Assistant Professor, University of Sargodha
Metal based drugs have been used for medicinal purposes since ages but their potential was realized after the discovery of the first metal based chemotherapeutic agent, i.e., cisplatin, which became one of the most successful anticancer drugs espcecially for the treatment of testicular cancer. Other members of this class include oxaliplatin, carboplatin and nedaplatin. The use of platinum based drugs is limited due to their adverse side effects (e.g., nephrotoxicity, neurotoxicity, nausea, vomiting etc.) and intrinsic or acquired resistance. These limitations prompted bioinorganic chemists to develop new strategies to treat cancer with other metal based anticancer agents with higher efficacy and lesser undesired effects. Therefore, different metal complexes of titanium, iron, cobalt, gallium, ruthenium and osmium etc. were investigated. Among these NAMI-A (imidazolium [tetrachlorido(dimethylsulfoxide)(1H-imidazole)ruthenate (III)]), KP46 (trismaltolate gallium) and KP1019 (indazolium trans-[tetrachloridobis (1H-indazole)ruthenate(III)]) have entered clinical trials. On the other hand, Ru(II)/Os(II) half sandwich organometallic complexes increase the lipophilic character of complexes and facilitate their uptake into cells. RAPTA type complexes are among the most popular examples of half sandwich organometallics. Furthermore, the coordination of bioactive ligands with these established organometallic pharmacophores may enhance the efficacy of these biologically active compounds by altering their physicochemical and pharmacological properties. In particular, the use of bioactive ligands such as hydroxypyrones, quinolones and non-steroidal anti-inflammatory drugs (NSAIDs) often resulted in promising bioactivity of the compounds. In this thesis, the use of oxicam based NSAIDS as ligands for Ru(II) and Os(II) was investigated. For this purpose, different piroxicam and meloxicam analogues were prepared. Further, these ligands were reacted with Ru(II) and Os(II) cymene dimer to obtain organometallic complexes. All the ligands and complexes were characterized with different spectroscopic techniques including FTIR, 1D and 2D NMR, high resolution mass spectrometry and X-rays crystallography. The anticancer evaluation indicate that most of the complexes are active against all the human cell lines.
Abstract: 1,2‐Benzothiazine‐3‐carboxamide 1,1‐dioxide derivatives such as meloxicam are known to display numerous pharmacological activities. We prepared a series of 4‐hydroxy‐2‐alkyl‐2H‐benzo[e][1,2]thiazine‐3‐carboxamide 1,1‐dioxide ligands 1a–f and their Ru(η6‐p‐cymene) complexes 2a–f, inspired by synergistic effects observed with other bioactive ligands coordinated to metal centres. The molecular structures of 1a, 2a, and 2b were determined by X‐ray diffraction analyses. The stability of the metal complexes was characterized in DMSO and DMSO/H2O on the basis of 1H NMR spectroscopy and their protein binding capabilities were studied using mass spectrometry. In vitro cytotoxicities of the Ru complexes were determined against human colorectal carcinoma (HCT116), non‐small cell lung carcinoma (NCI‐H460) and cervical carcinoma (SiHa) cell lines. The low levels of biological activity observed for these Ru complexes were put into context by considering their chemical reactivity with proteins. The binding of proteins resulted in cleavage of the benzothiazine backbone when the complex was present in concentrations equimolar with respect to protein.
Pub.: 23 Feb '16, Pinned: 24 Dec '17
Abstract: We report here the preparation of 2-hydroxy-4-(picolinamido)benzoic acid and its aspirin analogue 2-acetoxy-4-(picolinamido)benzoic acid. Both ligands were used to synthesize organoruthenium and -osmium complexes. The compounds were characterized by NMR spectroscopy, electrospray ionization mass spectrometry and elemental analysis. The molecular structures of Ru and Os complexes of 2-hydroxy-4-(picolinamido)benzoic acid were determined by single crystal X-ray diffraction analysis. They showed a typical piano-stool configuration and the ligand coordinated as an N,N-bidentate chelator to the metal center. The cytotoxic potential of the selected compounds was evaluated in human colon (HCT116, SW480), non-small cell lung (NCI-H460) and cervical (SiHa) carcinoma cells. Surprisingly none of the compounds exhibited antiproliferative activity given the fact that other metal complexes of aspirin derivatives have shown promising anticancer activity.
Pub.: 27 Jan '17, Pinned: 24 Dec '17
Abstract: The nitrogen- and sulfur-containing 1,2-benzothiazines meloxicam and piroxicam are widely used as nonsteroidal antiinflammatory drugs. Intrigued by the presence of multiple donor atoms and therefore a potentially rich coordination chemistry, we prepared a series of organometallic Ru and Os compounds with meloxicam and piroxicam featuring either as mono- or bidentate ligand systems. The choice of the solvent and the pH value was identified as the critical parameter to achieve selectively mono- or bidentate coordination. The coordination modes were confirmed experimentally by NMR spectroscopy and a wide variety of single crystal X-ray diffraction analyses. Using DFT calculations, it was established that complexes where meloxicam acts as a bidentate N,O donor are energetically more favorable than coordination as O,O and S,O donor systems. Since meloxicam and piroxicam derivatives have shown anticancer activity in the past, we aimed to compare the complexes with mono- and bidentate ligands on their in vitro anticancer activity. However, stability studies revealed that only the latter complexes were stable in DMSO-d6/D2O (5/95) and therefore no direct comparisons could be made. The meloxicam complexes 1 and 2 showed moderate cytotoxicity, while the piroxicam derivatives 5 and 6 were hardly active against the utilized cell lines.
Pub.: 16 Feb '17, Pinned: 24 Dec '17
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