ANTICANCER ACTIVITY OF HETEROCYCLIC LIGAND-PLATINUM METAL COMPLEXES

A wide range of research activities have been carried out so far on benzimidazole and pyridine derivatives to evaluate their Antiviral, Anticancer, Anticonvulsant, Anthelmintic Activity and many promising results are obtained with respect to the anticancer activity. Out of the various ligands used, the alkylating agents are found to be highly active with respect to cancer chemotherapy. Nitrogen mustards, ethylenemines, alkylsulfonates, nitrosourea, and triazines are all members of the alkylating agents. The presence of active nitrogen atom in a particular structure enhances the binding efficacy of number of metals and hence forms metal complexes. The overall aim of the review is to study cytotoxicity of various platinate and other metal complexes which are effectively formed by platinum and other metals respectively by obtaining the lone pair of electrons from nitrogen. Also in support of the anticancer activity, the derivatives obtained by metal complexation with number of nitrogen containing heterocyclic ligands have been shown. Keyword: Benzimidazole, Pyridine, Platinum Complexes, Anticancer Activity, Cytotoxic Activity


Introduction 1-6
The Benzimidazole (1) heterocycle is represented in nature as an integral part of the structure of vitamin B 12 and has been incorporated into pharmaceutical agents to form enzyme inhibitors, and DNA intercalators. Benzimidazoles are very useful intermediates subunits for the development of molecules of pharmaceutical or biological interest. The substituted benzimidazole derivatives have found applications in diverse therapeutic areas including antiulcer, antihypertensive, antifungal, anticancer, and antihistaminic. Some benzimidazole derivatives show diverse biological activities with significant clinical potential, including the treatment of leukemia and cancer.

1
The pyridine (2) substructure is one of the most prevalent heterocycle found in natural products, pharmaceuticals, and functional materials. Many powerful methodologies for the synthesis of these heterocycles rely on condensation of amines and carbonyl compounds or cycloaddition reactions. Cross-coupling chemistry also allows introduction of substituents to activated heterocycles. 2 2 2. Cancer chemotherapy 7, 8, 9, 10 The initial signs of cancer were detected in the bones of ancient Egyptian and Peru mummies, who lived in the 3000 BC. The high mortality rate associated with cancer worldwide is the reason for the ongoing research for the cure for this disease. Four methods of treatment have been discovered; these are: 1) surgery 2) radiotherapy 3) hormonal therapy and 4) chemotherapy. Surgery has been the most popular form of treatment, but over the last five years there has been an increase in the use of chemotherapy. Surgery involves careful removal of the malignant cells from the patient's body and have been reported very effective for removal of small tumors. Surgery treatment has also shown effectiveness when used in combination with radiotherapy or chemotherapy. Radiotherapy, which involves destroying cellular components of tumor cells by high energy waves, has also been reported highly effective for cancer treatment though it is limited

