DNA Alkylator/Crosslinker

DNA Alkylator/Crosslinker

Alkylation of DNA is used in chemotherapy to damage the DNA of cancer cells. Alkylation is accomplished with the class of drugs called alkylating antineoplastic agents. crosslinking of DNA occurs when various exogenous or endogenous agents react with two different positions in the DNA. This can either occur in the same strand (intrastrand crosslink) or in the opposite strands of the DNA (interstrand crosslink). Crosslinks also occur between DNA and protein. DNA replication is blocked by crosslinks, which causes replication arrest and cell death if the crosslink is not repaired.

An Overview of DNA Alkylator/Crosslinker

Alkylation of DNA is a method used in chemotherapy to destroy the DNA of cancer cells for anti-tumor purpose. The drugs used for alkylation of DNA are named as alkylating antineoplastic agents, also as DNA Alkylator or crosslinker. Alkylating antineoplastic agents can be used as a cytotoxic drug. Its alkylating group can be alkylated with important biologically active groups in the cell, such as amino, sulfhydryl, and hydroxyl groups, so that it cannot function in cellular metabolism and eventually cause cancer cells to die. This can occur in the same chain (cross-linking in the chain) or in the opposite strand of DNA (cross-linking between chains). Besides, there is also a cross-linking between DNA and protein. Crosslinking blocks DNA replication. If the crosslink is not repaired, it can lead to replication stagnation and cell death.

Major types of DNA Alkylator/Crosslinker

DNA Alkylator is one of the anti-tumor drugs used in clinical treatment. According to their chemical structures, DNA Alkylator can be divided into nitrogen mustard (Chlormethine Hydrochloride), ethyleneimine (Thiotepa), sulfonate and polyol (Busulfan), nitrosourea (Carmustine), triazene imidazole (Dacarbazine) and anthraquinone (Procarbazine Hydrochloride).

The Inhibition of DNA Alkylator/Crosslinker

DNA Alkylator is the earliest cytogenetic drug, which has the characteristics of broad-spectrum and strong anti-tumor activity, and shows a good application value in clinical trials. DNA Alkylator is the main drug used to treat malignant tumors. It kills tumor cells by destroying DNA and inducing apoptosis. Chloroethyl nitrosourea alkylating agents are highly lipophilic and easily penetrate the blood-brain barrier. Therefore, they are considered to be effective chemotherapeutic drugs for the treatment of malignant tumors such as glioma, leukemia and glioma.

DNA Alkylator/Crosslinker and Diseases

The main reaction sites of alkylator with DNA bases are N3, O6, N7 of guanine, N1, N3, N7 of adenine, O2, O4, N3 of thymine/uracil and O2, N3 of cytosine. They form alkylated guanine (N3-alkylguanines, N7-alkylguanines, O6-alkylguanines), alkylated adenines (N1-alkyladenines, N3-alkyladenines, N7-alkyladenines), alkylated thymine (O2-alkylthymines, O4-alkylthymines, N3-alkylthymines) and alkylated cytosine (O2-alkylcytosines, N3-alkylcytosines). These alkylated bases can alter the genetic information carried by the gene during DNA replication, which may be the cause of the disease.


Singh, R. K., Kumar, S., Prasad, D. N., Bhardwaj, T., R. (2018) Therapeutic journery of nitrogen mustard as alkylating anticancer agents: Historic to future perspectives. European Journal of Medicinal Chemistry. 151: 401-433.

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