The Half Decent Pharmaceutical Chemistry Blog

Finally, the time has come for me to handle really amazing stuff! Generally speaking, when you think of a drug, it’s huge and complicated, with a lot of banal elements such as carbon, hydrogen, oxygen and aromatic rings. Recently, however, I’ve embarked on an immunoprecipitation of chromatin of MRC-V fibroblasts treated with different concentration of one the things I like the most of pharma chem: Cisplatin. This structure features none of the said things. You look at it and instantly realise it’s a completely different animal: a central, shiny, loot-at-me platinum coordinated with pretty ordinary chlorides plus a couple of ammonias. Not an hydroxyl, not a methylene. Nothing.
Look at it: isn’t it a beauty?

Cisplatin started a trend of platinum-based, alkylating-like agents, which features Carboplatin and Oxaliplatin. Despite the shocking simplicity, the mechanism through which they trigger their cytotoxic effect is still partly unknown, although it’s reasonable to relate it with that of traditional alkylating agents. I mean, they obviously cannot alkylate anything as they have no alkylating group. Still, those chlorides might remind of molecules such as bischloroethylamines and nitrosureas and, so, what about a mechanism where both chlorides get removed and, through a nucleophilic attack, two guanines bind to the platinum, which, in turn, causes a catastrophic distortion of DNA? There is an unquestionable in vivo observation to prove this theory: platinum complexes inhibits the division in E. coli. This is also the reason why chemists looked at compound such as this cis-diamminedichloroplatinum (the extended name of cisplatin).
Unlike modern, precise anticancer drugs which (try to) sort of surgically operate and, therefore, are effective against a rather limited spectrum of tumours, cisplatin belongs to the old-school, which can be summarized as having a broad spectrum as well as a long list of frightening side effects. For what concerns the former, cisplatin has proved its worth in the treatment of head, neck, lung, oesophageal, gastric, bladder, ovarian and bladder cancer. Impressive, isn’t?

However, my supervisor forced me to handle it as you would do with homemade explosives. Although she may be exaggerated, cisplatin is indeed very dangerous and, in fact, is always used in combined regimens so that its dosage could be dramatically reduced. Most of the toxicity comes, unsurprisingly, from the very clinically relevant mechanism: the ability to efficiently and in a cell-cycle independent way massively damage to DNA in cancer cells, depends only on their peculiar feature of replicating at an abnormally high rate. Therefore, cisplatin is all but selective: it attacks every tissue, with the cytotoxic effect being particularly evident where replication or, generally speaking, metabolic activity is physiologically abundant. In a nutshell, alopecia, nausea and gastrointestinal toxicity, nephrotoxicity (due to free oxygen radicals), ototoxicity and neurotoxicity are all, common adverse effects experienced by patients taking cisplatin, although for all of them, except ototoxicity, it’s possible to reduce their incidence. Or, you can look at carboplatin (which causes myelosuppresion but less gastrointestinal toxicity and nephrotoxicity) or oxaliplatin (which triggers reversible, peripheral sensory neuropathy).