mustard compounds

Summary

Summary: Strong alkylating and immunosuppressive agents whose biological activity is based on the presence of bis(2-chloroethyl)- groups. Although otherwise structurally diverse, the compounds have in common the capacity to contribute alkyl groups to DNA. They are generally highly toxic but include among their number many widely used and effective antineoplastic agents.

Top Publications

  1. Jacoby J, Erez B, Korshunova M, Williams R, Furutani K, Takahashi O, et al. Treatment with HIF-1alpha antagonist PX-478 inhibits progression and spread of orthotopic human small cell lung cancer and lung adenocarcinoma in mice. J Thorac Oncol. 2010;5:940-9 pubmed publisher
    ..These results suggest the inclusion of lung cancer patients in phase I clinical trials of PX-478. ..
  2. Lee K, Kim H. A novel approach to cancer therapy using PX-478 as a HIF-1? inhibitor. Arch Pharm Res. 2011;34:1583-5 pubmed publisher
    ..This article provides a review of PX-478 as the first novel HIF-1? inhibitor in clinical stage for the treatment of solid tumors. ..
  3. Stuart J, Murray K, Ursano R, Wright K. The Department of Defense's Persian Gulf War registry year 2000: an examination of veterans' health status. Mil Med. 2002;167:121-8 pubmed
    ..Overall, the self-reported general health of veterans with symptoms was much poorer (females had higher rates of "fair to poor" health than males) than that of veterans with no reported symptoms...
  4. Koh M, Spivak Kroizman T, Powis G. HIF-1alpha and cancer therapy. Recent Results Cancer Res. 2010;180:15-34 pubmed publisher
    ..In this chapter, we summarize recent findings regarding the regulation of HIF-1alpha and the progress made in identifying new therapeutic agents that inhibit HIF-1alpha. ..
  5. Jordan B, Black K, Robey I, Runquist M, Powis G, Gillies R. Metabolite changes in HT-29 xenograft tumors following HIF-1alpha inhibition with PX-478 as studied by MR spectroscopy in vivo and ex vivo. NMR Biomed. 2005;18:430-9 pubmed
  6. Welsh S, Williams R, Kirkpatrick L, Paine Murrieta G, Powis G. Antitumor activity and pharmacodynamic properties of PX-478, an inhibitor of hypoxia-inducible factor-1alpha. Mol Cancer Ther. 2004;3:233-44 pubmed
  7. Russell D, Blain P, Rice P. Clinical management of casualties exposed to lung damaging agents: a critical review. Emerg Med J. 2006;23:421-4 pubmed
    ..There is limited evidence to suggest that repletion of glutathione reduces and/or prevents lung damage by these agents. This may provide an opportunity for therapeutic intervention. ..
  8. Chen C, Lin Y, Zhang X, Chou T, Tsai T, Kapuriya N, et al. Synthesis and in vitro cytotoxicity of 9-anilinoacridines bearing N-mustard residue on both anilino and acridine rings. Eur J Med Chem. 2009;44:3056-9 pubmed publisher
    ..3 nM and is as potent as taxol (IC(50)=1.1 nM). The structure-activity relationship study showed that the length of the spacer and the position of the substituent do affect their cytotoxicity. ..
  9. Fedorova O, Adeenah Zadah A, Knorre D. Cooperative interactions in the tandem of oligonucleotide derivatives arranged at complementary target. Quantitative estimates and contribution of the target secondary structure. FEBS Lett. 1995;369:287-9 pubmed

More Information

Publications62

  1. Vycudilik W. Detection of bis(2-chlorethyl)-sulfide (Yperite) in urine by high resolution gas chromatography-mass spectrometry. Forensic Sci Int. 1987;35:67-71 pubmed
    ..Bis(2-chlorethyl)-sulfide (Yperite) could be detected by GC/MS in urine samples, concentration ranging from 1 to 30 ppb. These results were supported by high resolution mass spectral data. ..
  2. Louis S, Johnstone D, Russell N, Jamieson A, Dockray G. Antibodies to calcitonin-gene related peptide reduce inflammation induced by topical mustard oil but not that due to carrageenin in the rat. Neurosci Lett. 1989;102:257-60 pubmed
    ..The results indicate that CGRP, which is probably released from the peripheral endings of cutaneous primary afferents, plays a role in the inflammatory response to mustard oil, but not carrageenin. ..
