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Anti-Cancer Agents in Medicinal Chemistry

Editor-in-Chief

ISSN (Print): 1871-5206
ISSN (Online): 1875-5992

Review Article

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

Author(s): Ghansham S. More*, Asha B. Thomas, Sohan S. Chitlange, Rabindra K. Nanda and Rahul L. Gajbhiye

Volume 19, Issue 9, 2019

Page: [1080 - 1102] Pages: 23

DOI: 10.2174/1871520619666190305141458

Price: $65

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.

Keywords: Alkylating agents, nitrogen mustard compounds, cross-linking reagents, bendamustine hydrochloride, USFDA, anti-cancer agents.

Graphical Abstract
[1]
Wheeler, G.P. Studies related to the mechanism of action of cytotoxic alkylating agents: A review. Cancer Res., 1962, 22(6), 651-688.
[2]
Edward, C.; Edelson, R. Yale cancer center: Past, present, and future. Yale J. Biol. Med., 2006, 79(3-4), 199-200.
[3]
Weber, G.F. DNA-damaging drugs, WeberEd. Springer International Publishing Switzerland, 2015, Vol. 2,, 2-18.
[4]
Scholar, E. Alkylating agents. Biomed. Sci., 2007, 1-4.
[5]
Gilman, A. The initial clinical trial of nitrogen mustard. Am. J. Surg., 1963, 105(5), 574-578.
[6]
Kater, A.P. Efficacy and safety of first-line therapy with Chlorambucil, Rituximab, and Lenalidomide (Revlimid®) (CR2) in elderly patients and youngfrail patients with advanced Chronic Lymphocytic Leukemia (CLL): A phase I/II trial. Hoven109 CLL, 2014, 6, 1-79.
[7]
Francesco, P.; Fermo, S.L. Lights and shadows of cyclophosphamide in the treatment of multiple sclerosis. Autoimmune Dis., 2011.961702
[8]
Brayfield, A. Cyclophosphamide: Martindale: The Complete Drug Reference, Medicines Complete Ed.;UK Pharmaceutical Press: London, 2017.
[9]
Devrieze, B.W.; Hurley, J.A. Goodpasture Syndrome (Antiglomerular Basement Membrane Antibody Disease); Ed. Statpearls Publishing LLC: Treasure Island, USA . , 2018.
[10]
Facon, T.; Mary, J.Y.; Hulin, C. Melphalan and prednisone plus thalidomide versus melphalan and prednisone alone or reduced-intensity autologous stem cell transplantation in elderly patients with multiple myeloma (IFM 99-06): A randomised trial. Lancet, 2007, 370(9594), 1209-1218.
[11]
Zalupski, M.; Baker, L.H. Ifosfamide. J. Natl. Cancer Inst., 1988, 80(8), 556-566.
[12]
Plosker, G.L.; Carter, N.J. Bendamustine: A review of its use in the management of indolent Non-Hodgkin lymphoma. Drugs, 2008, 68(18), 2645-2660.
[13]
Cancer statistics, 2018. CA Cancer J. Clin., 2018, 68(1), 7-30.
[15]
Vardanyan, R.; Hruby, V. Antineoplastics, Victor J. Hruby Ed.. Elsevier: Amsterdam,, 2006; pp. 389-418.
[16]
Sriram, D.; Yogeeswari., P. Anticancer Agents; Thomas Mathew, Ed. Pearson Education V: India,. , 2010, pp. 557-584.
[17]
National Library of Medicine. Medline Plus. Drugs, herbs, and supplements: Mechlorethamine.. medlineplus.gov/druginfo/meds/a682223.html (Accessed Aug 25,2018).
[18]
Bunn, P.A.; Hoffman, S.J.; Norris, D.; Golitz, L.E.; Aeling, J.L. Systemic therapy of cutaneous T-cell lymphomas (mycosis fungoides and the Sezary syndrome). Ann. Intern. Med., 1994, 121(8), 592-602.
[19]
Huazhong, J.Q.S.L. A synthetic process of antineoplastic agents chlorambucil butyrate. Chinese Patent CN104447376B, , Nov 05 . 2014.
