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Nucleic Acids as Therapeutic Targets and Agents
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
Procarbazine is most often used in Hodgkin’s disease, for example, in “MOPP” combination therapy, which includes Mustine (chlormethine), OncovinTM (vincristine), Procarbazine, and Prednisolone. It is administered orally in capsule form, and its toxic effects include nausea, myelosuppression, and a hypersensitivity rash that precludes further use. The mild monoamine-oxidase inhibitory effect of procarbazine does not require any dietary restrictions, although alcohol may cause a disulfiram-like reaction.
The Fight Against Cancer
Published in Nathan Keighley, Miraculous Medicines and the Chemistry of Drug Design, 2020
The first alkylating agent to be used medicinally was chlormethine, in 1942. Its mechanism of action, shown in Figure 5.1, involves displacement of a chloride ion via intramolecular nucleophilic substitution to produce a highly electrophilic aziridium ion. Alkylation of DNA can then occur when the nucleophilic N-7 of guanine attacks the β-carbon of the electrophile. This process is repeated with the other strand of DNA to cause cross-linking, halt DNA replication, and thus serve as an anti-cancer agent.
Organoboronic acids/esters as effective drug and prodrug candidates in cancer treatments: challenge and hope
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2023
Mothana K. Al-Omari, Mai Elaarag, Raed M. Al-Zoubi, Ahmad R. Al-Qudimat, Ayman A. Zarour, Enas A. Al-Hurani, Zainab E. Fares, Leena M. Alkharraz, Mohanad Shkoor, Abdulilah D. Bani-Yaseen, Omar M. Aboumarzouk, Aksam Yassin, Abdulla A. Al-Ansari
The use of boron intake has an inverse relation with lung cancer in women. Although the mechanism is still unclear, it has a role in regulating the levels of oestradiol and testosterone hormone levels in women124. Boronate chlormethine 28 (Figure 3) was synthesised as a nitrogen mustard prodrug by Kuang and co-workers89. It was found to inhibit cancer cell lines at 10 μM concentrations. It inhibited 90% of SR cancer cell lines in leukaemia and 85% NCI-H460 of cancer cell lines in NSCLC. The mechanism of action is investigated and found that 28 get activated first through the high level of reactive oxygen species (ROS) located in the cancer cell or by hydrogen peroxide (H2O2). The boron group gets hydrolysed and leads to form aziridinium ring in a few steps, which is linked to forming alkylating DNA16,18,89. Boronate chlormethine 28 has been investigated in preclinical studies, but there is limited data on its safety and efficacy in humans. Some potential side effects of boronate chlormethine may include myelosuppression, which may result in a decrease in white blood cells, red blood cells, or platelets. Other potential side effects may include gastrointestinal disturbances such as nausea, vomiting, diarrhoea, or constipation, as well as skin reactions16,18,89.
Real-life experience with chlormethine gel for early-stage mycosis fungoides with emphasis on types and management of cutaneous side-effects#
Published in Journal of Dermatological Treatment, 2022
Hadas Prag Naveh, Iris Amitay-Laish, Omri Zidan, Yael A. Leshem, Shany Sherman, Yehonatan Noyman, Joseph Taieb, Elena Didkovsky, Emmilia Hodak
Topical chlormethine (mechlorethamine, nitrogen mustard), an alkylating agent with a cytotoxic effect, has been used since the 1950s for the treatment of mycosis fungoides (MF), with proven efficacy mainly in early-stage disease (1–9). However, until several years ago, it was available only as a compounded product, either aqueous chlormethine or a petrolatum-based ointment (1–9), which had limited stability and lacked quality assurance. In 2013, a novel chlormethine gel (CG) received US Food and Drug Administration approval (brand name Valchlor®) for use in the treatment of patients with early-stage (IA, IB) MF who have received one or more skin-targeted therapies. Several years later, it was approved also in Israel for the treatment of early- stage MF (IA, IB), while the European Medicines Agency extended the approval of CG (brand name Ledaga®) for any stage of MF. All major guidelines currently recommend the use of topical chlormethine for treatment of adult MF patients (10–12). Approval was based on the results of a pivotal phase 2 study, demonstrating a noninferior overall response rate (ORR) of once-daily application of CG 0.02% monotherapy compared to equal-strength chlormethine ointment, in patients with early-stage MF (I–IIA) (13). In each arm, treatment was associated with high rates of cutaneous side effects and 17–20% of patients withdrew, mainly due to contact dermatitis.
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).