Journal of Photochemistry and Photobiology B: Biology
De novo design of chiral organotin cancer drug candidates: Validation of enantiopreferential binding to molecular target DNA and 5′-GMP by UV–visible, fluorescence, 1H and 31P NMR
Highlights
► De novo synthesis of N,N-bis[(R-/S-)-1-benzyl-2-ethoxyethane] tin (IV) complexes. ► Elemental analysis, IR, ESI-MS, 1H, 13C and 119Sn, NMR spectroscopy and XRD study. ► 2J [1H–117/119Sn] coupling constant. ► Chiral discrimination of R- and S-enantiomer with CT DNA by employing biophysical techniques. ► R-enantiomer complex binds more avidly to DNA as compared to S-enantiomer complex.
Introduction
There has been tremendous research drive in recent years towards the design of non-platinum chemotherapeutics with the aim to optimize the features of classical platinum drugs constituting the basic cisplatin framework viz: their toxic side effects, inherent intrinsic resistance and high cost [1]. Among the noteworthy, organotins have emerged as a promising class of cancer chemotherapeutics.
The antitumor properties of tin complexes have been established since 1929 [2]. Gielen [3] have published a series of research articles on this subject during past two decades. Since then many researchers have shown keen interest in this field and a number of reviews recording advances in the screening for antitumor potential of organotins have been published. Organotin compounds exhibiting potent anticancer activity may act via different mechanisms at the molecular level. The binding propensity of organotin compounds towards DNA, the ultimate drug target molecule depends essentially on the coordination number/stereochemistry and the nature of groups directly attached to the central tin scaffold [4]. Recent literature reports reveal many studies on DNA–Sn complexes interaction [5], [6], [7]. Cationic Sn(IV) exerts electrostatic interaction towards polyanionic phosphate backbone as a result of its hard Lewis acidic property, thus, neutralizing the negative charge of the CT-DNA resulting in significant contraction and conformational changes in the DNA [8]. Besides this, chirality plays a profound role in dictating the DNA binding propensity and binding mode as DNA itself is inherently chiral in nature (B-form of DNA has right handed conformation) [9]. Single enantiomeric drugs constitute more than 30% of the total therapeutic drugs used in recent years and their growing use is closely related to structure–function relationship. The structure–function relationship in nature is so powerful that when a functional disorder is manifested in the form of disease, it can be handled in many cases by using a molecule of specific chiral structure. Consequently, the appropriate design of tumor inhibiting motifs demonstrating enantiospecificity can actually modulate the resistance by specific tagging at the molecular target site. The structural relationship and kinetic parameters of new chiral organotins (poly oxaalkyl) clusters was established and their antitumor activity and ID50 values were evaluated against seven human tumor cell lines [10]. In general, the complexes that fit best to the double helical structure of DNA exhibit the highest binding affinity. Such differences in binding affinities have also been classified in a variety of platinum complexes wherein DNA-cross links exhibit different conformational features due to the enantiomeric amine ligands [11]. In general, the complexes that fit best to the double helical structure of DNA exhibit the highest binding affinity. Such differences in binding affinities have been classified in a variety of platinum complexes wherein DNA-cross links exhibit different conformational features due to the enantiomeric amine ligands [12]. As a consequence of these conformational effects, enantiomers were processed differently by cellular machinery in the biological systems. Although, the molecular shape of the drug molecule is apparently a decisive factor for DNA binding nevertheless, enantiospecificity of the DNA double helix could play an important role in reckoning the binding potential of chiral complexes with DNA. Herein, we describe a comparative study of enantiospecific interaction of (R-/S-) N,N-bis[1-benzyl-2-ethoxyethane]tin(IV) complexes 1 and 2 respectively, with CT DNA by employing UV–visible, fluorescence and CD measurements in order to gain better understanding of the predominant binding mode and the conformational effect induced by the complex-DNA interactions.
Section snippets
Materials and physical measurements
Reagent grade chemicals were used without further purification for all syntheses. (R/S) 2-amino-2-phenylethanol, dibromoethane, dimethyltin(IV) dichloride were purchased from E. Merck “Calf thymus DNA (CT DNA) and guanosine 5′-monophosphate disodium salt (5′-GMP)” were purchased from Sigma Aldrich chemical Co. Stock solution of CT DNA were prepared in aerated Tris–HCl/NaCl buffer (0.01 M, pH 7.2 5:50 mM). Solutions of the calf thymus DNA in buffer gave a ratio of UV absorbance at 260 and 280 nm of
Synthesis and spectroscopic study of the complexes
New chiral organotin complexes (R)- and (S)-(1 and 2) were designed and synthesized as shown in Scheme 1. The synthesis involves the in situ addition of [(CH3)2SnCl2] to the preformed condensation product of (R)-/(S)-2-amino-2-phenylethanol and dibromoethane to yield the complexes 1 and 2, respectively. Empirical formulae and proposed structure were ascertained by elemental analysis, polarimetry, molar conductivity measurements, UV–visible, ESI-MS and NMR spectroscopy. Molar conductance
Conclusion
New chiral enantiomeric organotin complexes 1 and 2 derived (R)- and (S)-2-amino-2-phenylethanol with –CH2–CH2– linker have been synthesized and thoroughly characterized. The proposed structure was further validated by XRD measurements, 1H NMR and 13C NMR, 119Sn NMR spectra and 2J [1H–117/119Sn] coupling constant values revealing hexacoordinate environment around tin(IV) atom. In vitro DNA binding studies of complexes 1 and 2 were carried out by employing various biophysical methods and further
Acknowledgements
The authors are grateful to the DBT, New Delhi, India for generous financial support through Research Grant No. BT/PR9208/Med/30/13/2007. Thanks to Mr. Avtar Singh for his support to carry out NMR experiments, and SAIF Chandigarh for elemental analysis, and ESI mass analysis.
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