[20]
Walter, C.J.R.; Everett, J.L.; Roberts, J.J.N. N-Dichloroethylaminobutyrates and preparation thereof. U.S. Patent 2944079 , July 05. 1960.
[21]
Phillips, A.P. Tuckahoe; Mentha, J.W.; Hartsdale.; Method of making Chlorambucil. U. Patent 3046301,, July 24 . 1962.
[22]
National Cancer Institute. About Cancer., Cancer Treatment Chlorambucil.Cancer.gov/about-cancer/treatment/drugs/chlorambucil (Accessed Aug 25, 2018).
[23]
Nedaa, I.; Sonnenburga, R.; Schmutzler, R.; Niemeyerb, U.; Kutscher, B.; Engel, J.; Kleemann, A. A new method for the preparation of ifosfamide and cyclophosphamide. J. Nat. Res., 1997, 52, 943-946.
[24]
Anon., Drugs of choice for cancer. Med. Lett., 2003, 1, 41-52.
[25]
National Cancer Institute. About cancer. Cancer treatment cyclophosphamide. cancer.gov/about-cancer/treatment/drugs/cyclophosphamide (Accessed Aug 25, 2018).
[26]
Gurjar, M.K.; Tripathy, N.K.; Kotharkar, S.A.; Patil, P.N.; Mehta, S.S. Process for the preparation of melphalan hydrochloride. U.S. Patent 0116117 A1, May 10, . 2012.
[27]
Ashnagar, A.; Gharib Naseri, N.; Darakhshanmehr, M. Synthesis and elucidation of 4-bis(2-Chloroethyl)-amino-L-phenylalanine. Asian J. Chem., 2007, 19(7), 5399-5406.
[28]
Niemeyer, U.; Niege, H.; Kutscher, B.; Neda, I. Process for the preparation of Oxaphosphorine-2-amines. U.S. Patent 0047103 A1, Nov 29. 2001.
[29]
Pankiewicz, K.; Kinas, R.; Stec, W.J.; Foster, A.B.; Jarman, M.; Van Maanen, J.M.S. Synthesis and absolute configuration assignments of enantiomeric forms of ifosphamide, sulfosphamide, and trofosphamide. J. Am. Chem. Soc., 1979, 101(26), 7712-7718.
[30]
Schickaneder, H. Eckental.; Schickaneder, C.; Lauf, A.D.; Pegnitz; Limmert, M. Dresden.; Process for the preparation of bendamustine hydrochloride and related compounds. U.S. Patent 2013/0184471 A1, Jul 18. 2013.
[31]
Mishra, B.B.; Shambhubha, N.; Kachhadia, ; Tomar, V.S.; Lahiri, S. Process for the preparation of bendamustine hydrochloride. U.S. Patent 2014/0121383 A1, May 1 . 2014.
[32]
Ozegowski, W.; Krebs, D. Aminosäureantagonisten. III. ω-[Bis-(β-chloräthyl)-amino-benzimidazolyl-(2)]-propion- bzw.-buttersäurenalspotentielle Cytostatika. J. Prakt. Chem., 1963, 20, 178-186.
[33]
Madkou, L.H. Biotechnology of nucleic acids medicines as gene therapeutics and their drug complexes. Chron. Pharma Sci, 2017, 1(4), 204-253.
[34]
Trituration of Mustargen, Merck & Co., Whitehouse Station, NJ 08889, USA, 741793X..
[35]
Bruce, A. Chabner, Bertino, J.; Cleary, J.; Ortiz, T.; Lane, A.; Supko, J.G.; Ryan, D. Cytotoxic compounds; Alkylating Agents and Platinum co-ordination complexes; Goodman & Gilman’s The Pharmacological Basis of Therapeutics; Ed. The McGraw-Hill Companies, Inc., 2011, pp. 1677-1678.
[36]
Beglleiter, A.; Mowat, M.; Israels, L.G.; Johnston, J.B. Chlorambucil in chronic lymphocytic leukemia: Mechanism of action. Leuk. Lymphoma, 1996, 23(3-4), 187-201.
[37]
Accessdata FDA, LEUKERAN Chlorambucil Tablet Prescribing Information, Reference ID 3036543, GlaxoSmithKline, Research Triangle Park, NC 27709..
[38]
Chighizola, C.; Ong, V.H.; Denton, C.P. Cyclophosphamide as disease-modifying therapy for scleroderma. Int. J. Clin. Rheumatol., 2011, 6(2), 219-230.
