermogravimetric analysis techniques. It was found that sample S2 loaded with a mixture of kaolin and modified kaolin had significantly reduced the smoke generation and had a heat release rate comparable to that with kaolin. It was also found that samples S4 and S5 loaded with modified kaolin burned out earlier than did the other samples. © 2004 Wiley Periodicals, Inc. J Appl Polym Sci 92: 3119–3125, 2004