Therapeutics
typically used in the treatment of advanced Hodgkin’s disease and against testicular cancer. The inhibition of tubulin polymerisation is the mechanism of action of vinblastine, which leads to cell cycle arrest, halting cancer cell division3. Indolocarbazoles are a closely-related derivative of indoles which, much like with the wider remit of heterocycles themselves, exhibit a broad range of activities, and have therefore received significant focus in recent years for their anti-cancer potential. Of particular significance is the proficiency of many indolocarbazoles as protein kinase inhibitors, where constitutively active protein kinases are often key factors in the malignant transformation of cells during cancer initiation. One such indolocarbazole, the anti-cancer agent midostaurin (an indolocarbazole-based multi-target protein kinase inhibitor), has been approved by the FDA for the treatment of acute myeloid leukaemia as recently as April 2017, which demonstrates just how relevant nitrogen-based heterocycles are for anti-cancer drug design, even to this day.
Oxygen-based heterocycles
Oxygen-containing heterocycles also feature prominently in many anti-cancer drugs. Among the
Figure 2
The molecular structure of cabazitaxel
earliest to be discovered, paclitaxel is a key drug in cancer therapy. Containing an oxetane ring, its mode of action is based on the depolymerisation of microtubule polymers, resulting in progression inhibition of mitosis in cancer cells. Similar to the mode of action taken by vinblastine, this results in the retardation of cancer cell division, ultimately halting cancer in its tracks. Despite its benefits, however, there are a number of systemic side- effects
that have been correlated to the drug, including hypersensitivity, hematological issues and neurotoxicity. As a result, much effort has been devoted to finding alternative therapies that have fewer adverse effects, but still demonstrate the strong therapeutic potential of paclitaxel. More recently-developed oxygen-containing het- erocyclic anti-cancer drugs include microtubule inhibitors cabazitaxel and eribulin, used to treat prostate and metastatic breast cancer respectively. Cabazitaxel (Figure 2) is a tubulin-stabiliser, but is thought to be of particular interest for the treat- ment of multidrug-resistant tumours owing to its resistance to cellular efflux by the p-glycoprotein efflux pump, expressed by a number of resistance cancer cells4,5. Cabazitaxel is also able to cross the blood-brain barrier. Eribulin’s mechanism of action
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Drug Discovery World Summer 2017
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