[39]
Tilby, M.J.; Hall, A.G. Mechanisms of action of, and modes of resistance to, alkylating agents used in the treatment of haematological malignancies. Blood Rev., 1992, 6(3), 163-173.
[40]
Emadi, A.; Jones, R.J.; Brodsky, R.A. Cyclophosphamide and cancer: Golden anniversary. Nat. Rev. Clin. Oncol., 2009, 6, 638-647.
[41]
Osborne, M.R.; Lawley, P.D.; Crofton-sleigh, C.; Warren, W. Products from alkylation of DNA in cells by melphalan: Human soft tissue sarcoma cell line RD and Escherichia coli WP2. Chem. Biol. Interact., 1995, 97(3), 287-296.
[42]
Povirk, L.F.; Shuker, D.E. DNA damage and mutagenesis induced by nitrogen mustards. Mutat. Res., 1994, 318(3), 205-226.
[43]
Highlights of prescribing information, EVOMELA; 2016.Reference ID 3900023, Spectrum Pharmace.uticals, Ins., Irvine, CA 92618.
[44]
Furlanut, M.; Franceschi, L. Pharmacology of ifosfamide. Oncology, 2003, 65(2), 2-6.
[45]
Ifosfamide, injection solution; Highlights of prescribing Information,; 2015.Teva Pharmaceuticals USA, Inc., North Wales, PA 19454..
[46]
Struck, R.F.; Dykes, D.J.; Corbett, T.H.; Suling, W.J.; Trader, M.W. Isophosphoramide mustard, a metabolite of ifosfamide with activity against murine tumors comparable to Cyclophosphamide. Br. J. Cancer., 1983, 47, 015-026.
[47]
Accessdata, F.D.A. TREANDA Bendamustine hydrochloride for injection, for intravenous infusion, Highlights of Prescribing Information; , 2008. Cephalon Inc., Frazer, PA 19355.
[48]
Hartley, J.A. Alkylating agents. Oxford textbook of oncology.Ed. Oxford University Press, 2001, pp. 639-654.
[49]
Lorenzo, M. Leoni. Bendamustine: Rescue of an effective antineoplastic agent from the mid-twentieth century. Semin. Hematol., 2011, 48(1), S4-S11.
[50]
Cheson, B.D.; Leoni, L. Bendamustine: Mechanism of action and clinical data. Clin. Adv. Hematol. Oncol., 2011, 9(8), 19.
[51]
Arnau, M.; Eriong, L.; Jocabed, R.; Jiménez, L.; Cabezas, S.; Clot, G.; Pinyol, M.; Torrent, X.V.; Rosich, L.; Nardi, C.; Aymerich, M.; Villamor, N.; Guillermo, A.; Galan, P.; Roue, G.; Anglada, M.P.; Campo, E.; Guerra, L.; Colomer, D. CD69 expression potentially predicts response to bendamustine and its modulation by ibrutinib or idelalisib enhances cytotoxic effect in chronic lymphocytic leukemia. Oncotarget, 2016, 7(5), 5507-5520.
[52]
Kalaycio, M. Clinical experience with Bendamustine: A new treatment for patients with chronic lymphocytic leukemia. Clin. Leuk., 2008, 2, 223-229.
[53]
Accessdata, FDA, VALCHLOR, Mechlorethamine gel, for topical use, Highlights of prescribing information,; , 2013. Reference ID 3362301, Ceptaris Therapeutics, Inc., Malvern, PA 19355.
[54]
Koler, R.D.; Forsgren, A.L. Hepatotoxicity due to Chlorambucil; report of a case. J. Am. Med. Assoc., 1958, 167(3), 316-317.
[55]
Fraiser, L.H.; Kanekal, S.; Kehrer, J.P. Cyclophosphamide toxicity. Characterizing and avoiding the problem. Drugs, 1991, 42(5), 781-795.
[56]
Accessdata, FDA, ALKERAN, Melphalan hydrochloride for injection, Prescribing Information,; , 2002. GlaxoSmithKline, Research Triangle Park, NC 27709..
[57]
