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

2019 ◽  
Vol 19 (9) ◽  
pp. 1080-1102 ◽  
Author(s):  
Ghansham S. More ◽  
Asha B. Thomas ◽  
Sohan S. Chitlange ◽  
Rabindra K. Nanda ◽  
Rahul L. Gajbhiye
Keyword(s):  
Side Effects ◽  
Mechanism Of Action ◽  
Anticancer Agents ◽  
Nitrogen Mustard ◽  
Alkylating Agents ◽  
Cross Linking ◽  
Nitrogen Mustards ◽  
Information Leaflets ◽  
Anti Cancer ◽  
Approved Drugs

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.

Discovery of steroidal lactam conjugates of POPAM-NH2 with potent anticancer activity

2020 ◽  
Vol 12 (1) ◽  
pp. 19-35 ◽  
Author(s):  
Dimitrios Trafalis ◽  
Panagiotis Dalezis ◽  
Elena Geromichalou ◽  
Sofia Sagredou ◽  
Eleni Sflakidou ◽  
...  
Keyword(s):  
Anticancer Activity ◽  
Anticancer Agents ◽  
Alkylating Agents ◽  
Experimental Models ◽  
The Novel ◽  
Nitrogen Mustards ◽  
Experimental Systems ◽  
High Antitumor Activity

Aim: Steroidal prodrugs of nitrogen mustards such as estramustine and prednimustine have proven effective anticancer agents in clinical use since the 1970s. In this work, we aimed to develop steroidal prodrugs of the novel nitrogen mustard POPAM-NH2. POPAM-NH2 is a melphalan analogue that was coupled with three different steroidal lactams. Methodology: The new conjugates were preclinically tested for anticancer activity against nine human and one rodent cancer experimental models, in vitro and in vivo. Results & conclusion: All the steroidal alkylators showed high antitumor activity, in vitro and in vivo, in the experimental systems tested. Moreover, these hybrid compounds showed by far superior anticancer activity compared with the alkylating agents, melphalan and POPAM-NH2.

scholarly journals Review on Pharmacology of Cisplatin: Clinical Use, Toxicity and Mechanism of Resistance of Cisplatin

2019 ◽  
Vol 12 (1) ◽  
pp. 07-15 ◽  
Author(s):  
Sara A. Aldossary
Keyword(s):  
Drug Resistance ◽  
Side Effects ◽  
Dna Adducts ◽  
Mechanism Of Action ◽  
Germ Cell Tumors ◽  
Resistance Mechanism ◽  
Future Studies ◽  
Anti Cancer ◽  
Chemotherapeutic Treatment ◽  
Dna Reduction

Cisplatin is a chemotherapeutic drug that has been used in the treatment of various types of human cancers such as ovarian, lung, head and neck, testicular and bladder. Cisplatin has demonstrated efficacy against various types of cancers such as germ cell tumors, sarcomas, carcinomas as well as lymphomas. The current study presents a pharmacological review on the drug including its mechanism of action, resistance mechanism, and toxicity as well as its clinical applications. The mechanism of action of cisplatin has been associated with ability to crosslink with the urine bases on the DNA to form DNA adducts, preventing repair of the DNA leading to DNA damage and subsequently induces apoptosis within cancer cells. However, the drug exhibits certain level of resistance including increased repair of the damaged DNA, reduction in the accumulation of the drug intracellular and cytosolic inactivation of cisplatin. The drug is also characterized by various toxic side effects including nausea, nephrotoxicity, Cardiotoxicity, hepatotoxicity and neurotoxicity. Due various side effects as well as drug resistance, other anti-cancer drugs that contain platinum such as carboplatin and oxaliplatin among others have been used in combination with cisplatin in chemotherapeutic treatment of cancer. Strong evidence from research has demonstrated higher efficacy of combination of chemotherapies of cisplatin together with other drugs in overcoming drug resistance and in reducing toxic effects as well. Future studies that explore combinational techniques that target various mechanisms such as reduction in the uptake of cisplatin as well as inflammation could enhance efficacy of cisplatin.

Ursolic and Oleanolic Acids as Potential Anticancer Agents Acting in the Gastrointestinal Tract

2018 ◽  
Vol 16 (1) ◽  
pp. 78-91 ◽  
Author(s):  
Mateusz Pięt ◽  
Roman Paduch
Keyword(s):  
Gastrointestinal Tract ◽  
Side Effects ◽  
Anticancer Agents ◽  
In Vivo Studies ◽  
Pentacyclic Triterpenoids ◽  
Liver Cancers ◽  
Anti Cancer ◽  
Tumorigenic Activity

