Nitrogen Mustards as Alkylating Agents: A Review on Chemistry, Mechanism of Action and Current USFDA Status of Drugs

Abstract

Background & Objective: : Nitrogen mustard derivatives form one of the major classes of anti-cancer agents in USFDA approved drugs list. These are polyfunctional alkylating agents which are distinguished by a unique mechanism of adduct formation with DNA involving cross-linking between guanine N-7 of one strand of DNA with the other. The generated cross-linking is irreversible and leads to cell apoptosis. Hence it is of great interest to explore this class of anticancer alkylating agents. Methods:: An exhaustive list of reviews, research articles, patents, books, patient information leaflets, and orange book is presented and the contents related to nitrogen mustard anti-cancer agents have been reviewed. Attempts are made to present synthesis schemes in a simplified manner. The mechanism of action of the drugs and their side effects are also systematically elaborated. Results:: This review provides a platform for understanding all aspects of such drugs right from synthesis to their mechanism of action and side effects, and lists USFDA approved ANDA players among alkylating anticancer agents in the current market. Conclusion: : Perusing this article, generic scientists will be able to access literature information in this domain easily to gain insight into the nitrogen mustard alkylating agents for further ANDA development. It will help the scientific and research community to continue their pursuit for the design of newer and novel heterocyclic alkylating agents of this class in the coming future.

Hydrogen‐Borrowing Alkylation of 1,2‐Amino Alcohols in the Synthesis of Enantioenriched γ‐Aminobutyric Acids

“…Given the ubiquity of nitrogen‐containing compounds, [7] we envisaged expanding the scope of C−C bond‐forming hydrogen borrowing to 1,2‐amino alcohols. Our decision to use 1,2‐amino alcohols was in part driven by the fact that the classical equivalent of such alcohols in alkylation reactions are highly toxic 1,2‐amino halides [8] . Another attractive facet of 1,2‐amino alcohols was that they may be readily synthesized in enantiopure form from amino acids, allowing us to examine the functional group and stereochemical compatibility of a variety of side chains.…”

“…Our decision to use 1,2-amino alcohols was in part driven by the fact that the classical equivalent of such alcohols in alkylation reactions are highly toxic 1,2-amino halides. [8] Another attractive facet of 1,2-amino alcohols was that they may be readily synthesized in enantiopure form from amino acids, allowing us to examine the functional group and stereochemical compatibility of a variety of side chains. The proposed transformation was to first synthesize protected 1,2amino alcohols from amino acids, optimize a hydrogen borrowing alkylation reaction with Ph* methyl ketone, and remove the Ph* to give 1,4-amino acids, hopefully in enantioenriched form (Scheme 1 B).…”

Preclinical in vitro screening of newly synthesised amidino substituted benzimidazoles and benzothiazoles

“…Nowadays there is still an increasing interest in medicinal and pharmaceutical chemistry for incorporation of benzimidazole/benzothiazole highly-privileged building substructures in order to developed novel heterocycles with possible pharmacological, chemical or industrial applications 7,8 . Suchlike derivatives display a broad spectrum of different biological features such as anticancer, antiviral, antioxidant, antibacterial, antifungal, antihistaminic, anti-inflammatory, etc [9][10][11] . Furthermore, the structural similarity of benzimidazole scaffold with naturally occurring purines is of great importance for studying the role of prepared derivatives in the function of many biologically important molecules like DNA, RNA or different proteins in living organisms 12,13 .…”

Photocontrolled Release of the Anticancer Drug Chlorambucil with Caged Harmonic Nanoparticles

“…Nowadays, the main therapeutic strategies for tumor removal include surgery, chemotherapy and radiotherapy. Since the discovery of nitrogen mustards as potent cytotoxic agents in the 1940’s, several classes of chemotherapeutics were approved by the U. S. Food and Drug Administration (FDA) for cancer treatment, including alkylating agents such as cisplatin, anti‐metabolites such as 5‐fluorouracil, topoisomerase inhibitors such as daunorubicin and signal transduction inhibitors such as gefitinib . Unfortunately, several limitations are associated with conventional chemotherapeutic regimens such as low solubility in physiological medium besides intravenous administration, low efficacy due to poor access to tumor site, off‐target activities resulting in side‐damages to healthy cells and tissues .…”