Therapeutics


Figure 1


The molecular structure of vincristine


The role of heterocycles in anti-cancer drug design


It is precisely because heterocycles are so prevalent in nature that they have become so important for anti-cancer drug design. Representing an extremely large cohort of molecules with such an unprece- dented level of variability in terms of the interac- tions they can engage with, heterocycle-based com- pounds not surprisingly have formed the basis of drug therapies time and again. As many enzyme- binding pockets are predisposed to interacting with heterocyclic moieties, heterocycles are a good choice when designing molecules that will interact with targets and disrupt the biological pathways associated with cancer progression. Pathways related to cell growth and development are often targeted by such anti-cancer therapies. Moreover, the relative ease by which heterocyclic rings can be modified with additional substituents allows them to cover a broad area of chemical space, further qualifying them as excellent starting points for anti-cancer drug development.


As a result of these factors, heterocyclic struc- tures have long played a key role in anti-cancer drug design, featuring prominently in anti-cancer drug compounds currently available on the mar- ket. Indeed, 65% of the anti-cancer drugs granted market approval by the FDA between 2010 and


Drug Discovery World Summer 2017


2015 contained a heterocycle, and heterocycles form the basis of many of the anti-cancer agents currently in development today.


Nitrogen-based heterocycles Nitrogen-based heterocycles are of particular importance in anti-cancer drug design, featuring in almost


three-quarters of


the heterocyclic anti-


cancer agents approved by the FDA between 2010 and 2015. Of all the nitrogen heterocycles, indoles are among the most valuable, with research having demonstrated their ability to induce cell death in a number of cancer cell lines2.


Over the last few decades, indole and its deriva- tives have been shown to modulate a number of biological pathways implicated in the progression of cancer. These include the prevention of cell sig- nalling, normal cell cycle progression, tumour vas- cularisation and DNA repair, as well as the ability to induce cellular oxidative stress and cell death. Two of the most important early indole-based anti- cancer agents are vincristine and vinblastine – recognised for their tubulin polymerisation inhibi- tion since the early-mid 1960s, and both still of clinical importance today. Vincristine (Figure 1) is used as a combinatorial treatment for acute lym- phoblastic leukaemia and both Hodgkin’s and non-Hodgkin’s lymphoma, whereas vinblastine is


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