Dacarbazine Synthesis

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Interaction of Dacarbazine with Human Serum Albumin: Spectroscopic Analysis and Molecular Modeling

Abstract

Background: The interactions of dacarbazine with blood constituents, particularly with serum albumin (HSA) may have a major influence on its pharmacology and efficacy.
Method: In the present work, the binding of dacarbazine to human serum albumin has been investigated through UV/visible, CD, fluorescence spectroscopy, isothermal titration calorimetry (ITC) techniques and docking studies.
Results: UV-visible spectra displayed two isobestic points upon addition of drug to HSA. Fluorescence results indicated that the binding of dacarbazine to HSA quenches the intrinsic fluorescence of tryptophan. To study the influence of dacarbazine …show more content…
However, according to reported studies, HSA can affect the binding affinities of the drug, which in turn influence the concentration of the drug in the blood, thereby affecting its biological functions [3]. Dacarbazine is an anti-cancer drug and classified as an "alkylating agent." Dacarbazine (5-[3,3-dimethyl-1-triazenyl]- imidazole-4-carboxamide, or DTIC) is the only chemotherapeutic agent approved by the FDA for treatment of melanoma. However, it is also used for malignant melanoma, Hodgkin's disease, soft tissue sarcomas, neuroblastoma, fibrosarcomas, rhabdomyosarcoma, islet cell carcinoma, and medullary carcinoma of the thyroid [4]. The capability of serum albumins to bind chemotherapeutic durgs depends largely on the existence of two major binding regions, namely Sudlow's site I and site II [5] which are located within specialized cavities in subdomains IIA and IIIA, respectively [6]. The hydrophobic binding pockets enable the serum albumins to increase the apparent solubility of hydrophobic drugs in the plasma and modulate the delivery to the cells in vivo and in vitro [7]. Thus, in view of above, we become interested in evaluating the binding potential of human serum albumin with dacarbazine and this can be equally beneficial to various biological …show more content…
The binding of dacarbazine to conformational forms of HSA was studied by ITC, carried out on a VP-ITC (Microcal Inc., Northampton, MA) at 25 ºC. Protein solutions in different buffers (20 mM sodium phosphate buffer at physiological pH 7.4) were dialyzed extensively before injecting. The sample cell (approximately 1.4 mL) was loaded with HSA (conc. 30 µM) and dacabazine (conc. 2.2 mM) was injected into the reaction cell. The titration cell was stirred continuously at 307 rpm, which ensured rapid mixing but did not cause foaming on the protein solution. Titrations were performed to ensure full occupancy of the binding sites and until the titration signal was constant. The calorimetric data were analyzed using the MicroCal Origin 7.0 software provided with the instrument. The enthalpy change for each injection was calculated by integrating the area under the peaks. The other thermodynamic parameters were calculated according to the
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