YSN-ASM Column: One small change

Small molecular alterations – The solution to drug resistance in cancer may lie in small changes to biologically-active synthetic molecules.

I remember the moment like it was yesterday. A final year Chemistry student, meeting her advisor to discuss a project that she did not have much knowledge about. “We are going to create structurally similar compounds that have vastly different anticancer properties” he said. “Imagine the possibilities!” So I pondered and wondered. ‘What if he is right? What if he is wrong? Can we really do this?’ Fast forward to today, with years of research in the chemical synthesis field, I am now confident that this is possible. There are two factors that motivate me in pursuing my research:

  1. We are rapidly losing the war on cancer. Today, the number of people who get cancer in the course of their life has multiplied greatly from what it was merely 20 years ago. There is no specific cure and to add to that, there is an increasing resistance to the current drug regime in cancer treatment.
  2. The possibility of creating tailor-made drugs for the treatment of specific cancers, by merely introducing tiny changes in the molecular structures of the synthesised compounds may render them stronger killing abilities. Or quite the opposite effect may occur – and make them completely inactive. As a synthetic chemist, finding an answer to the reasons behind the selectivity and specificity of the synthesised drugs has been a highly challenging yet exciting journey.

Cancer is a group of about 120 different diseases that can affect any part of the human body. According to WHO (World Health Organisation), cancer alone accounted for 7.6 million deaths (around 13% of all deaths) worldwide in 2008, and this is expected to continue rising, reaching an estimated 13.1 million in 2030. The most common newly diagnosed cancers are lung, breast, colorectal, stomach, prostate and liver cancers. According to Cancer Research Malaysia, around 5,000 Malaysian women are diagnosed with breast cancer every year, most of them aged between 30 and 60 years. According to www.malaysiaoncology.org, bladder cancer is the most common malignancy of the urinary tract and the fourth most common malignancy in males after lung, colorectal and nasopharynx cancers in Malaysia.

Drug resistance in current cancer therapy is a huge problem. Drug resistance is the failure of cancer cells to respond to a drug used to kill them. The cells may be resistant to the drug at the beginning of treatment, or after being exposed to the drug for an extended period of time. Many drugs used in the treatment of cancer have been ineffective due to this reason. As a consequence, many cancers have been untreatable and have a high recurrence rate.

To find a solution to this issue, my research group at the Faculty of Science, Universiti Putra Malaysia is working with small bioactive ligands and their metal complexes. Ligands are ions or molecules that can bond to a metal atom or ion. These ligands can be designed with small variations in structure. For example, one ligand molecule could have an extra chlorine atom or perhaps an extra carbon, oxygen or nitrogen atom in its make-up.

The purpose of this is to synthesise compounds that have similar features to the current medication used in cancer treatment, but yet, are slightly different. At the end, a database of structurally similar molecules can be obtained, and their action against different cancer cells can be investigated. The ligands are then bound to biologically relevant metals like copper and nickel to enhance their anticancer action.

Other biologically significant small molecules can be combined with metals and ligands as well to enhance their biological activity. For example, saccharin, a zero-calorie sweetener has been used as a co-ligand. According to Medicalnewstoday.com in 2015, saccharin can be used as a key ingredient in new drugs for treating aggressive cancers with fewer side effects through its interaction with a protein called carbonic anhydrase. This was in-line with the findings in our research group, where saccharin-derived compounds had remarkably promising activities against breast and bladder cancer cell lines. The mechanism of action of the bioactive ligands and their metal complexes at a cellular level is currently under investigation.

An example of a copper complex containing saccharin (circled).

The synthesis of these ligands and their metal complexes is a relatively cheaper technique as compared to extracting bioactive compounds from plants. The latter often produces low yields, and may be impure as they contain other contaminants that are difficult to separate. In contrast, good yields and the exact structures of the pure, synthesized products can be determined precisely from analytical measurements.

Since our studies have shown that these particular ligands and the metals containing them are selective and specific against different cancer cells, we have now initiated studies to see how these compounds work at a cellular level. Although we are all rather insignificant in the grand scheme of the universe, we fervently believe that small changes CAN make all the difference. With our passionate search for new anticancer compounds, we hope that one day, these synthetic compounds would allow us to win the war on cancer.

References:

  1. http://www.medicalnewstoday.com/articles/291284.php
  2. http://www.sciencedirect.com/science/article/pii/S0277538706001343
  3. http://www.sciencedirect.com/science/article/pii/S0022286017302983

About the author:

Dr Thahira Begum is a senior lecturer at the Department of Chemistry, Faculty of Science, Universiti Putra Malaysia. She is passionate about finding out why certain compounds ‘tick’ and why some do not, in cancer research. She admits she is quite a bookworm but enjoys long conversations and welcomes research collaborations. She can be reached at [email protected].

She also wishes to acknowledge the Fundamental Research Grant Scheme, Science Fund and Geran Putra UPM for providing the research funding.