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Overview and Current Status of Cancer
Published in Franklyn De Silva, Jane Alcorn, The Elusive Road Towards Effective Cancer Prevention and Treatment, 2023
Franklyn De Silva, Jane Alcorn
Today, cytotoxic chemotherapeutic agents remain the cornerstone of anticancer drug use. Nitrogen mustard derivatives were one of the first chemotherapies, and despite their severe toxicity, these agents were used for decades as effective treatments of malignant lymphoma [65]. At present, their application is limited owing to poor selectivity and severe adverse reactions [65], a limitation suffered by other traditional chemical treatments of cancer [66, 67]. Their unavoidable toxic side effects result from the inability of conventional chemotherapies to distinguish rapidly dividing cancer cells from rapidly dividing normal cells. For many chemotherapeutic agents, tumor responses are sometimes partial, brief, and unpredictable [68]. Consequently, cytotoxic chemotherapies are generally inadequate in addressing the increasing incidence of cancer worldwide.
Cancer Biology and Genetics for Non-Biologists
Published in Trevor F. Cox, Medical Statistics for Cancer Studies, 2022
Chemotherapy has its roots in World Wars I and II, when mustard gas was used as a weapon. It was noticed that those not killed had immune cells destroyed by the gas. That lead to a nitrogen mustard as the first chemotherapy agent that could kill tumour cells. Since then more and more chemotherapy drugs have been discovered, and now over 100 are in current use. The drugs kill cancer cells that are dividing, but at the same time, they also kill normal cells. However, as cancer cells divide much more often than normal cells, more cancer cells than normal cells are destroyed. It is a balance between too little of the drug, and the cancer is not treated enough, or too much of the drug that will kill the cancer completely, but also the patient.
Nucleic Acids as Therapeutic Targets and Agents
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
In addition to MDR-related resistance, the activity of nitrogen mustards can be significantly reduced by tumor cells elevating their levels of glutathione. The highly nucleophilic glutathione forms adducts with nitrogen mustards, causing them to become non-electrophilic and unable to react with DNA. Alternatively, some cancer cells become resistant to nitrogen mustards by carrying out repair processes through which the mustard adducts are excised, and DNA from the damaged areas resynthesized. To minimize this type of resistance, one approach is to co-administer DNA-repair inhibitors; however, this has not proved to be an effective strategy in the clinic.
Design and synthesis of chromone-nitrogen mustard derivatives and evaluation of anti-breast cancer activity
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2022
Jianan Sun, Jiahui Mu, Shenglin Wang, Cai Jia, Dahong Li, Huiming Hua, Hao Cao
Nitrogen mustards, a class of DNA alkylating agents, mark the beginning of modern cancer chemotherapy and have been developed into many therapeutic compounds with broad antitumor activity42,43. They exert their cytotoxic effects through the formation of DNA interstrand cross-links44,45 and have been widely used in the treatment of various blood cancers and solid tumours46,47. In addition, nitrogen mustards are representative of dichloroethylamine alkylating agents. Aliphatic nitrogen mustard has the characteristics of sufficient therapeutic index but high reactivity and peripheral cytotoxicity. In contrast, aromatic nitrogen mustard is less electrophilic with low reactivity and can be administered orally. Nevertheless, this kind of nitrogen mustard derivatives still causes severe side effects and acquired drug resistance due to non-specific affinity to cancer cells46,48,49. To solve these problems, linking aromatic nitrogen mustards to natural products is a good way to reduce the side effects and improve activities, such as E and F (Figure 1)50,51. Thus, we designed and synthesised a series of chromone-nitrogen mustard derivatives, and evaluated their antiproliferative activities as well as further mechanisms on breast cancer cells in order to obtain candidate compounds with stronger antitumor activities and lower side effects.
A review on synthetic chalcone derivatives as tubulin polymerisation inhibitors
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2022
Wenjing Liu, Min He, Yongjun Li, Zhiyun Peng, Guangcheng Wang
Nitrogen mustard is one of the earliest antitumor drugs used clinically. As a representative of bioalkylation agents, nitrogen mustard can stably bind to affinity groups after entering the body, affect cell metabolism and promote cell apoptosis116,117. Based on molecular hybridisation strategy118, Sabina and co-workers synthesised a novel range of p-[N, N-bis(2-chloroethyl)amino]benzaldehyde substituted chalcone conjugates 65 (Figure 42) and evaluated for their inhibitory activity against A549 and HepG2 cancer cells119. Compound 65a displayed more activity in both the cancer cell lines and tubulin than the other substances (IC50 in the range of 0.089 to 0.200 µM). Docking results showed that the synergistic effect of nitrogen mustard made compound 65a bind tightly to tubulin. Besides, SAR analysis showed that the compounds with methyl or nitro groups in the A ring were more active. Interestingly, dimethoxy substituents at the 2 and 4 sites of the A ring showed the highest activity against A549, while the lowest activity against HepG2.
Have molecular hybrids delivered effective anti-cancer treatments and what should future drug discovery focus on?
Published in Expert Opinion on Drug Discovery, 2021
The use of nitrogen mustards in cancer chemotherapy, as a class of DNA-cross linking or alkylating agent, has a history of over 80 years after the recognition of its efficiency in treating malignant lymphoma [12,13]. Some nitrogen mustards, including Chlormethine (or Mechlorethamine), Cyclophosphamide, Chlorambucil, and Melphalan, once remained first line antitumor agents. However, severe side effects along with low potency and drug resistance caused by their reduced cellular uptake, augmented DNA repair, and endurance to DNA damage have impeded the further development of these derivatives [14–16]. The hybridization of nitrogen mustards [17] with various pharmacophores is considered as an efficient approach for: (i) recuperating their own activity, physicochemical properties while minimizing side-effects (ii) significantly optimize the potency and safety profile of other lead compounds (synthetic or natural molecules).