Exploration of Electrochemical Intermediates of the Anticancer Drug Doxorubicin Hydrochloride Using Cyclic Voltammetry and Simulation Studies with an Evaluation for Its Interaction with DNA
Electrochemical behavior of the anticancer drug doxorubicin hydrochloride was studied using cyclic voltammetry in aqueous medium using Hepes buffer (pH~7.4). At this pH, doxorubicin hydrochloride undergoes a reversible two-electron reduction with value ？ ？mV (versus Ag/AgCl, saturated KCl). Depending on scan rates, processes were either quasireversible (at low scan rates) or near perfect reversible (at high scan rates). This difference in behavior of doxorubicin hydrochloride with scan rate studied over the same potential range speaks of differences in electron transfer processes in doxorubicin hydrochloride. Attempt was made to identify and understand the species involved using simulation. The information obtained was used to study the interaction of doxorubicin hydrochloride with calf thymus DNA. Cathodic peak current gradually decreased as more calf thymus DNA was added. The decrease in cathodic peak current was used to estimate the interaction of the drug with calf thymus DNA. Nonlinear curve fit analysis was applied to evaluate the intrinsic binding constant and site size of interaction that was compared with previous results on doxorubicin hydrochloride-DNA interaction monitored by cyclic voltammetry or spectroscopic techniques. 1. Introduction Anthracycline anticancer drugs are amongst the most active agents in oncology [1, 2], first recognized for their antibacterial properties in 1939. Their chemical characterization led to an increase in use after therapeutic value of their antineoplastic activity was described in the early 1960s. Two anthracyclines, daunomycin (daunorubicin) and doxorubicin hydrochloride (hydroxyl daunomycin or doxorubicin), were initially isolated from Streptomyces peucetius var. caesitue [3, 4] and exhibit the widest spectrum of antitumor activity [5, 6]. The presence of a side chain primary alcohol group in doxorubicin hydrochloride has important consequences in antitumor activity that makes it more valuable than other anthracyclines. Doxorubicin hydrochloride is used in the treatment of breast cancer, childhood solid tumors, soft tissue sarcomas, and aggressive lymphomas. However, its use is often hampered by cumulative dose-limiting cardiotoxicity resulting in cardiomyopathy and congestive heart failure that may be irreversible [7]. Though there is still some controversy with regard to their mode of action, anticancer activity or cytotoxic effects involve interaction with nuclear components, especially DNA and type-II topoisomerase [8, 9]. The anthracyclines contain a planar aglycone ring coupled with an aminosugar. The
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