Theoretical investigation of organotin(IV) complexes of substituted benzohydroxamic acids

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Highlights

  • Coordination structures of Sn(IV) complexes with organoligands and p-substituted benzohydroxamate ligands studied.

  • Structures intermediate between distorted octahedron and bicapped tetrahedron.

  • Complex having Me as alkyl group and p-amino benzohydroxamate ligand most stable.

  • Cytotoxicity follows the reverse order to stability.

Abstract

The complexing abilities of para-substituted benzohydroxamates to the tin metal center of organotin(IV) ions have been investigated using DFT, since organotin(IV) compounds have been touted as promising anti-cancer agents. We have studied the coordination structures of Sn(IV) complexes (R2SnL2) with organoligands (R = Me, Et, n-Bu) and para-substituted benzohydroxamate ligands (L) so as to study the effect of electron withdrawing (Cl, F, NO2) and electron donating substituents (OCH3, NH2) in the ligand as well as in the alkyl group of the organotin compound. The structures of all the complexes are found to be intermediate between distorted octahedron and bicapped tetrahedron, in agreement with experiment. We have analyzed all the complexes in detail, using their Mayer bond orders, ESP charges, HOMO-LUMO plots and Fukui indices. Of all the complexes, the one having methyl as the alkyl group and the para-amino benzohydroxamate ligand is found to be the most stable. This is owing to the stronger ionic and covalent interaction of Sn(IV) with the para-amino benzohydroxamate ligand and methyl group, respectively.

Introduction

Metal-based drugs are known for their potency and have been in use as therapeutic agents. They are used for the treatment of a variety of diseases, ranging from cancer, rheumatoid arthritis to inflammatory and cardiovascular diseases [1], [2]. This therapeutic property of metal-based drugs prompted researchers all over the world to look for new metal-based compounds with superior activities, especially against tumors [3].

Among the metal-based compounds, organotin(IV) compounds form a widely studied class because of their apoptotic inducing character [4], [5]. Organotin(IV) compounds exhibit remarkable anti-tumor, anti-bacterial, anti-viral, anti-inflammatory and anti-tuberculosis activities [6], [7], [8], [9], [10], [11], [12], [13], [14]. Recently, many researchers have reported the cytotoxic effects of organotin(IV) compounds against various cancer cell lines, including human tumor cell lines [15], [16], [17], [18], [19], [20], [21]. One more advantage of these compounds is that they are useful in overcoming the multidrug resistance generally associated with chemotherapeutic treatment by other metal-based drugs [6]. Despite their promising activity against a wide range of tumors, organotin(IV) compounds-related studies have failed to reach the clinical trials due to their severe neurotoxicity [22], the mechanism of which is still a mystery [23]. However, their extraordinary anti-cancer activity surmounts their negative effects [24]. The aim has now shifted to developing more specific organotin(IV)-based anti-tumor agents, keeping these disadvantages in mind.

In the search for more effective carriers for organotin(IV), interactions of organotin(IV) acceptors with the structurally and biologically relevant class of hydroxamic acids have been extensively studied [25], [26], [27]. Most of the bioactivities of hydroxamic acids are due to their chelating behavior [28], [29], [30], [31], [32], [33]. Among the hydroxamic acids, complexes of benzohydroxamic acid (BHA) and its derivatives with diorganotin(IV) acceptors were found to be effective against a series of human tumor cell lines in vitro [34], [35], [36], [37]. The interaction of BHA with organotin(IV) has been studied extensively because BHA itself is a nucleoside reductase inhibitor, due to which it has anti-cancer activity [38]. Sn(IV) complexes (R2SnL2) have been studied with organoligands (R = Me, Et, n-Bu) and para-substituted BHA ligands (L). These complexes were characterized by FT-IR, 1H, 13C, 119Sn NMR spectroscopies, elemental analysis, melting point measurements and X-ray diffraction analysis [30], [31]. Their anti-tumor activity in vitro was tested on various human tumor cell lines (immature granulocyte leukemia (HL-60), nasopharyngeal (KB), hepatocellular (Bel-7402) and ovarian (Hela) carcinomas) and mouse tumor cell lines (lymphocyte carcinomas B & T). X-ray studies showed that BHA forms complexes with diorganotin(IV) having structures intermediate between distorted octahedron and bicapped tetrahedron, as shown in Scheme 1 [30], [31].

Since the biological activity of organotin(IV) compounds is greatly influenced by their molecular and electronic structure, we have studied the coordination structures of the Sn(IV) complexes (R2SnL2) with organoligands (R = Me, Et, n-Bu) and para-substituted benzohydroxamate ligands (L), which have so far not been investigated theoretically, though extensive experimental data are available [30], [31]. The effect of the R and L groups on the stability of the resulting complex is also analyzed in this work. The structural properties of the complexes are also studied in detail.

Section snippets

Computational details

The GGA-PBE functional [39] was used for our calculations using the DMol3 code [40], [41], [42], [43], [44] in the Materials Studio 5.5 package. The numerical basis sets used were of double-ζ quality plus polarization functions (DNP), the numerical equivalent of the Gaussian 6-31G** basis set. The integration grid was set to Fine. The core was modeled using DFT semi-core pseudopotentials (DSPP) [44]. The complexes were geometry optimized and their Gibbs energies calculated using standard

Structures of benzohydroxamic acids and their anions

Before studying the molecular structures of the complexes, it is imperative to study the conformational behavior of the various BHAs. As has already been discussed in detail in our earlier work [57], BHA can exhibit amide/ imide tautomerism. It can also adopt either the Z (cis) or E (trans) conformation resulting from free rotation about the Csingle bondN bond (Scheme 2). The Z-amide (1Z) form of BHA was found to have the least energy, both in the gas phase and in aqueous solution, and the E-imide (2E)

Conclusions

The structures of all the complexes are intermediate between the distorted octahedron and bicapped tetrahedron. The benzohydroxamate moiety binds Sn(IV) via both its oxygens (carbonyl and hydroxyl) asymmetrically, the carbonyl oxygen forming longer Snsingle bondO bonds than the hydroxyl oxygen. Both the oxygens of benzohydroxamate and the Sn(IV) center lie in one plane and both the alkyl groups occupy axial positions, one lying above this plane and the other below it. The bulky alkyl groups are bent

Acknowledgements

Two of the authors (RA & UI) thank the Council of Scientific and Industrial Research (CSIR) and University Grants Commission (UGC), respectively, for Junior and Senior Research Fellowships.

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