  3. Prakash A, Denny W, Gourdie T, Valu K, Woodgate P, Wakelin L. DNA-directed alkylating ligands as potential antitumor agents: sequence specificity of alkylation by intercalating aniline mustards. Biochemistry. 1990;29:9799-807 pubmed
    ..Relationships between the DNA alkylation patterns of these compounds and their biological activities are discussed. ..
  4. Czerny K, Ciszewska Popiołek B, Mitura K. [Histochemical studies of the kidney of white rats after experimental external application of sulfur mustard gas]. Gegenbaurs Morphol Jahrb. 1990;136:89-94 pubmed
    ..It was noted that the prolonged application of Psoriazin caused changes in the convoluted tubules. ..
  5. Linder S, Mele J, Harries T. Chronic hyperpigmentation from a heated mustard compress burn: a case report. J Burn Care Rehabil. 1996;17:351-2 pubmed
    ..A photograph of the presenting burn with the region of hyperpigmentation 3 days after the injury is provided. ..
  6. Garber K. New drugs target hypoxia response in tumors. J Natl Cancer Inst. 2005;97:1112-4 pubmed
  7. Kumar D, Veldhuyzen W, Zhou Q, Rokita S. Conjugation of a hairpin pyrrole-imidazole polyamide to a quinone methide for control of DNA cross-linking. Bioconjug Chem. 2004;15:915-22 pubmed
    ..Equivalent intramolecular alkylation of a polyamide by its attached chlorambucil mustard was not observed under similar condition. The presence of DNA, however, did facilitate hydrolysis of this mustard conjugate. ..
  8. Macpherson G, Figg W. Small molecule-mediated anti-cancer therapy via hypoxia-inducible factor-1 blockade. Cancer Biol Ther. 2004;3:503-4 pubmed
    ..Though the mechanism of action for PX-478 is not completely understood, inhibition of glycolysis rather than angiogenesis appeared to be the primary mode of anti-cancer activity. ..
  9. Cozzi P, Beria I, Caldarelli M, Capolongo L, Geroni C, Mazzini S, et al. Phenyl sulfur mustard derivatives of distamycin A. Bioorg Med Chem Lett. 2000;10:1653-6 pubmed
    ..Cinnamoyl sulfur mustard derivative (7) proved to be one of the most active distamycin-derived cytotoxics, about 1000 times more potent than melphalan. ..
  10. Smaill J, Fan J, Denny W. DNA minor groove targeted alkylating agents based on bisbenzimidazole carriers: synthesis, cytotoxicity and sequence-specificity of DNA alkylation. Anticancer Drug Des. 1998;13:857-80 pubmed
  11. Coley H, Mongelli N, D INCALCI M. The effects of a benzoic acid mustard derivative of distamycin A (FCE 24517) and related minor groove-binding distamycin analogues on the activity of major groove-binding alkylating agents. Biochem Pharmacol. 1993;45:619-26 pubmed
    ..This study has highlighted the complex nature of the DNA interactive compound FCE 24517 which possess potent and broad spectrum antitumour activity. ..
  12. Sorscher D, Conolly R. Pretreatment of primary rat cutaneous epidermal keratinocyte culture with a low concentration of MNNG: effect on DNA cross-linking measured in situ after challenge with bis-2-chloroethyl sulfide. J Toxicol Environ Health. 1989;27:367-79 pubmed
    ..e., a return to control levels of DSDNA) was not seen in these experiments. The activity that resulted in decreases in the level of DSDNA during postchallenge incubation response was unaffected by MNNG pretreatment. ..
  13. JANCSO N, Jancsó Gábor A, Szolcsanyi J. Direct evidence for neurogenic inflammation and its prevention by denervation and by pretreatment with capsaicin. Br J Pharmacol Chemother. 1967;31:138-51 pubmed
  14. Saladi R, Smith E, Persaud A. Mustard: a potential agent of chemical warfare and terrorism. Clin Exp Dermatol. 2006;31:1-5 pubmed
    ..Prevention and management of mustard exposure are briefly discussed. The need for awareness and preparedness in the dermatological community regarding mustard exposure is emphasized. ..
  15. Baraldi P, Núñez M, Espinosa A, Romagnoli R. Distamycin A as stem of DNA minor groove alkylating agents. Curr Top Med Chem. 2004;4:231-9 pubmed
    ..Several classes of distamycin derivatives that have been reported in the published literature have been described in this review article. ..
  16. Requena L, Requena C, Sanchez M, Jaqueti G, Aguilar A, Sanchez Yus E, et al. Chemical warfare. Cutaneous lesions from mustard gas. J Am Acad Dermatol. 1988;19:529-36 pubmed
    ..In these last cases there also were ocular, respiratory, and gastrointestinal manifestations. In the skin this mustard gas seems to act through a primary irritant mechanism and without allergic contact sensitization. ..
