Elsevier

Bioorganic & Medicinal Chemistry

Volume 14, Issue 18, 15 September 2006, Pages 6333-6340
Bioorganic & Medicinal Chemistry

Synthesis, characterization, antibacterial and cytotoxic study of platinum (IV) complexes

https://doi.org/10.1016/j.bmc.2006.05.047Get rights and content

Abstract

Platinum (IV) complexes [Pt (L)2Cl2] [where, L = benzyl-N-thiohydrazide (L1), (benzyl-N-thio)-1,3-propanediamine (L2), benzaldehyde-benzyl-N-thiohydrazone (L3) and salicylaldehyde-benzyl-N-thiohydrazone (L4)] have been synthesized. The thiohydrazide, thiodiamine and thiohydrazones can exist as thione-thiol tautomer and coordinate as a bidentate N–S ligand. The ligands were found to act in monobasic bidentate fashion. Analytical data reveal that metal to ligand stoichiometry is 1:2. The complexes have been characterized by elemental analysis, IR, mass, electronic and 1H NMR spectroscopic studies. In vitro antibacterial and cytotoxic studies have been carried out for some complexes. Various kinetic and thermodynamic parameters like order of reaction (n), activation energy (Ea), apparent activation entropy (S#) and heat of reaction (ΔH) have also been carried out for some complexes.

Graphical abstract

Platinum (IV) complexes [Pt (L)2Cl2] [where, L = benzyl-N-thiohydrazide (L1), (benzyl-N-thio)-1,3-propanediamine (L2), benzaldehyde-benzyl-N-thiohydrazone (L3) and salicylaldehyde-benzyl-N-thiohydrazone (L4)] have been synthesized. The thiohydrazides, thiodiamine and thiohydrazones can exist as thione-thiol tautomer and coordinate as a bidentate N–S ligand. Platinum (IV) complexes of the thiohydrazide, thiodiamine and thiohydrazones were characterized by elemental analysis, IR, mass, electronic and 1H NMR spectroscopic studies. The complexes were also screened for antibacterial and cytotoxic activity. Thermodynamic parameters such as activation energy (Ea), apparent activation entropy (S#) and enthalpy change (ΔH) for the dehydration and decomposition reactions of the complexes have also been evaluated.

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Introduction

Platinum (IV) complexes are widely applied in the treatment of various types of cancers such as testicular, ovarian and bladder carcinomas.1, 2, 3, 4, 5 Cisplatin is used in the treatment of head and neck cancer, lung carcinoma, stomach carcinoma, and so on.6, 7 However, the clinical usefulness of cisplatin has been frequently limited by its severe side effects such as nephrotoxicity, nausea, ototoxicity, neurotoxicity and myelotoxicity.8, 9, 10 Besides, there is development of acquired resistance low activity against breast and colon cancer. Therefore, it is desirable to develop new platinum-based drugs with broader spectrum of activity, improved clinical efficacy and reduced toxicity, better than cisplatin.11

Platinum (IV) complexes have revealed significantly greater activity in human than that of cisplatin.12, 13 The high activity was ascribed to high cellular uptake, but in vivo reduction alters the pharmacological properties and thus the effectiveness of the drug. However, platinum (IV) complexes have enormous potential as anticancer agents in terms of both high activity and low toxicity, but this potential has not been realized by the drugs investigated to date, probably because they are reduced too readily in the bloodstream. The potential advantages of platinum (IV) complexes that remain in the higher oxidation state in the bloodstream are low reactivity that would diminish loss of active drugs and also lowers the incidence of unwanted side reactions that lead to side effects.14

Platinum complexes suitable for oral administration have been known to be water-soluble, lipophilic, and robust enough to survive the gastric environment. For the platinum (IV) complexes, ligand substitution reactions are slow as compared with their platinum (II) analogues. The platinum (IV) complexes may be required to be reduced to the kinetically more labile and reactive platinum (II) derivatives in vivo.14, 15 Nowadays attention is focused on platinum (IV) complexes with bioactive ligands, because of the lower toxicity of platinum (IV) and the possibility of oral administration of some potent platinum (IV) compounds as well as the fact that they can coordinate to DNA. In view of number of applications of the thiohydrazides and thiohydrazones16, 17, 18 and the well-proven clinical utility of the platinum-metal complexes, we have prepared platinum (IV) complexes of the thiohydrazide, thiodiamine and thiohydrazones. These complexes were characterized and screened for antibacterial and cytotoxic activity. Thermodynamic parameters such as activation energy (Ea), apparent activation entropy (S#) and enthalpy change (ΔH) for the dehydration and decomposition reactions of the complexes have also been evaluated.

Section snippets

Elemental analysis

Elemental analysis (Table 1) reveals the purity of the complexes. All the complexes are soluble in DMSO. The molar conductance values of the isolated complexes measured in DMSO are found to be less than 15 ohm−1 cm2 mol−1 suggesting their non-electrolytic nature.

Electronic spectra

The electronic spectra (Table 2) of the thiohydrazides (L1), thiodiamines (L2) and thiohydrazones (L3 and L4) show spectral bands because of π  π* and n →π* transition. On complexation these bands are shifted. Strong charge transfer

Conclusion

All the complexes are found to be diamagnetic, so the platinum (IV) complexes must be octahedral. Platinum (IV) is d6 system and four bands are expected corresponding to 1A1g  3T1g, 1A1g  3T2g, 1A1g  1T1g and 1A1g  1T2g transitions. The shift towards lower frequency on complexation indicates the coordination to metal ion is through thioamide sulfur. The antibacterial study of the complexes shows significant activity. The bacterial strains with the zone of inhibition were observed, 8 mm. One complex

General

Materials and chemicals: All the reagents used were of AR grade. The analysis of CHNS/O contents of ligands and metal complexes was done on Elementar Analysensysteme GmbH Vario El-III. IR and far IR were recorded on Perkin-Elmer spectrum 2000 FTIR spectrometer. Electronic spectra were recorded on Shimadzu UV–vis spectrophotometer Model 1601. Conductance measurements were carried out on Digital Conductometer Model PT-827, India. Model Jeol SX102/DA-600 (KV 10MA) was used for recording Mass

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