Molecular Aspects of Anti-Cancer Drug Action

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Echinomycin and Related Quinoxaline Antibiotics. Design of Sequence-specific Agents: Lexitropsins. Their prevalence is partly down to the broad range of interactions these structures are involved with, made possible due to the physicochemical properties of their heteroatoms that can behave as either acids or bases, depending on the pH of their environment 1. In addition, their wide range of ring sizes and structural permutations means heterocycles come in a broad range of shapes and sizes, allowing them to match the equally diverse structural range of enzyme binding pockets.

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 unprecedented level of variability in terms of the interactions they can engage with, heterocycle-based compounds not surprisingly have formed the basis of drug therapies time and again. As many enzymebinding 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.

The importance of halichondrin

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 structures have long played a key role in anti-cancer drug design, featuring prominently in anti-cancer drug compounds currently available on the market. Nitrogen-based heterocycles are of particular importance in anti-cancer drug design, featuring in almost three-quarters of the heterocyclic anticancer agents approved by the FDA between and 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 lines 2.

Over the last few decades, indole and its derivatives have been shown to modulate a number of biological pathways implicated in the progression of cancer. These include the prevention of cell signalling, normal cell cycle progression, tumour vascularisation and DNA repair, as well as the ability to induce cellular oxidative stress and cell death.

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Two of the most important early indole-based anticancer agents are vincristine and vinblastine — recognised for their tubulin polymerisation inhibition since the early-mid s, and both still of clinical importance today. The inhibition of tubulin polymerisation is the mechanism of action of vinblastine, which leads to cell cycle arrest, halting cancer cell division 3.

Anti-Cancer Drugs I - Chemistry LibreTexts

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 , which demonstrates just how relevant nitrogen-based heterocycles are for anti-cancer drug design, even to this day. Oxygen-containing heterocycles also feature prominently in many anti-cancer drugs. Among the earliest to be discovered, paclitaxel is a key drug in cancer therapy.

Scientists synthesize anticancer drug in 'landmark discovery'

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 sideeffects 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 heterocyclic anti-cancer drugs include microtubule inhibitors cabazitaxel and eribulin, used to treat prostate and metastatic breast cancer respectively.

Molecular Oncology: Past, Present and Future of Anti-Cancer Drug Design

Cabazitaxel Figure 2 is a tubulin-stabiliser, but is thought to be of particular interest for the treatment of multidrug-resistant tumours owing to its resistance to cellular efflux by the p-glycoprotein efflux pump, expressed by a number of resistance cancer cells 4,5. Cabazitaxel is also able to cross the blood-brain barrier.


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As mentioned, eribulin is used to treat advanced breast cancer, and is not only effective but exhibits a low level of toxicity compared to alternative cytotoxic agents, making it ideal for patients 7. 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 compound 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 cancer 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 associated with novel candidate identification and other research and development activities 8.

Sulfur is a key component in several vitamin cofactors, sugars and nucleic acids, and plays an important role in regulating translation via the sulfuration of transfer RNA. Given the significance of sulfur in biological systems, sulfur-containing heterocycles have received much attention in the development of anti-cancer drugs, much like their oxygen- and nitrogen-based counterparts.

Molecular Aspects of Anticancer Drug-DNA Interactions

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-effects 9. In addition, thiadiazole and thiazole structures have also shown to be of importance for cancer research in recent years; with a number of thiazolebased nitrogen mustard heterocycles having recently 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 for use in patients with cancers associated with the mutated version of the BRAF gene.