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• Alternative drugs to cisplatin is needed due to the cisplatin side effects.

  other drugs also develop a resistance to cisplatin.
• Platinum drugs – the platinum complexes should be:

  Neutral to easily cross membrane

  Easily replaceable ligands so they can interact with DNA

  Leaving ligands should be in cis configuration

  Platinum oxidation state (II) or (IV)

  Non leaving ligands stabilizes structure by forming bonds with DNA and recognizes it.
• Carboplatin discovered in 1980s. Reduces kidney damage and is known to stop certain types of cancer. Treatment for small cell lung cancer and ovarian cancer.
• draw carboplatin structure

  A) carboplatin

  
• Carboplatin similar structure to cisplatin.

  Both are square planar complexes with central metal Pt with side NH3 ligands. Instead of the 2 Cl- ligands, carboplatin has cyclobutene – 1,1-dicarboxylate ligand.
• Carboplatin is a chelate. The cyclobutene – 1,1-dicarboxylate is a bidentate ligand. Cl and NH3 are monodentate ligands. Carboplatin forms a chelate ring when the metal ion interacts with the cyclobutene -1,1-dicarboxylate ligand.
• Carboplatin is a drug for ovarian cancers. Similar cisplatin mechanism.

  Much less nephrotoxic and less toxic to peripheral nervous system.
• Oxaliplatin structure - Shares similar properties of cisplatin and carboplatin as they have a square planar. However oxaliplatin has 2 chelate rings. The active complex is a trans configuration with the diaminocyclohexane ring.
• Oxaliplatin undergoes hydrolysis like carboplatin and cisplatin and reacts with DNA forming lesions which disrupt DNA replications.
• Oxaliplatin differences – difference is mainly because of the DACH ligand. DNA repair mechanism cannot recognize the DNA damage done by the DACH ligands. Despite the adducts formed by both cisplatin and oxaliplatin having similar structures, the bulky adduct can interact with DNA in unique way. This can give the adducts different biological properties. Compared to cisplatin, oxaliplatin requires lower levels of DNA adducts for the same cytotoxicity.
• Colorectal cancer – tradiational treatments depend on drugs like 5-FU as they disrupt DNA structure. There are moderate reactions to 5-FU alone. Combining both 5-FU with Leucovorin (LV) gives better response. Despite this, patients do not respond or develop resistance to this drug.
• 5-FU and LV – 5-FU inhibits thymidylate synthase which makes pyrimidine for DNA replication. This slows down cancer cell growth. LV is given to restore normal cells DNA replication. This reduces chemotherapy side effects and maintains healthy cells. 
• Clincial use of oxaliplatin – shows anti-cancer properties and has a better safety compared to cisplatin. Lack of resistance in tumor cells is an advantage. Due to the chemical and steric characteristics of the DACH – platinum- DNA adducts formed.

  It has also shown effectiveness to various colon cancer cell lines. 
• Other Pt alternatives – picoplatin is derived from cisplatin. Due to the presence of bulky ligand (2-methylpyridine) the steric hinderance allows inactivation resistance to certain substances like thiols. Works with various cancers which are also platinum drug resistant. There has been no nephron and neurotoxicity observed yet.
• Picoplatin – showed effectiveness against Pt-sensitive ovarian cancer and small cell lung cisplatin resistant lung cancer.
• Satraplatin – orally active Pt (IV) compound. Converts to Pt(II) in body after loss of 2 acetate ligands. As effective as cisplatin but can combat some cisplatin resistant prostate cancers.
• Ruthenium – has different mode of action, toxicity and biodistribution. It has an iron mimicking ability. Has range of accessible oxidation state and is has a favourable rate of ligand exchange.
• NAMI-A : showed efficacy in inhibiting growth and formation of lung metastasis without organ toxicity.
• KP1019 – targets colorectal cancers and solid tumors. Has limited side effects but is cytotoxic. Activated by reduction. Mechanism is by DNA damage through intrastrand adduct formation.