Carbohydrates, Strange DNA Structures and Anti-Cancer Drugs

Keywords: carbohydrates, medicinal chemistry, drug discovery, DNA, anti-cancer drugs, bonding

Cancer is one of the biggest killers in the developed world. It has been predicted that 1 in 2 people born after 1960 will contract some form of cancer in their lifetime.

Cancer is a disease that is caused by mutations to cells inside your body. Cancer remains such a challenging disease to treat because finding methods to selectively kill cancer cells without also killing healthy cells is very hard. Scientists look at every subtle difference between healthy cells and cancerous cells, to hopefully discover new methods to selectively target cancerous cells. One of the changes makes the cells start growing uncontrollably, with some cancer cells dividing as quickly as once every 24 hours. This is why chemotherapy drugs have to be 100% effective, as if just one cancer cell remains, the tumor can regrow. Many non-selective anti-cancer drugs (like cyclophosphamide and cisplatin, figure. 1) work by targeting DNA, stopping the two strands of your DNA from separating, halting all cell division throughout your body.

Figure 1. Structure of chemotherapy drugs cyclophosphamide and cisplatin.

One area of current cancer research involves targeting unique four stranded DNA structures called G-quadruplexes (figure 2). These guanine (G) rich structures occur in several cancer-causing genes throughout the human genome, as well as in telomeres (chemical part at the ends of genes), where they can stop an enzyme called telomerase from working, which is responsible for immortalizing ~85% of all human cancers. Cancer cells are immortal as, if provided with the correct nutrients, they can live forever.

Figure 2. Structure of a DNA G-quadruplex. They occur in guanine rich DNA, and are stabilised by sodium or potassium ions.

Small molecules are capable of binding to the G-quadruplex, stabilising the structure and leading to rapid death of the cancer cells. Chemists have made a variety of molecules that can do this, but so far none have passed clinical trials. One approach is to use carbohydrates – these are highly bioactive ‘hydrates of carbon’ (figure 3) and exist throughout nature. As carbohydrates are the main source of energy for human cells, they can be taken-up inside cells easily. By attaching cationic groups to carbohydrates such as glucose and mannose, and then linking them together via a polyaromatic core (a part of a molecule that has several rings structures based on benzene), we can develop molecules such as 1 (figure 4). Mannose glycoconjugate 1 is capable of binding to the human telomeric G-quadruplex (figure 5), exhibiting a record selectivity. 1 is however non-toxic to cancer cells, possibly due to hydrolysis of the carbohydrate moieties (part of a large molecule). More work is needed before this type of molecule can become a commercial drug.

A different approach uses a similar compound 2 (figure 4), that lacks carbohydrates. This molecule has potent (nM) anti-cancer activity and is an excellent platform for further development.

Figure 3. Structure of two common carbohydrates, glucose (left) and mannose (right).

Figure 4. Structure of mannose glycoconjugate 1 and amine based compound 2, which lacks a carbohydrate.

Figure 5. Computer generated model of 1 bound to the human telomeric G-quadruplex.

Steven Street is a postgraduate synthetic organic chemist and chemical biologist working with Professor M. Carmen Galan at the University of Bristol. His PhD project involved developing new carbohydrate based small molecules with anti-cancer activity. Steve is a passionate science communicator, with an interest in chemistry outreach.

Carbohydrates, Strange DNA Structures and Anti-Cancer Drugs?

Questions

1. How many carbon atoms does the structure of mannose represent? (1 mark)2. Consider the planar molecule cisplatin. What would transplatin look like? (1 mark)3. What type of bond joins the ammonia molecule to the platinum in cisplatin? Where do the

bonding electrons originate? (2 marks)4. How many carbon atoms are there indicated in the drug cyclophosphamide? (1 mark)5. In the G-Tetrad structure (figure 2 A) what type of bonding, indicted by the dotted lines-

holds the 4 guanine molecules in place? (1 mark)6. Telomerase is an enzyme. What is an enzyme? (1 mark)7. What are the chemical formulae of (a) glucose and (b) mannose? (2 marks)8. Why are sugars such as mannose and glucose soluble in water? (2 marks)

ExtensionWhy do you think that reacting a telomer with a G quadruplex bonding drug will stop telomerase working? (2 marks)

Carbohydrates, Strange DNA Structures and Anti-Cancer Drugs?

Questions1. How many carbon atoms does the structure of mannose represent? (1 mark)

2. Consider the planar molecule cisplatin. What would transplatin look like? (1 mark)

3. What type of bond joins the ammonia molecule to the platinum in cisplatin? Where do the bonding electrons originate? (2 marks)

4. How many carbon atoms are there indicated in the drug cyclophosphamide? (1 mark)

5. In the G-Tetrad structure (figure 2 A) what type of bonding, indicted by the dotted lines- holds the four guanine molecules in place? (1 mark)

6. Telomerase is an enzyme. What is an enzyme? (2 marks)

7. What are the chemical formulae of (a) glucose and (b) mannose? (2 marks)

8. Why are sugars such as mannose and glucose soluble in water? (2 marks)

ExtensionWhy do you think that reacting a telomer with a G quadruplex bonding drug will stop telomerase working? (4 marks)