Latcha, S.; Maki, R.G.; Schwartz, G.K.; Flombaum, C.D. Ifosfamide may be safely used in patients with end stage renal disease on hemodialysis. Sarcoma, 2009.Article ID 575629
[58]
Klastersky, J. Side effects of ifosfamide. Oncology, 2003, 65(2), 7-10.
[59]
Frisk, P.; Stalberg, E.; Stromberg, B.; Jakobson, A. Painful peripheral neuropathy after treatment with high-dose ifosfamide. Med. Pediatr. Oncol., 2001, 37(4), 379-382.
[60]
Knauf, W.U.; Lissichkov, T.; Aldaoud, A.; Liberati, A.; Loscertales, J.; Herbrecht, R.; Juliusson, G.; Postner, G.; Gercheva, L.; Goranov, S.; Becker, M.; Fricke, H.J.; Huguet, F.; Del, G.I.; Klein, P.; Tremmel, L.; Merkle, K.; Montillo, M. Phase III randomized study of Bendamustine compared with chlorambucil in previously untreated patients with chronic lymphocytic leukemia. J. Clin. Oncol., 2009, 27(26), 4378-4384.
[61]
Kahl, B.S.; Bartlett, N.L.; Leonard, J.P.; Chen, L.; Ganjoo, K.; Williams, M.E.; Czuczman, M.S.; Robinson, K.S.; Joyce, R.; Vander, J.R.H.; Cheson, B.D. Bendamustine is effective therapy in patients with Rituximab-refractory, indolent B-cell non-Hodgkin lymphoma: Results from a Multicenter Study. Cancer, 2010, 116(1), 106-114.
[62]
Cheson, B.D.; Friedberg, J.W.; Kahl, B.S.; Vander, J.R.H.; Tremmel, L. Bendamustine produces durable responses with an acceptable safety profile in patients with Rituximab-refractory indolent non-Hodgkin lymphoma. Clin. Lymphoma Myeloma Leuk., 2010, 10(6), 452-457.
[63]
Fischer, K.; Cramer, P.; Busch, R.; Bottcher, S.; Bahlo, J.; Schubert, J.; Pfluger, K.H.; Schott, S.; Goede, V.; Isfort, S.; Von, T.J.; Fink, A.M.; Buhler, A.; Winkler, D.; Kreuzer, K.A.; Staib, P.; Ritgen, M.; Kneba, M.; Dohner, H.; Eichhorst, B.F.; Hallek, M.; Stilgenbauer, S.; Wendtner, C.M. Bendamustine in combination with rituximab for previously untreated patients with chronic lymphocytic leukemia: A multicenter phase II trial of the German Chronic Lymphocytic Leukemia Study Group. J. Clin. Oncol., 2012, 30(26), 3209-3216.
[64]
Ohmachi, K.; Niitsu, N.; Uchida, T.; Kim, S.J.; Ando, K.; Takahashi, N.; Takahashi, N.; Uike, N.; Eom, H.S.; Chae, Y.S.; Terauchi, T.; Tateishi, U.; Tatsumi, M.; Kim, W.S.; Tobinai, K.; Suh, C.; Ogura, M. Multicenter phase II study of bendamustine plus rituximab in patients with relapsed or refractory diffuse large B-cell lymphoma. J. Clin. Oncol., 2013, 31(17), 2103-2109.
[65]
Borchers, A.T.; Hagie, F.; Keen, C.L.; Gershwin, M.E. The history and contemporary challenges of the US Food and Drug Administration. Clin. Ther., 2007, 29(1), 1-16.
[66]
Stephen, B. Over-the-counter products in line for user fee program. Pharm. Therapeut., 2017, 42(12), 723-724.
[67]
Kaitin, K.; Melville, A.; Morris, B. FDA advisory committees and the new drug approval process. J. Clin. Pharmacol., 1989, 29(10), 886-890.
[68]
Cristancho, R.A.; Andia, T.; Barbosa, T.; Watanabe, J.H. Definition and classification of generic drugs across the world. Appl. Health Econ. Health Policy, 2015, 13(1), 5-11.
[69]
Thakkar, K.B.; Billa, G. The concept of Generic drugs and patented drugs vs. brand name drugs and non-proprietary (generic) name drugs. Front. Pharmacol., 2013, 4, 113.
[70]
