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Selected Organophosphorus Compounds with Biological Activity

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Selected Organophosphorus Compounds with Biological Activity RSC Advances View Article Online REVIEW View Journal | View Issue Selected organophosphorus compounds with biological activity. Applications in medicine Cite this: RSC Adv.,2016,6,7101 Sebastian Demkowicz,* Janusz Rachon, Mateusz Dasko´ and Witold Kozak The purpose of this article is to provide an overview of the latest applications of organophosphorus compounds (OPs) that exhibit biological activity. A large family of OPs have become popular in recent years. The practical application of OPs in modern medicine has been attributed to their unique properties. In this article, the methods used to select these compounds will be emphasized. This paper Received 30th November 2015 will first outline the findings of a literature review on OPs, including anticancer and antiviral agents, Accepted 7th January 2016 bisphosphonates, phosphorus analogues of amino acids and peptides, and organophosphorus metal DOI: 10.1039/c5ra25446a complexes, and secondly, it will classify the compounds according to their biological activity and www.rsc.org/advances applications in the treatment of diseases. 1. Introduction 2. Bisphosphonates in the treatment of osteoporosis Organophosphorus compounds (OPs), which are a wide class of chemical compounds containing organic moieties usually Osteoporosis is one of the most serious health problems in the bonded directly to phosphorus or bonded through a hetero- world, and prevention and treatment are of great interest in the atom, such as sulfur, oxygen or nitrogen, are some of the European Union, which issued “Report on Osteoporosis in most common chemicals in the human environment. the European Community – Action for Prevention”.8 The scale of Because of their unique properties and high biological the problem is alarming. One in three women and one in eight activity, they have largely been used worldwide in agricul- men over the age of 50 years will experience at least one fracture 1 tural (pesticides), industrial (production of lubricants, due to osteoporosis in their lifetime. The main criterion for Published on 12 1 2016. Downloaded 2021-09-29 4:19:56. 2 hydraulic uids, and plastics materials), medicinal (drugs selecting an osteoporosis therapy is its impact on the risk of 3,4 against osteoporosis, anticancer and antiviral compounds) osteoporotic fracture (femoral neck, spine, wrist). The following 5 or veterinary (anthelmintics) applications. The rst potent pharmacological methods are used: synthetic organophosphorus poison, tetraethyl pyrophos- hormone replacement therapy; phate (TEPP), was synthesized by Clermont in 1854. At the specic estrogen receptor modulators (SERMs); beginning of the twentieth century, some very toxic calcitonin; compounds were used in many armed conicts as chemical vitamin D3 with active metabolites and calcium; weapons, known as chemical warfare agents (CWA). uorine. Following the German laboratories discovery of soman, sarin Bisphosphonates are currently the most important and and tabun, the United States and England developed VX effective class of drugs developed for the treatment of metabolic production technologies. The book “Chemical Warfare bone disorders associated with increased osteoclast-mediated 6 Agents” discusses the physicochemical properties of bone resorption, such as osteoporosis9,10 and Paget's chemical warfare agents, their dispersion and fate in the disease.11,12 They are effective inhibitors of tumor-induced bone environment, their toxicology and management of their destruction and signicantly reduce the incidence of skeletal effects on humans, decontamination, and protective equip- complications in patients with bone metastases from several ment. Aer the Second World War, OPs have been used forms of cancer, including breast and prostate cancer.13 mainly as pesticides for plants and animals. Furthermore, Bisphosphonates have a high affinity for calcium and therefore OPs have practically contributed to the substantial benets specically target bone mineral, where they are internalized by for efficient food production and the ght against many bone-destroying osteoclasts and inhibit their function.14 7 serious diseases, such as malaria, yellow fever, typhus, or Importantly, potential of bisphosphonates has also been iden- 4 smallpox. tied in areas ranging from parasite-growth inhibition to immunological and cancer therapeutics.3 These compounds primarily affect the function of osteoclasts, but recent preclin- Department of Organic Chemistry, Chemical Faculty, Gdansk University of Technology, ical evidence indicates that other neighboring cell types, such as Narutowicza 11/12, 80-233 Gdansk, Poland. E-mail: [email protected] This journal is © The Royal Society of