  17. Kurihara T, Nojima K, Sakagami H, Motohashi N, Molnar J. Electronic structure and cytotoxic activity of "half-mustard type" phenothiazines by MM3 and PM3 methods. Anticancer Res. 1999;19:3895-9 pubmed
    ..Actually, the urea site of "half-mustard type" phenothiazines displayed extensive variability in the energy of lone pair orbital and net atomic charges of N1, 0 and N3 atoms. ..
  18. Papac R. Chemotherapy plus involved-field radiation in early-stage Hodgkin's disease. N Engl J Med. 2008;358:742-3; author reply 743 pubmed
  19. Graifer D, Babkina G, Matasova N, Vladimirov S, Karpova G, Vlassov V. Structural arrangement of tRNA binding sites on Escherichia coli ribosomes, as revealed from data on affinity labelling with photoactivatable tRNA derivatives. Biochim Biophys Acta. 1989;1008:146-56 pubmed
  20. Nakamura M, Rikimaru T, Yano T, Moore K, Pula P, Schofield B, et al. Full-thickness human skin explants for testing the toxicity of topically applied chemicals. J Invest Dermatol. 1990;95:325-32 pubmed
    ..The toxicant type seemed to be caused by an invagination of the plasma membrane. Only toxicant-type vacuoles increased appreciably in number when skin explants were exposed to mustard, and to other toxicants. ..
  21. Palmer B, Wilson W, Cliffe S, Denny W. Hypoxia-selective antitumor agents. 5. Synthesis of water-soluble nitroaniline mustards with selective cytotoxicity for hypoxic mammalian cells. J Med Chem. 1992;35:3214-22 pubmed
    ..Lack of aerobic bioactivation of 20 by DT diaphorases may be responsible for its higher hypoxic selectivity than that of 23. ..
  22. Satyam A, Hocker M, Kane Maguire K, Morgan A, Villar H, Lyttle M. Design, synthesis, and evaluation of latent alkylating agents activated by glutathione S-transferase. J Med Chem. 1996;39:1736-47 pubmed
    ..These results substantially extend previous efforts to develop drugs targeting GST and provide a paradigm for development of other latent drugs. ..
  23. Davies L, Friedlos F, Hedley D, Martin J, Ogilvie L, Scanlon I, et al. Novel fluorinated prodrugs for activation by carboxypeptidase G2 showing good in vivo antitumor activity in gene-directed enzyme prodrug therapy. J Med Chem. 2005;48:5321-8 pubmed
  24. Wheeler J, Stourman N, Armstrong R, Guengerich F. Conjugation of haloalkanes by bacterial and mammalian glutathione transferases: mono- and vicinal dihaloethanes. Chem Res Toxicol. 2001;14:1107-17 pubmed
    ..Vuilleumier, S., Rose, J. A., Armstrong, R. N., and Guengerich, F. P. (2001) Chem. Res. Toxicol. 14, 1118-1127], indicative of an inherent difference in the catalytic mechanisms of the bacterial and mammalian GSH transferases. ..
  25. Shrestha P, Davis D, Veeranna R, Carey R, Viollet C, Yarchoan R. Hypoxia-inducible factor-1 alpha as a therapeutic target for primary effusion lymphoma. PLoS Pathog. 2017;13:e1006628 pubmed publisher
    ..These results offer further evidence that HIF-1? plays a critical role in the pathogenesis of PEL, and that inhibition of HIF-1? can be a potential therapeutic strategy in this disease. ..
  26. Schoene K, Bruckert H, Schreiber G, Wodtke G. A method for correlating skin exposure to S-mustard vapor with skin damage. Am Ind Hyg Assoc J. 1989;50:569-73 pubmed
    ..min/cm3 corresponding to doses from about 0.1 to 1.1 micrograms/cm2. A comparison with older data reveals that human skin, in this respect, is about eight times more sensitive than the inner side of the rabbit's ear. ..
  27. Watson A, Jones T, Griffin G. Sulfur mustard as a carcinogen: application of relative potency analysis to the chemical warfare agents H, HD, and HT. Regul Toxicol Pharmacol. 1989;10:1-25 pubmed
    ..These values are considered upper limit estimates. ..