Colombo, G.; Rosei, E.A.; Margonato, A.; Mencacci, A.; Maurizio, C.; Montecucco, C.M.; Trevisan, R. Off-patent generic medicines vs. off-patent brand medicines for six reference drugs: A retrospective claims data study from five local healthcare units in the lombardy region of Italy. PLoS One, 2013, 8(12), 82990.
[71]
Garattini, L.; Vooren, K. Safety and quality of generic drugs: A never-ending debate fostered by economic interests? Appl. Health Econ. Health Policy, 2015, 13, 13-14.
[72]
Dunne, S.; Shannon, B.; Dunne, C.; Cullen, W. A review of the differences and similarities between generic drugs and their originator counterparts, including economic benefits associated with usage of generic medicines, using Ireland as a case study. BMC Pharmacol. Toxicol., 2013, 14, 1.
[73]
Hansen, R.A.; Qian, J.; Berg, R.; Linneman, J.; Vazquez, E.S.; Dutcher, S.K.; Raofi, S.; David, C.; Peissig, P. Comparison of generic-to-brand switchback patterns for generic and authorized generic drugs. Pharmacotherapy, 2017, 37(4), 429-437.
[74]
Barlas, S. Brand and generics companies unite to pressure FDA: They want the agency to drop its safety-label plan and adopt their alternative. PT, 2015, 40(8), 501-503.
[75]
Handoo, S.; Arora, V.; Khera, D.; Nandi, P.K.; Sahu, S.K. A comprehensive study on regulatory requirements for development and filing of generic drugs globally. Int. J. Pharm. Investig., 2012, 2(3), 99-105.
[76]
Lionberger, A.; Lee, S.L.; Lee, L.M.; Raw, A.; Lawrence, X.Y. Quality by Design: Concepts for ANDAs. AAPS J., 2008, 10(2), 268-276.
[77]
Bedson, J.; Whitehurst, T.; Lewis, M.; Croft, P. Factors affecting over-the-counter use of aspirin in the secondary prophylaxis of cardiovascular disease. Br. J. Gen. Pract., 2001, 51(473), 1001-1003.
[78]
USFDA. Home, Drugs Development & Approval Process (Drugs), How Drugs are Developed and Approved, Types of Applications, DrugApplications for Over-the-Counter Drugs. fda.gov/drugs/ developmentapprovalprocess/howdrugsaredevelopedandapproved/approvalapplications/over-the-counterdrugs/default.htm (Accessed Sept 05, 2018)
[79]
USFDA. Drugs Resources for You, Information for Consumers (Drugs), Buying & Using Medicine Safely, Generic Drugs. fda.gov/Drugs/ResourcesForYou/Consumers/BuyingUsingMedicineSafely/GenericDrugs/default.html (Accessed Sept 05, 2018).
[80]
Drugs@FDA: FDA Approved Drug Products, MUSTARGEN,. accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=006695 (Accessed Sept 05, 2018)
[81]
Drugs@FDA: FDA Approved Drug Products, VALCHLOR,. accessdata.fda.gov/scripts/cder/daf/index.cfm?event=BasicSearch.process (Accessed Sept 05, 2018
[82]
Drugs@FDA: FDA Approved Drug Products, LEUKERAN,. accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=010669 (Accessed Sept 05, 2018)
[83]
Drugs@FDA: FDA Approved Drug Products, CYTOXAN,. accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=012141 (Accessed Sept 05, 2018).
[84]
Drugs@FDA: FDA Approved Drug Products, ALKERAN,. accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=014691 (Accessed Sept 05, 2018)
[85]
Drugs@FDA: FDA Approved Drug Products, IFECX,. accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=019763 (Accessed Sept 05, 2018)

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