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Therapeutic journery of nitrogen mustard as alkylating anticancer agents: Historic to future perspectives
Rajesh K Singh1, Sahil Kumar2, D N Prasad1
1Department of Pharmaceutical Chemistry, Shivalik College of Pharmacy, Nangal, Dist. Rupnagar, 140126, Punjab, India.
Abstract:
Cancer is considered as one of the most serious health problems today. The discovery of nitrogen mustard as an alkylating agent in 1942, opened a new era in the cancer chemotherapy. This valuable class of alkylating agent exerts its biological activity by binding to DNA, cross linking two strands, preventing DNA replication and ultimate cell death. At the molecular level, nitrogen lone pairs of nitrogen mustard generate a strained intermediate "aziridinium ion" which is very reactive towards DNA of tumor cell as well as normal cell resulting in various adverse side effects alogwith therapeutic implications. Over the last 75 years, due to its high reactivity and peripheral cytotoxicity, numerous modifications have been made in the area of nitrogen mustard to improve its efficacy as well as enhancing drug delivery specifically to tumor cells. This review mainly discusses the medicinal chemistry aspects in the development of various classes of nitrogen mustards (mechlorethamine, chlorambucil, melphalan, cyclophosphamide and steroidal based nitrogen mustards). The literature collection includes the historical and the latest developments in these areas. This comprehensive review also attempted to showcase the recent progress in the targeted delivery of nitrogen mustards that includes DNA directed nitrogen mustards, antibody directed enzyme prodrug therapy (ADEPT), gene directed enzyme prodrug therapy (GDEPT), nitrogen mustard activated by glutathione transferase, peptide based nitrogen mustards and CNS targeted nitrogen mustards.
Insights
Nitrogen mustards are crucial chemotherapy agents that damage cancer cell DNA. Research focuses on modifying these alkylating agents to improve efficacy and target tumors, minimizing side effects.
Area of Science:
- Medicinal Chemistry
- Oncology
- Pharmacology
Background:
- Nitrogen mustards, discovered in 1942, revolutionized cancer chemotherapy as alkylating agents.
- Their mechanism involves DNA binding and cross-linking, leading to cancer cell death.
- High reactivity and cytotoxicity necessitate modifications for improved therapeutic outcomes.
Purpose of the Study:
- To review medicinal chemistry advancements in nitrogen mustard development.
- To explore historical and recent progress in nitrogen mustard drug design.
- To highlight novel targeted delivery strategies for enhanced efficacy.
Main Methods:
- Literature review focusing on medicinal chemistry aspects.
- Analysis of historical and contemporary developments in nitrogen mustard research.
- Compilation of data on various nitrogen mustard classes and targeted delivery systems.
Main Results:
- Discussion of key nitrogen mustard classes: mechlorethamine, chlorambucil, melphalan, cyclophosphamide, and steroidal derivatives.
- Overview of 75 years of modifications aimed at improving efficacy and reducing side effects.
- Presentation of recent targeted delivery approaches including ADEPT, GDEPT, and others.
Conclusions:
- Nitrogen mustards remain vital in cancer treatment, with ongoing research focused on optimizing their use.
- Medicinal chemistry has significantly advanced nitrogen mustard design and application.
- Targeted delivery strategies show promise for increasing therapeutic index and patient outcomes.
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