Therapeutics
Figure 3
The molecular structure of olaparib
on the other hand is somewhat unique, binding only to the growing ends of microtubules during cell division (where other drugs bind both the grow- ing and shortening ends), which leads to prolonged mitotic blockage and ultimately cell death via apop- tosis6. As mentioned, eribulin is used to treat advanced breast cancer, and is not only effective but exhibits a low level of toxicity compared to alterna- tive cytotoxic agents, making it ideal for patients7. In addition to this, recent research has led to the repurposing of existing oxygen-based heterocyclic drugs originally developed for other disease areas, for use as anti-cancer agents. One notable example is auranofin, a gold-containing heterocyclic com- pound used historically for the treatment of rheumatic arthritis. Numerous studies are being undertaken to assess auranofin as a therapeutic agent for the treatment of many cancer types, including leukaemia, lymphoma and ovarian can- cer (where it recently received FDA approval to undergo Phase II clinical trials). Repurposing drugs in this way is a far more affordable approach to drug discovery, owing to the significant costs asso- ciated with novel candidate identification and other research and development activities8.
Sulfur-based heterocycles
Sulfur is a key component in several vitamin co- factors, sugars and nucleic acids, and plays an important role in regulating translation via the sul- furation of transfer RNA. Given the significance of
Drug Discovery World Summer 2017
sulfur in biological systems, sulfur-containing hete- rocycles have received much attention in the devel- opment of anti-cancer drugs, much like their oxy- gen- and nitrogen-based counterparts. For instance, in a recent screening study, thiophene derivatives were assessed for their antiproliferative activity against human breast adenocarcinoma cells, with a number of compounds found to show promising inhibitory effects. The researchers reported that their findings could provide a basis by which future tyrosine kinase inhibitors may be designed, with fewer side-effects9.
In addition, thiadiazole and thiazole structures have also shown to be of importance for cancer research in recent years; with a number of thiazole- based nitrogen mustard heterocycles having recent- ly been shown to exhibit strong inhibitory activity towards a panel of human cancer cell lines. Dabrafenib is a thiazole-containing anti-cancer drug molecule that was approved by the FDA in 2013 for use in patients with cancers associated with the mutated version of the BRAF gene. One such group of patients were those suffering from metastatic melanoma, in which almost half of indi- viduals have been shown to possess the mutated version of BRAF. Initial studies had shown that these patients had had vastly improved clinical out- comes and truly encouraging rates of survival as a result of being treated with dabrafenib10. It is clear from these advances that heterocycles of many different species continue to form the
References 1 Komeilizadeth, H (2006). Does Nature Prefer Heterocycles? Iranian Journal of Pharmaceutical Research, 4: 229-230. 2 El Sayed, MT et al (2015). Indoles as Anticancer Agents. Adv Mod Oncol Res, 1: 20-25. 3 Haque, IU (2010). Vinblastine: A Review. J Chem Soc Pak, 2: 245-258. 4 National cancer institute (2017). NCI Drug Dictionary: Cabazitaxel. Online link:
https://www.cancer.gov/publica tions/dictionaries/cancer- drug/?CdrID=534131. 5 Callagham, R et al (2014). Inhibition of the Multidrug Resistance P-Glycoprotein: Time for a Change of Strategy? Drug Metab Dispos, 42: 623-631. 6 Shetty, N and Gupta, S (2014). Eribulin Drug Review. South Asian J Cancer, 3: 57-59. 7 Ates, O et al (2016). Efficacy and Safety of Eribulin Monotherapy in Patients with Heavily Pretreated Metastatic Breast Cancer. J BUON, 21: 375-381.
Continued on page 70 69
Page 1 |
Page 2 |
Page 3 |
Page 4 |
Page 5 |
Page 6 |
Page 7 |
Page 8 |
Page 9 |
Page 10 |
Page 11 |
Page 12 |
Page 13 |
Page 14 |
Page 15 |
Page 16 |
Page 17 |
Page 18 |
Page 19 |
Page 20 |
Page 21 |
Page 22 |
Page 23 |
Page 24 |
Page 25 |
Page 26 |
Page 27 |
Page 28 |
Page 29 |
Page 30 |
Page 31 |
Page 32 |
Page 33 |
Page 34 |
Page 35 |
Page 36 |
Page 37 |
Page 38 |
Page 39 |
Page 40 |
Page 41 |
Page 42 |
Page 43 |
Page 44 |
Page 45 |
Page 46 |
Page 47 |
Page 48 |
Page 49 |
Page 50 |
Page 51 |
Page 52 |
Page 53 |
Page 54 |
Page 55 |
Page 56 |
Page 57 |
Page 58 |
Page 59 |
Page 60 |
Page 61 |
Page 62 |
Page 63 |
Page 64 |
Page 65 |
Page 66 |
Page 67 |
Page 68 |
Page 69 |
Page 70 |
Page 71 |
Page 72