Diorganotin(IV) Complexes with Methionine Methyl Ester. Equilibria and Displacement by DNA Constituents

RESEARCH ARTICLE M.M. Shoukry, A. Al-Alousi and S.M. Tarek, S. Afr. J. Chem., 2014, 67, 94–98, <http://journals.sabinet.co.za/sajchem/>. 94 Diorganotin(IV) Complexes with Methionine Methyl Ester. Equilibria and Displacement by DNA Constituents 1,2, 2 M.M. Shoukry * Ayser Al-Alousi and Sameya M. Tarek 1 Deparment of Chemistry, Faculty of Science, Islamic University, Madina, Saudi Arabia. 2 Department of Chemistry, Faculty of Science, Cairo University, Egypt. Received 18 August 2013, revised 15 April 2014, accepted 29 April 2014. ABSTRACT The coordination of methionine methyl ester with dimethyltin(IV) (DMT), dibutyltin(IV) (DBT) and diphenyltin(IV) (DPT) was investigated at 25 °C and 0.1 mol dm–3 ionic strength in water for dimethyltin(IV) and in 50 % dioxane–water mixture for dibutyltin(IV) and diphenyltin(IV). Methionine methyl ester forms 1:1 and 1:2 complexes with diorganotin(IV). The corresponding formation constants were calculated by using the non-linear least-squares program MINIQUAD-75. The concentration distribution of the various complex species was evaluated as a function of pH. The displacement of coordinated methionine methyl ester with some DNA constituents was calculated based on equilibrium aspects. KEYWORDS Dimethyltin(IV), dibutyltin(IV), diphenyltin(IV), methionine methyl ester, stability constant. 1. Introduction A tremendous amount of research is directed towards the design of non-platinum chemotherapeutic agents with the aim to optimize the features of classical platinum drugs containing the basic cisplatin framework, viz. their toxic side effects, inherent intrinsic resistance and high cost.1 Among the most noteworthy cases, organotins have emerged as a promising class of cancer chemotherapeutics. It has been well established that organotin(IV) compounds are very important in cancer chemotherapy because of their apoptotic inducing character.2,3 During the last few years it has been noticed that organotin compounds occupy an important place in cancer chemotherapy.4–7 Blower8 described thirty interesting inorganic pharmaceuticals, four of which are tin compounds. Numerous diorganotin(IV) derivatives have been found to exhibit high in vivo cytotoxicity against P388 lymphocytic leukaemia but to exhibit less or no activity against other murine systems.9–14 However, the new in vitro human tumour cell-screening tests have once again demonstrated the potential of organotin complexes, some of which have exhibited high activity15 and thus interest in them has been revitalized. Organotin(IV) compounds are involved in cancer treatment via different mechanisms at the molecular level. The binding ability of organotin compounds towards DNA, the ultimate drug target, depends on the DNA structure. The phosphate groups of the DNA sugar backbone usually act as an anchoring site and binding at the nitrogens of the DNA bases is extremely effective, thus often resulting in the stabilization of the tin centre as an octahedral stable species.16 The antitumour activity of the coordination compounds R2SnX2L2 is controlled by the nature of R, the leaving group (X) and the ligand (L). The coordinated ligand (L) favours in some way the transport of the drugs into cells, while the antitumour activity is exerted by the diorganotin (IV) moiety dissociated from the complex.17 The latter interacts with nucleic acids, similar to the widely used anticancer drug cisplatin. Therefore, there is a relationship between the stability * To whom correspondence should be addressed. E-mail: of the organotin(IV) compounds and their antitumour activity. In conjuction with our previous studies on organotin(IV) complexes,18–22 the present paper aims to study the complex formation equilibria of dimethyltin(IV), dibutyltin(IV) and diphenyltin(IV) with methionine methyl ester. The displacement of coordinated methionine methyl ester with DNA constituents is also investigated. 2. Experimental Experimental Organotin(IV) compounds used were dimethyltin(IV) dichloride (DMT), dibutyltin(IV) dichloride (DBT) and diphenyltin(IV) dichloride (DPT) obtained from Sigma-Aldrich Chem. Co. Methionine methyl ester hydrochloride and sodium nitrate were obtained from Acros Organics. Carbonate-free NaOH (titrant) was prepared and standardized against potassium hydrogen phthalate solution. The DMT solution was prepared in water, but the DBT and DPT solutions were prepared in dioxane due to their insolubility in water. The methionine methyl ester solution was prepared in water. Potentiometric measurements were made by using a Metrohm 686 titroprocessor equipped with a 665 Dosimat (Switzerland). The titroprocessor and electrode were calibrated with standard buffer solutions, prepared according to NBS specifications.23 The titrations were carried out in a purified N2 atmosphere by using a previously described titration vessel.24 The temperature was maintained constant by a Colora ultrathermostat. The protonation constants of methionine methyl ester. hydrochloride were determined by titrating a 40 cm3 aliquot of 2.5 × 10–3 mol dm–3 methionine methyl ester hydrochloride solution. The hydrolysis constants of DMT, DBT and DPT were determined by titrating 40 cm3 aliquots of 2.5 × 10–3 mol dm–3 solutions of each substance. The formation constants of the organotin(IV) complexes were determined by titrating 40 cm 3 of a solution containing methionine methyl ester hydrochloride (2.5 × 10–3 mol dm–3) and organotin(IV) with a concentration of 1.25 × 10–3 mol dm–3. The titration was performed at 25 °C in water for DMT but in 50 % dioxane-water solution for DBT and DPT. The ionic strength RESEARCH ARTICLE M.M. Shoukry, A. Al-Alousi and S.M. Tarek, S. Afr. J. Chem., 2014, 67, 94–98, <http://journals.sabinet.co.za/sajchem/>. was 0.1 mol dm–3, adjusted with NaNO3. The pKw in dioxane– water solution was determined as described previously.22,25 For this purpose, various amounts of a standard NaOH solution were added to a solution containing 0.1 mol dm–3 NaNO3 solution. The [OH–] was calculated from the amount of base added. The [H+] was calculated from the pH value. The product of [OH–] and [H+] was taken. The mean value of pKw obtained in this way was 15.46 for 50 % dioxane–water solution. The equilibrium constants were evaluated from the titration data, defined by Eq. (1) and Eq. (2). (1) pM + qL + rH ƒ MpLqHr [Mp Lp Hr ] , (2) βpqr = [M]p [L]q [H]r where M, L and H represent organotin(IV), methionine methyl ester. and proton respectively and p, q and r are their stoichiometric coefficients, respectively. The calculations were performed by using the computer program MINIQUAD-75.26 The stoichiometries and stability constants of the complexes formed were determined by trying various possible composition models. The model finally selected was the one that gave the best statistical fit and was chemically consistent with the titration data without giving any systematic drifts in the magnitudes of various residuals, as descr (...truncated)