Background:Cancer is one of the main causes of death worldwide. Contemporary therapies, including chemo- and radiotherapy, are burdened with severe side effects. Thus, there exists an urgent need to develop therapies that would be less devastating to the patient’s body. Such novel approaches can be based on the anti-tumorigenic activity of particular compounds or may involve sensitizing cells to chemotherapy and radiotherapy or reducing the side-effects of regular treatment.Objective:Natural-derived compounds are becoming more and more popular in cancer research. Examples of such substances are Ursolic Acid (UA) and Oleanolic Acid (OA), plant-derived pentacyclic triterpenoids which possess numerous beneficial properties, including anti-tumorigenic activity.Results:In recent years, ursolic and oleanolic acids have been demonstrated to exert a range of anticancer effects on various types of tumors. These compounds inhibit the viability and proliferation of cancer cells, prevent their migration and metastasis and induce their apoptosis. Both in vitro and in vivo studies indicate that UA and OA are promising anti-cancer agents that can prevent carcinogenesis at each step. Furthermore, cancers at all stages are susceptible to the activity of these compounds. </P><P> Neoplasms that are formed in the gastrointestinal tract, i.e. gastric, colorectal, pancreatic, and liver cancers, are among the most common and most lethal malignancies. Their localization in the digestive system, however, facilitates the action of orally-administered (potential) anti-cancer agents, making chemopreventive drugs more accessible.In this paper, the anti-tumorigenic effect of ursolic and oleanolic acids on gastric, colon, pancreatic, and liver cancers, as well as the mechanisms underlying this process, are presented.

scholarly journals ENDOCRINE SIDE-EFFECTS OF ANTI-CANCER DRUGS: mAbs and pituitary dysfunction: clinical evidence and pathogenic hypotheses

2013 ◽  
Vol 169 (6) ◽  
pp. R153-R164 ◽  
Author(s):  
Francesco Torino ◽  
Agnese Barnabei ◽  
Rosa Maria Paragliola ◽  
Paolo Marchetti ◽  
Roberto Salvatori ◽  
...  
Keyword(s):  
Side Effects ◽  
Cancer Patients ◽  
Anticancer Agents ◽  
Cytotoxic T Lymphocyte ◽  
Hormonal Treatment ◽  
Primary Tumors ◽  
Pituitary Dysfunction ◽  
Solid Malignancies ◽  
Anti Cancer ◽  
Life Threatening

mAbs are established targeted therapies for several diseases, including hematological and solid malignancies. These agents have shown a favorable toxicity profile, but, despite their high selectivity, new typical side-effects have emerged. In cancer patients, pituitary dysfunction may be mainly due to brain metastases or primary tumors and to related surgery and radiotherapy. Anticancer agents may induce hypopituitarism in patients cured for childhood cancers. These agents infrequently affect pituitary function in adult cancer patients. Notably, hypophysitis, a previously very rare disease, has emerged as a distinctive side-effect of ipilimumab and tremelimumab, two mAbs inhibiting the cytotoxic T-lymphocyte antigen-4 receptor, being occasionally seen with nivolumab, another immune checkpoint inhibitor. Enhanced antitumor immunity is the suggested mechanism of action of these drugs and autoimmunity the presumptive mechanism of their toxicity. Recently, ipilimumab has been licensed for the treatment of patients affected by metastatic melanoma. With the expanding use of these drugs, hypophysitis will be progressively encountered by oncologists and endocrinologists in clinical practice. The optimal management of this potentially life-threatening adverse event needs a rapid and timely diagnostic and therapeutic intervention. Hypopituitarism caused by these agents is rarely reversible, requiring prolonged or lifelong substitutive hormonal treatment. Further studies are needed to clarify several clinical and pathogenic aspects of this new form of secondary pituitary dysfunction.

scholarly journals Novel selective anticancer agents based on Sn and Au complexes. Mini-review

2020 ◽  
Vol 92 (8) ◽  
pp. 1201-1216
Author(s):  
Elena R. Milaeva ◽  
Dmitry B. Shpakovsky ◽  
Yulia A. Gracheva ◽  
Taisiya A. Antonenko ◽  
Tatyana D. Ksenofontova ◽  
...  
Keyword(s):  
Side Effects ◽  
Anticancer Agents ◽  
Antitumor Agents ◽  
Inorganic Compounds ◽  
Acquired Resistance ◽  
Cytotoxic Action ◽  
Mitochondrial Potential ◽  
Anti Cancer ◽  
Gold Compounds