  28. Elsayed N, Omaye S, Klain G, Inase J, Dahlberg E, Wheeler C, et al. Response of mouse brain to a single subcutaneous injection of the monofunctional sulfur mustard, butyl 2-chloroethyl sulfide (BCS)*. Toxicology. 1989;58:11-20 pubmed
    ..Because these changes are consistent with oxidative stress, we conclude that the effect of BCS administered subcutaneously may be translocated, reaching mouse brain, and causing oxidative stress. ..
  29. Bismuth C, Borron S, Baud F, Barriot P. Chemical weapons: documented use and compounds on the horizon. Toxicol Lett. 2004;149:11-8 pubmed
    ..While these weapons are fearsome elements, the dangers should be viewed in the context of the widespread availability and efficacy of conventional weapons. ..
  30. Bodell W. Molecular dosimetry for sister-chromatid exchange induction and cytotoxicity by monofunctional and bifunctional alkylating agents. Mutat Res. 1990;233:203-10 pubmed
  31. Voak A, Gobalakrishnapillai V, Seifert K, Balczo E, Hu L, Hall B, et al. An essential type I nitroreductase from Leishmania major can be used to activate leishmanicidal prodrugs. J Biol Chem. 2013;288:28466-76 pubmed publisher
    ..We conclude that LmNTR can be targeted for drug development by exploiting its prodrug activating property or by designing specific inhibitors to block its endogenous function. ..
  32. Higuchi K, Kajiki A, Nakamura M, Harada S, Pula P, Scott A, et al. Proteases released in organ culture by acute dermal inflammatory lesions produced in vivo in rabbit skin by sulfur mustard: hydrolysis of synthetic peptide substrates for trypsin-like and chymotrypsin-like enzymes. Inflammation. 1988;12:311-34 pubmed
    ..The catalytic site of endopeptidases that are entrapped and inhibited by alpha M is known to remain active on (and reachable by) small synthetic peptide substrates such as LGA-AFC and BPN.(ABSTRACT TRUNCATED AT 400 WORDS) ..
  33. Lacotte B, Ceuterick M, Geerts M, Willems J. [Cutaneous burns caused by Yperite. Apropos of 2 new cases]. J Chir (Paris). 1989;126:315-8 pubmed
    ..The treatment of patients, with this rare condition, remains symptomatic. ..
  34. Easton D, Peto J, Doll R. Cancers of the respiratory tract in mustard gas workers. Br J Ind Med. 1988;45:652-9 pubmed
    ..The results provide strong evidence that exposure to mustard gas can cause cancers of the upper respiratory tract and some evidence that it can cause lung cancer and non-malignant respiratory disease.(ABSTRACT TRUNCATED AT 250 WORDS)..
  35. Otrock Z, Hatoum H, Awada A, Ishak R, Shamseddine A. Hypoxia-inducible factor in cancer angiogenesis: structure, regulation and clinical perspectives. Crit Rev Oncol Hematol. 2009;70:93-102 pubmed publisher
    ..In this paper, we review what has been described about HIF-1: its structure, its regulation and target genes, its role in cancer, and its implication for cancer therapy. ..
  36. Salles J, Wallace M, Fain J. Differential effects of alkylating agents on the multiple muscarinic receptor subtypes linked to activation of phospholipase C by carbachol in rat brain cortical membranes. J Pharmacol Exp Ther. 1993;264:521-9 pubmed
    ..abstract truncated at 250 words)..
  37. Kapuriya N, Kakadiya R, Dong H, Kumar A, Lee P, Zhang X, et al. Design, synthesis, and biological evaluation of novel water-soluble N-mustards as potential anticancer agents. Bioorg Med Chem. 2011;19:471-85 pubmed publisher
    ..A pharmacokinetic profile of the representative 9aa' in rats was also investigated. The current studies suggest that this agent is a promising candidate for preclinical studies. ..
  38. Hosoya K, Kyoko H, Toyooka N, Kato A, Orihashi M, Tomi M, et al. Evaluation of amino acid-mustard transport as L-type amino acid transporter 1 (LAT1)-mediated alkylating agents. Biol Pharm Bull. 2008;31:2126-30 pubmed
    ..These findings suggest that phenylglycine-mustard is a better substrate for LAT1 than melphalan and other amino acid-mustards. ..
  39. Opresko D, Young R, Faust R, Talmage S, Watson A, Ross R, et al. Chemical warfare agents: estimating oral reference doses. Rev Environ Contam Toxicol. 1998;156:1-183 pubmed
    ..The key study did identify a toxic effect that is consistent with the vesicant properties of sulfur mustard. In none of the other available studies was there any indication of a different effect occurring at a lower exposure level. ..
