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Monday Article #70: The BIG killer - Cancer and Alkylating agents

Figure 1: The formation of tumor cells

As a disease with the leading cause of deaths worldwide, cancer remains one of the most deadliest diseases feared by mankind. According to the World Health Organization (WHO), cancer accounts for nearly 10 million deaths in 2020, nearly one in six deaths [1]. Viruses have been proven to implicate cancer, leading to 15% of the world’s cancer deaths. For instance, sexually transmitted Human papillomaviruses cause cervical cancer and Burkitt's lymphoma and nasopharyngeal carcinoma is caused by Epstein–Barr virus [2].

Immortality and sustained telomeres: Cancer cells are infamous for being immortal since they have no limitations to the number of times they divide. For a normal cell, their lifespan is determined by the number of times of DNA replication, which is about 50-60 cell divisions. Undoubtedly, telomeres are involved in the immortality of cancer cells. Telomeres prevent the degradation of DNA and protect the loss of genes during DNA replication as DNA polymerase cannot completely replicate the chromosomal DNA. About 50-100 base pairs are lost from the telomere after each DNA replication and eventually, the telomere becomes too short and is no longer effective. Then, the DNA becomes unstable, unravels and apoptosis occurs. The length of telomeres are maintained with nucleotides added to the end of the DNA by the enzyme telomerase. Initially, the gene encoding the telomerase should be suppressed after birth but cancer cells are capable of removing the said suppression [2]. The mechanism behind alkylating agents: The discovery of bis(2-chloroethyl) sulfide, a mustard gas initially designed as a toxicant and vesicant for war, exhibiting therapeutic potential on leukemia initiated a new era and hope on cancer treatment. However, due to its toxicity, it could not be used as an antitumor drug, therefore, nitrogen mustard derivatives were developed as alkylating agents [3].

Figure 2: The origin of nitrogen mustards

Alkylating agents are highly electrophilic compounds and react with nucleophilic groups on DNA to form strong covalent bonds. Having two alkylating groups, the drugs are able to cause cross linking to disrupt DNA replication or transcription. Even though they have poor selectivity as they also alkylate nucleophilic groups on proteins, they have been proven effective in the treatment of cancer. As tumor cells often divide more rapidly than normal cells, they would be affected by the action of alkylating agents more drastically than normal cells. Unfortunately, due to the ability of damaging DNA in normal, healthy cells, these alkylating agents possess carcinogenic and mutagenic effects [2]. Chlorethamine, a form of nitrogen mustard, was first used clinically as modern medicine in 1942 after it was proven effective in treating lymphomas. It is capable of cross linking guanine groups on DNA. Being highly reactive with water, blood and tissues, it must be administered intravenously instead of the oral route. Less reactive derivatives have been made, such as melphalan. To reduce the reactivity of the alkylating agent, a benzene ring is incorporated so nitrogen’s lone pair interacts with its pi system and becomes less available to displace the chloride ions. Therefore, the formation of intermediate aziridinium ions is reduced and only strong nucleophiles such as guanine can react with it. Moreover, melphalan has an added advantage of moiety in which it mimics the amino acid phenylalanine. Hence, it is more likely to be taken into cells by transport proteins as it is recognized as an amino acid. With an increased stability, it also means that the drug can now be given orally [2 & 4]. The solution to its poor selectivity? Uracil mustard has been developed in an attempt to solve the poor selectivity in alkylating agents. With a nucleic acid building block attached to the alkylating group, a certain amount of selectivity for tumor cells over normal cells will be displayed. Tumor cells require more nucleic acid building blocks as they have greater rate of nucleic acid synthesis to keep up with the rapid division. Therefore, tumor cells scavenge more than their fair share of building blocks. Unfortunately, a high level of selectivity desired for effective eradication and prevention of damaging the DNA of other cells cannot be achieved with this approach [2].

Alkylating agents in cancer chemotherapy: Cyclophosphamide, a prodrug commonly used in cancer chemotherapy, is activated by metabolic and non metabolic processes to become an active drug in the body. In the liver, the ring in the compound is oxidized by the enzyme cytochrome P450 enzymes. The ring is then opened to produce phosphoramide and acrolein from hydrolysis to generate the cytotoxic alkylating agent. Due to the presence of lone pair atoms in the phosphoramide groups the nucleophilicity of the nitrogen is then enhanced, making it more reactive and selective for stronger nucleophiles such as guanine. Despite being non toxic itself, the acrolein released is proven toxic to the kidneys and bladder as it alkylates cysteine residues in cell proteins [2 & 4].

Figure 3: Skeletal structures of Cyclophosphamide and Phosphoramide mustard

Conclusion: While nitrogen mustard had a horrific history as a chemical weapon, its alkylating properties makes it valuable tools in treating cancer. Although it is toxic, its derivatives can be used and dosages can be controlled to mitigate its toxicity. Certainly, the long term challenge and goal is to balance the medicinal benefits of these alkylating agents while minimizing the harm to healthy cells.

Reference(s): [1] World Health Organization. (3 February 2022). Cancer Retrieved from:

[2] Graham L Patrick. (2013). An introduction to medicinal chemistry. 5th ed. Oxford: Oxford University Press [3] Frontiers in pharmacology. (December 17, 2018). Therapeutic Potential of Nitrogen Mustard Based Hybrid Molecules Retrieved from: [4] Pharmafactz. (November 18, 2020). Medicinal Chemistry of Anticancer Drugs. Retrieved from:


This article was prepared by Ang Kai Yue


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