AbstractCancer is one of the most common causes of death in modern medicine. Molecular design of novel substances with pharmacological activity is one of the goals of medicinal inorganic chemistry. Platinum complexes are widely used in the treatment of cancer, despite high efficacy their use is limited by side effects, as well as primary or acquired resistance. In this regard, the search for novel metal-containing antitumor compounds is underway. Organotins and gold compounds are promising pharmacological agents with anti-cancer properties. The introduction of protective antioxidant fragments into inorganic compounds molecules is a way to reduce the side effects of anti-cancer drugs on healthy cells. 2,6-dialkylphenols belonging to vitamin E (α-tocopherol) mimetics are widely used as antioxidants and stabilizers. The properties of Ph3SnCl (Sn-I), Ph3PAuCl (Au-I) and complexes Ph3SnSR (Sn-II) and Ph3PAuSR (Au-II) based on 2,6-di-tert-butyl-4-mercaptophenol (RSH) as radical scavengers and reducing agents were studied in model reactions. For Sn-II and Au-II the comparative study of cytotoxic action was made and the IC50 values on different cancer cell lines were found to be depended on the nature of metal. In general, Sn(IV) complexes possessed higher cytotoxicity than Au(I) complexes. In order to clarify the mechanism of cytotoxic mode of action the effect of compounds on Fe3+-induced lipid peroxidation, mitochondrial potential and mitochondrial permeability, cell cycle and induction of apoptosis was studied. Organotin compounds can bind tubulin SH-groups and inhibit its polymerization by a dose-dependent mechanism, whereas gold compounds inhibit Thioredoxin reductase (TrxR). In vivo experiments on acute toxicity of Sn-II and Au-II proved their moderate toxic action that opens prospects for the further study as antitumor agents.

Novel mononuclear ruthenium(ii) complexes as potent and low-toxicity antitumour agents: synthesis, characterization, biological evaluation and mechanism of action

RSC Advances ◽  
2016 ◽  
Vol 6 (36) ◽  
pp. 29963-29976 ◽  
Author(s):  
Pengchao Hu ◽  
Ying Wang ◽  
Yan Zhang ◽  
Hui Song ◽  
Fangfang Gao ◽  
...  
Keyword(s):  
Side Effects ◽  
Mechanism Of Action ◽  
Biological Evaluation ◽  
Cancer Drugs ◽  
Antitumour Agents ◽  
Anti Cancer ◽  
Antitumour Agent ◽  
Low Toxicity

The ruthenium(ii) complex, [Ru(dmb)2(salH)]PF6(Ru-2), is considered a potential antitumour agent that could avoid the side-effects of platinum-based anti-cancer drugs, such as cisplatin, carboplatin or oxaliplatin.

scholarly journals Potential of Tithonia diversifolia Hemsley A. Gray (Kembang Bulan) Leaf Extract as Anti-Cancer Agents

2021 ◽  
Vol 10 (2) ◽  
pp. 87-91
Author(s):  
Muflihah Rizkawati
Keyword(s):  
Side Effects ◽  
Anticancer Agents ◽  
Health Benefit ◽  
The Body ◽  
Tithonia Diversifolia ◽  
Lower Side ◽  
Anti Cancer ◽  
Herbal Plants ◽  
Global Concern ◽  
Positive Effect

The main objective of this review is to explain the great potential of herbal plants as anticancer agents. Cancer is a disease caused by abnormal cell growth in the body. The high number of cancer incidents still become a global concern because of the high mortality rate. The treatments of cancer such as chemotherapy can cause serious side effects by killing the normal cells. This is the reason why it is necessary to develop an alternative treatment of cancer. I discussed a plant that is believed to has health benefit. Many studies have showed the positive effect of Tithonia diversifolia plant for health. After 2000, the researchers discovered a new potential through its cytotoxicity to neoplastic cells. This plant needs to be developed sustainably. However, in the future this plant might become an effective alternative to treat cancer with lower side effects.

Nitrogen Mustards as Anticancer Chemotherapies: Historic Perspective, Current Developments and Future Trends

2019 ◽  
Vol 19 (9) ◽  
pp. 691-712 ◽  
Author(s):  
Benjamin Diethelm-Varela ◽  
Yong Ai ◽  
Dongdong Liang ◽  
Fengtian Xue
Keyword(s):  
Historical Development ◽  
Nitrogen Mustard ◽  
Alkylating Agents ◽  
Future Trends ◽  
Rational Structure ◽  
Nitrogen Mustards ◽  
The Subject ◽  
Active Research ◽  
Therapeutic Profile ◽  
Intense Research

Nitrogen mustards, a family of DNA alkylating agents, marked the start of cancer pharmacotherapy. While traditionally characterized by their dose-limiting toxic effects, nitrogen mustards have been the subject of intense research efforts, which have led to safer and more effective agents. Even though the alkylating prodrug mustards were first developed decades ago, active research on ways to improve their selectivity and cytotoxic efficacy is a currently active topic of research. This review addresses the historical development of the nitrogen mustards, outlining their mechanism of action, and discussing the improvements on their therapeutic profile made through rational structure modifications. A special emphasis is made on discussing the nitrogen mustard prodrug category, with Cyclophosphamide (CPA) serving as the main highlight. Selected insights on the latest developments on nitrogen mustards are then provided, limiting such information to agents that preserve the original nitrogen mustard mechanism as their primary mode of action. Additionally, future trends that might follow in the quest to optimize these invaluable chemotherapeutic medications are succinctly suggested.

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