EFFECT OF NUCLEOPHILIC AGENT ON THE CHEMICAL REACTIVITIES OF CHLORAMBUCIL AND MECHLORETHAMINE BY CYCLIC VOLTAMMETRIC IN SEVERAL SOLVENTS STUDIED

• Main Author: Setiyanto, Henry
• Format: Dissertations
• Language: Indonesia
• Subjects: Kimia
• Online Access: https://digilib.itb.ac.id/gdl/view/34557
• Institution: Institut Teknologi Bandung

Alkylating agents is typically used in the cancer chemotherapy due to reactivity in eradicating the growth of the cancer cell by directly reacting to the nucleophile center of DNA bases. Alkylating agents attack to non-selective targets, which implicated to attack healthy cells as well that may possibly inducing unexpected secondary cancers. Surveyes conducted by the International Agency for Research on Cancer (IARC) concluded that the secondary cancers cases is strongly caused the application of alkylating agents during the chemotheraphic treatment of the patients. Due to the potential hazzardous of the alkylating agents in causing the secondary cancer, in the presence work we developed a method to determined the chemical reactivity of alkylating drugs, i.e. chlorambucil (CLB) and mechlorethamine (MEC) in various solvents in the presence and the absent of additional nucleophile substances using cyclic voltammetric technique. Alkylation reactions of both drugs follow the mechanism of SN1 reaction and ErCi. The reaction take place in the following two-steps of reactions, namely (1) the formation of intermediates i.e. carbocations, whose reaction occurs slowly and (2) the fast reaction between the carbocation and the nucleophile. Alkylating agents will be reversibly electro–oxidized/reduced to form a carbocation compound then it irreversibly reacts with the nucleophile substance. Chemical reactivity was determined based on the value of the forward reaction rate constant (kf) on the second step of reactions. The chemical reactivity of CLB and MEC was calculated from the electrochemical parameters derived from their cyclic voltammogram measured in the solvents containing 0.1 M and 0.2 M sodium perchlorate. Nicholson-Shain approach has been applied to calculate the chemical reactivity based on the derived parameters of both alkylating agents. The same measurement procedure was employed when additional nucleophile substance was included into the solution of the alkylating agent. Solvents used to dissolve both alkylating agents were included water, acetone and acetonitrile, while 4-chloro butironitril (CBN), pyridine (Py) and nicotinamide adenine dinucleotide (NAD+) were added as the additional nucleophile substances. The important electrochemical parameters obtained from the cyclic voltammogram are an anodic and a cathodic peak’s currents (potentials). The rate constant of each forward reaction was determined with the competitive methods at different potential scan rates. The profile deduced from the voltammogram of CLB and MEC exhibited typical characteristics of the reversible electrochemical reaction followed by the irreversible chemical reaction. All voltammograms were characterized based on the respective parameters: anode peak’s potentials (Epa), cathode peak’s potential (Epc), both anode peak’s current (Ipa) and cathode peak’s current (Ipc), half-wave potential (E1/2) and peak’s potential separation (?Ep .) The range of working potential obtained from this study were 0.5 to 1.2 V for CLB in water; 0.8 to 1.5 V for CLB in acetone and acetonitrile, and 0.8 to 1.7 V for MEC in acetone and acetonitrile. The values of Ipa and Ipc were liniearly correlated with v1/2 as indicated by the high average correlation coefficient i.e. 90% (R2> 0.90). Such liniear correlation strongly suggested that the system being studied obeyed Randles-Sevcik equation. In addition those parameters showed that the processes occurred on the surface of working electrode were diffusion-controlled. The average ratio of Ipc/Ipa was less than one, which conlude the reaction mechanism should be the reversible electrochemical reaction followed by irreversible chemical reaction. At the potential scan rate of 1 V/s, the obtained pairs potentials of Epa and Epc for CLB were 0896 V and 0.788 V ; 1.240 V and 1.160 ; 1.130 V and 1.070 V in water, acetone and acetonitrile, respectively. At the same scan rate, the resulting pairs potential of MEC were 1.200 V and 1.480 V ; 1.460 V and 1.200 V in acetone and acetonitrile, respectively. MEC was apparently not electroactive in water because its peak’s current of oxidation and reduction were hardly observed from its voltammogram. The addition of nucleophilic substance shifts the peaks’s of oxidation-reduction potential but did not alter the range of working potential . These results, therefore, gave insight into the effect of solvents variation to the oxidation-reduction potential of CLB and MEC. The calculated chemical reactivity based on the Nicholson-Shain method exhibited the dependency to the solvent property. The calculated chemical reactivity of CLB in three different solvents was 0.4485 s-1, 0.2248 s-1; 0.0245 s-1 in water, acetone, and acetonitrile, respectively. Whereas for MEC, its respective value were 0,4828 s-1 and 0.2724 s-1 in acetone and acetonitrile. Solvents with a larger donors number, i.e. water will provide a greater chemical reactivity for CLB and MEC. The addition of nucleophilic compounds i.e. CBN, Py and NAD+ changed the values of reactivities of CLB and MEC, but did not change the reactivities order of the solvents used. The respective reactivity value of CLB in in water, acetone and acetonitrile after the addition of CBN are 0.4897 s-1, 0.2715 s-1, and 0.2676 s-1; when after the addition of Py the value became: 0.0993 s-1, 0.0541 s-1, and 0.0077 s-1, while after the addition of NAD+ became 0.0248 s-1, 0.1773 s-1, 0.0868 s-1. In case for MEC, the reactivity value in the solvent of acetone and acetonitrile, in the presence of CBN are 0.1601 s-1 and 0.1365 s-1, respectively. While in the presence of Py and NAD+, its respective value became 0.2056 s-1 ; 0.1799 s-1 and 0.4323 s-1 ; 0.0398 s-1. The reactivity of MEC in water can not be calculated because this molecule is not electroactive in the water. The reactivities data of CLB and MEC in accordance with clinical data that is LD50. The reactivities obtained in this exhibited strong correlation with the clinical data of CLB and MEC so that the method developed here is worth to be considered to be applied in estimating the chemical reactivity of cancer related drugs.