Chemistry 2016 RSC Adv.,2016,6,7101–7112 | 7101 View Article Online RSC Advances Review macrophages, monocytes and cancer cells, could also be targets for these drugs.15 Bisphosphonates have been shown to induce tumor cell apoptosis, to modulate cells in the immune system and to inhibit tumor angiogenesis. Bisphosphonates used in clinical practice are characterized by a P–C–P structure.16 This structure allows for a wide variety of variations. The rst bisphosphonates were synthesized by German chemists and were rst used only for a few industrial applications, such as antiscaling agents. It was only in 1968– 1969 that H. Fleisch et al. demonstrated that these compounds had biological effects, specically on calcied tissues.17–20 Replacing the O atom with a CH2 group in the pyrophosphoric acid structure created new bioactive phosphorus agents and resulted in a major breakthrough in the treatment of bone disease. It is hypothesized that bisphosphonic acid 1 are isos- teric with pyrophosphoric acid 2 but are hydrolytically stable, and if attracted to bone, may block resorption since inorganic pyrophosphate inhibits the formation and dissolution of hydroxyapatite in bone (Fig. 1). E. Breuer's research group from the Hebrew University of Jerusalem between 1992 and 2005 had a signicant impact on Fig. 3 Chemical structures of bisphosphonates 7–20. the synthesis and biological evaluation of bisphosphonates. E. Breuer's research group authored numerous publications and patents concerning the use of bisphosphonates for the treatment of osteoporosis. These researchers were focused on The research eld is currently very active, and many new synthesizing novel bifunctional compounds, such as bisacyl- discoveries in bisphosphonate bone-disease therapy have been 25 phosphonates 3,21 tetrakisphosphonates 4,22 bisphosphonic published. Bisphosphonates are currently in the third gener- 16 17 acid betaine derivatives 5 (ref. 23) and hydroxy- ation, which includes incadronic acid , minodronic acid 18 iminophosphonates 6,24 and examining their effects compared and zoledronic acid . In addition, several bisphosphonates 19 to other clinically used drugs (Fig. 2). act as antidepressant and antihypercholesterolemic agents 20 26,27 The drugs clodronate 7, tiludronate 8 and etidronate 9 were (Fig. 3). among the rst to be used in the clinic. Published on 12 1 2016. Downloaded 2021-09-29 4:19:56. Attention has recently been drawn to the derivatives with 3. Organophosphorus compounds as aminoalkyl side chains for the next generation of bisphospho- anticancer drugs nates, as found in pamidronic acid 10, alendronic acid 11, olpadronic acid 12, neridronic acid 13, ibandronic acid 14 and Recent research ndings suggest that a number of OPs are used risedronic acid 15. as anticancer drugs or have potential anticancer properties. They are usually used in oncology as alkylating chemothera- peutic agents. These compounds react with DNA, RNA and some enzymes. N,N0,N00-Triethylenethiophosphoramide 21, sold under the trade name thioTEPA, is a compound used as an anticancer chemotherapeutic drug that binds to DNA, cross- links the two strands and prevents cell duplication. N,N0,N00- Fig. 1 Chemical structures of bisphosphonic acid 1 and pyrophos- Triethylenethiophosphoramide, developed in the 1950s, is phoric acid 2. a trifunctional alkylating agent with a broad spectrum of anti- tumor activity.28 This drug is used to treat many diseases, including breast cancer, ovarian cancer, lymphosarcoma, supercial papillary carcinoma of the urinary bladder, and Hodgkin's disease (Fig. 4).29 Several derivatives of N,N0,N00-triethylenethiophosphoramide have been synthesized, and their antitumor activity was evalu- ated. McCracken and co-workers carried out the synthesis of N- [bis(1-aziridinyl)phosphoro]-carbamate 22.30 In vivo studies demonstrated that the synthesized drugs had a higher toxicity Fig. 2 Chemical structures of bisacylphosphonates 3, tetraki- against cancer cells, and they did not invade other tissues. In 31 sphosphonates 4, bisphosphonic acid betaine derivatives 5 and 1963, Chernov et al. published the synthesis and biological hydroxyiminophosphonates 6. evaluation of phosphazine 23. Chernov's research 7102 | RSC Adv.,2016,6,7101–7112 This journal is © The Royal Society of Chemistry 2016 View Article Online Review RSC Advances and ifosfamide 29 are used commonly for the treatment of non- Hodgkin lymphomas and a variety of bone and so tissue sarcomas.37 Compared to many other anticancer drugs, cyclo- phosphamide exhibits relatively little non-hematopoietic toxicity. In 2000, a series of naphthoquinone 31 and benzimidazo- lequinone 32 phosphorodiamidates were synthesized and studied as potential cytotoxic prodrugs activated by DT-diaph- orase,38 and an activation process was proposed (Fig. 5). To activate the synthesized prodrugs, the quinone moiety
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