  40. Sun K, Halberg N, Khan M, Magalang U, Scherer P. Selective inhibition of hypoxia-inducible factor 1? ameliorates adipose tissue dysfunction. Mol Cell Biol. 2013;33:904-17 pubmed publisher
  41. Converso A, Saaidi P, Sharpless K, Finn M. Nucleophilic substitution by grignard reagents on sulfur mustards. J Org Chem. 2004;69:7336-9 pubmed
    ..2,6-Dichloro-9-thiabicyclo[3.3.1]nonane is especially useful in this regard, providing clean reactivity with organomagnesium nucleophiles on a topologically constrained scaffold. ..
  42. Loke W, Lau S, Yong L, Khor E, Sum C. Wound dressing with sustained anti-microbial capability. J Biomed Mater Res. 2000;53:8-17 pubmed
    ..The anti-microbial activity of the dressing against Pseudomonas aeruginosa and Staphylococcus aureus was tested using the Bauer-Kirby Disk Diffusion Test. ..
  43. Laktionov P, Dazard J, Piette J, Vives E, Rykova E, Vlassov V, et al. Uptake of oligonucleotides by keratinocytes. Nucleosides Nucleotides. 1999;18:1697-9 pubmed
  44. Baraldi P, Cozzi P, Geroni C, Mongelli N, Romagnoli R, Spalluto G. Novel benzoyl nitrogen mustard derivatives of pyrazole analogues of distamycin A: synthesis and antileukemic activity. Bioorg Med Chem. 1999;7:251-62 pubmed
  45. Kim M, Guengerich F. Interactions of N7-guanyl methyl- and thioether-substituted d(CATGCCT) derivatives with d(AGGNATG). Chem Res Toxicol. 1993;6:900-5 pubmed
    ..abstract truncated at 250 words) ..
  46. Blakey D, Valcaccia B, East S, Wright A, Boyle F, Springer C, et al. Antitumor effects of an antibody-carboxypeptidase G2 conjugate in combination with a benzoic acid mustard prodrug. Cell Biophys. 1993;22:1-8 pubmed
    ..In contrast, prodrug, conjugate, or active drug alone did not result in any antitumor activity in this tumor model. These studies demonstrate the advantage of a two-step ADEPT system for the treatment of colorectal cancer. ..
  47. Süli Vargha H, Bodi J, Meszaros M, Medzihradszky K. Decomposition of N-(2-chloroethyl)-N-nitrosocarbamoyl amino acid amides. J Med Chem. 1988;31:1492-5 pubmed
    ..The carbamoylating activity was also investigated in the presence of cyclohexylamine, and it was found to lead mainly to intramolecular carbamoylation with the formation of hydantoin derivatives. ..
  48. Fedorova O, Knorre D, Podust L, Zarytova V. Complementary addressed modification of double-stranded DNA within a ternary complex. FEBS Lett. 1988;228:273-6 pubmed
  49. Miko M, Krepelka J, Melka M. Inhibition of biosynthetic processes in P388 and Ehrlich ascites cells by cloturin. Drugs Exp Clin Res. 1988;14:575-80 pubmed
    ..A depletion of nucleotide pools can serve as an efficient tool to inhibit cellular growth and to induce cell death under some circumstances. ..
  50. Hu H, Cook Deegan R, Shukri A. The use of chemical weapons. Conducting an investigation using survey epidemiology. JAMA. 1989;262:640-3 pubmed
  51. Panajotovova V, Melka M. Effect of new purine analog 6-purinyl-N-[2-chloroethyl] thiocarbamate (Cloturin) on immune system of mice. Neoplasma. 1991;38:565-74 pubmed
    ..For its properties Cloturin could be useful not only as a cytostatic drug, but also as an immunosuppressive agent. ..
  52. Shan D, Nicolaou M, Borchardt R, Wang B. Prodrug strategies based on intramolecular cyclization reactions. J Pharm Sci. 1997;86:765-7 pubmed
    ..Such systems can be used for the preparation of esterase-, phosphatase-, and redox-sensitive prodrugs of amines and alcohols and esterase-sensitive cyclic prodrugs of peptides and peptide mimetics. ..
  53. Ferguson L, Turner P, Gourdie T, Valu K, Denny W. 'Petite' mutagenesis and mitotic crossing-over in yeast by DNA-targeted alkylating agents. Mutat Res. 1989;215:213-22 pubmed
    ..These data suggest very different modes of action between the DNA-targeted alkylators and their non-targeted counterparts. ..