4. Platinum Complexes 13-35
Recently, the wide spectrum of biological activities associated with benzimidazole have been of wide interest. This has included activity against viruses such as HIV, human cytomegalovirus, herpes (HSV-1), RNA, and influenza. These compounds have also been reported to act as anti-inflammatory, anthelmintic, antiparasitic, topoisomerase inhibitors, selective neuropeptide YY1 receptor antagonist, 5-lipoxygenase inhibitors, and factor Xa inhibitors. These properties, coupled with the findings indicate that benzimidazole compounds show antitumor activity. Although benzimidazole compounds have proven active against various cancers, there are recent reports on their combinatorial use with platinum and other metal to treat cancer. Platinum are chemotherapeutic drugs consisting of platinum (II) and platinum (IV) complex with various donor ligands. Cisplatin [cis-diammine dichloroplatinum (II)] (6) is one of the platinum complex that has gained worldwide popularity since 1970s. Cisplatin is reported active against testicular, ovarian, bladder, head and neck cancers. Despite these antitumor activities, neurological disorders such as nephrotoxicity, mylosuppression, ototoxicity greatly limit the use of cisplatin. Moreover, it has been reported that various cancer cells become resistant to this drug, for instance, murine ADJ/PC6 plasmacytoma. Thousand of analogues of cisplatin have been made and evaluated, with two major driving forces. The first has been to seek compounds with lower neurotoxicity than cisplatin. Whereas better clinical management has improved things, one of the main drivers of analogue development has been agents with less neurotoxicity. Carboplatin (7) has carboxylate instead of chloride-leaving groups. These hydrolyze much less rapidly, resulting in lower nephrotoxicity and neurotoxicity (the dose-limiting toxicity of carboplatin is mylosuppression), while retaining the broad spectrum of activity of cisplatin.
The second impetus to analogue development has been to seek agents active in cell lines that become resistant to cisplatin. One mechanism of resistance to cisplatin is an increased ability to repair the DNA adducts formed. However, analogues such tetraplatin (8; Ormaplatin) and Oxaliplatin (9), with trans-1, 2diaminocyclohexane (DACH) ligand, were shown to be more effective against such resistant cell lines. These compounds proved to be neurotoxic but Tetraplatin was difficult to formulate, but Oxaliplatin have shown promising results.  Interestingly, the replacement of amide by ester functionalities in the series of novel acridine-9carboxylate tethered (ethane-1,2-diamine) platinate complexes and connected by a polymethylene chain increased their cytotoxic effect which was higher than cisplatin or oxaliplatin in the three colic HCT 116, SW480 and HT-29 cell lines. The influence of the polymethylene linker in platinum complexes was dependent on the cell line: in HCT 116 and SW480, (23) having the hexamethylene chain, remained the most cytotoxic, whilst in HT-29, the most sensitive cell line to reference Pt compounds, (24) with the dimethylene linker was the most active. A relationship between cytotoxicity and polymethylene chain length in platinum compounds was also reported by Silva et  The transition metal complexes of 2-substituted benzimidazole ligands act as anticancer agents. Cancer cells are found to have less superoxide dismutase activity than normal cells and copper(II) complexes are known to mimic activity of copper, zinc-superoxide dismutase (Cu, Zn-SOD), an antioxidant enzyme that protect cells from the toxic effect of superoxide ion by its dismutation into dioxygen and hydrogen peroxide in biological systems. The antitumor activity of SOD metal complexes has been suggested to be due to their superoxide scavenging ability. It's Zn (II), Be (II), and Al (III) derivatives are photoluminescent. Hydroxyl benzimidazole shows excited-state intramolecular transfer (ESIPT) properties due to acidic protons of phenol and imidazole nitrogen. It has been reported that hydroxyl benzimidazole and benzoxazole behave as a structural mimic of DNA base pair for which tautomerism may be initiated at a definite time and position within duplex DNA. Structurally similar natural product bis (benzimidazole) UK-1 has been reported to posses anticancer activity, and the metal-binding studies of UK-1 indicates that benzoxazole-like compound are capable of binding a variety of biologically important metal ions. Benzimidazole derivatives have exhibited significant activity against several viruses such as HIV, human cytomegalovirus (HCMV), herpes (HSV-1) and influenza.

Conclusion
Since past few decades, there has been an increase in the scope of cancer therapy, especially the alkylating agents. Many attempts have been made by the researchers to synthesize and use platinum complexes as alkylating agents which are gaining wide importance in obtaining anticancer effect. Platinum containing complexes such as Cisplatin, Carboplatin, Oxyplatin etc are currently being marketed and are reported to be active against testicular, ovarian, bladder, head and neck cancers. However due to the neurotoxicity that are reported against these drugs, there is a need to develop more and more analogues with less toxicity, improved activity and active on cisplatin resistant tumors. Also, with an aim for complexation of heterocyclic derivatives, the number of metals such as Pt (II), Zn (II), Be (II) and Al (III) has been used so far to form corresponding metal complexes.