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A comparative account of sar studies of semicarbazones and thiosemicarbazones on cathepsins H and L

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Abstract

Cathepsins H and L, lysosomal cysteine proteases have been found in elevated levels in tumor invasion, metastasis, inflammation, atherosclerosis, and various other tissue degenerative diseases. In the past decade, work has largely been focused on evaluation of some non-peptidyl inhibitors of cathepsins as these have been considered as viable drug targets for major diseases. Semicarbazones and thiosemicarbazones, carbonyl derivatives are extensively studied for wide variety of biological activities such as anticonvulsant, anticancer, anti-inflammatory, antihypertensive, antimicrobial, and antiparasitic. These derivatives have also shown to possess parasiticidal activity against Plasmodium falciparum, Plasmodium berghei, Trypanosoma cruzi, Trypanosoma brucei rhodesiense and Toxoplasma gondii. With this background, the present work involved the inhibition and kinetic studies of substituted semicarbazones and thiosemicarbazones on cathepsin H and L. A comparative account of structure–activity relationship for inhibition exerted by synthesized semicarbazones and thiosemicarbazones with varied functional moieties on cathepsins H and L is presented.

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References

  • Aguiree G, Boiani L, Cerecetto H, Fernandez M, Gonzalez M, Denicola A, Otero L, Gambino D, Rigol C, Olea-Azar C, Faundez M (2004) In-vitro activity and mechanism of action against the protozoan parasite trypanosome cruzi of 5-nitrofuryl containing thiosemicarbazones. Bioorg Med Chem 12:4885–4893

    Article  Google Scholar 

  • Azaryan A, Galoyan A (1987) Human and bovine brain cathepsin L and cathepsin H: Purification, physic-chemical properties and specificity. Neurochem Res 12:207–213

    Article  CAS  PubMed  Google Scholar 

  • Brak K, Kerr ID, Barrett KT, Fuchi N, Debnath M, Ang K, Engel JC, McKerrow JH, Doyle PS, Brinen LS, Ellman JA (2010) Non-peptidic tetrafluoro phenoxymethyl ketone cruzain inhibitors as promising new leads for chagas disease. Chemother J Med Chem 53:1763–1773

    Article  CAS  Google Scholar 

  • Barrett A (1986) In proteinase inhibitors. In: Barrett A, Salvesen G, (eds) Proteinase Inhibitors. Elsevier, Amsterdam, pp 3–22

  • Chan SJ, Segundo BS, McCormick MB, Steiner DF (1986) Nuclotide and predicted amino acid sequences of cloned human and mouse preprocathepsin B cDNAs. Proc Natl Acad Sci 83:7721–7725

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chowdhary SF, Joseph L, Kumar S, Tulsidas SR, Bhat S, Ziomek E, Menard R, Sivaraman J, Purisima EO (2008) Exploring inhibitor binding at the S’ subsites of cathepsin L. J Med Chem 51:1361–1368

    Article  Google Scholar 

  • Cimerman N, Bruguljan PM, Krasovec M, Suskovic S, Kos J (2001) Serum concentration and circadian profiles of cathepsins B, H and L, and their inhibitors, stefins A and B, in asthma. Clin Chim Acta 310:113–122

    Article  CAS  PubMed  Google Scholar 

  • Dana D, Davalos AR, De S, Rathod P, Gamage RK, Huestis J, Afzal N, Zavlanov Y, Paroly SS, Rotenberg SA, Subramaniam G, Mark KJ, Chang EJ, Kumar S (2013) Development of cell-active non-peptidyl inhibitors of cysteine cathepsin. Bioorg Med Chem 21:2975–2987

    Article  CAS  PubMed  Google Scholar 

  • De-Oliveira RB, De Sauza-Fagundes EM, Soares RP, Andrade AA, Kretti AU, Zani CL (2008) Synthesis and antimalarial activity of semicarbazone and thiosemicarbazone derivatives. Eur J Med Chem 43:1983–1988

    Article  CAS  PubMed  Google Scholar 

  • Du X, Guo C, Hansell E, Doyle PS, Caffrey CR, Holler TP, McKerrow JH, Cohen FE (2002) Synthesis and structure–activity relationship study of potent trypanocidal thiosemicarbazone inhibitors of the trypanosomal cysteine protease cruzain. J Med Chem 45:2695–2707

    Article  CAS  PubMed  Google Scholar 

  • Frohlich E, Schlagenhauff B, Mohrle M, Weber E, Klessen C, Rassner G (2001) Activity expression and transcription of the cathepsins B, D, H and L in cutaneous malignant melanoma. Cancer 91:972–982

    Article  CAS  PubMed  Google Scholar 

  • Fujii N, Mallari JP, Hansell JE, Mackey HZ, Doyle P, Zhou YM, Gut J, Rosenthal PJ, McKerrow JH, Guy RK (2005) Discovery of potent thiosemicarbazone inhibitors of rhodesain and cruzain. Bioorg Med Chem Lett 15:121–123

    Article  CAS  PubMed  Google Scholar 

  • Guncar G, Podobnik M, Pungercar J, Strukelj B, Turk V, Turk D (1998) Crystal structure of porcine cathepsin H determined at 2.1 Å resolution: location of the mini-chain C-terminal carboxyl group defines cathepsin H aminopeptidase function. Structure 6:51–61

    Article  CAS  PubMed  Google Scholar 

  • Greenbaum DC, Mackey Z, Hansell E, Doyle P, Gut J, Caffrey CR, Lehrman J, Rosenthal PJ, McKerrow JH, Chibale K (2004) Synthesis and structure–activity relationships of parasiticidal thiosemicarbazone cysteine protease inhibitors against Plasmodium falciparum, Trypanosoma brucei and Trypanosoma cruzi. J Med Chem 47:3212–3219

    Article  CAS  PubMed  Google Scholar 

  • Henkin J (1993) Proteases and metastasis. Ann Rep Med Chem 28:151–160

    Article  CAS  Google Scholar 

  • Jain M, Bakhshi S, Shukla AA, Chauhan SS (2010) Cathepsins B and L in peripheral blood mononuclear cells of pediatric acute myeloid leukemia: potential poor prognostic markers. Ann Hematol 89:1223–1232

    Article  CAS  PubMed  Google Scholar 

  • Jedeszko C, Sloane BF (2004) Cysteine cathepsins in human cancer. Biol Chem 385:1017–1027

    Article  CAS  PubMed  Google Scholar 

  • Joyce JA, Hanahan D (2004) Mutiple roles for cysteine cathepsins in cancer. Cell Cycle 3:1516–1619

    Article  CAS  PubMed  Google Scholar 

  • Kamatsu K, Tsukuda K, Hosoya J, Satoh S (1986) Elevation of cathepsin B and Cathepsin L activities in fore limb and hind limb muscles of dystrophic mice. Exp Neurol 93:642–646

    Article  Google Scholar 

  • Kamboj RC, Pal S, Raghav N, Singh H (1993) Selective colorimetric assay for cathepsin L using Z-Phe-Arg-4-ethoxy-β-naphthylamide. Biochimie 75:873–878

    Article  CAS  PubMed  Google Scholar 

  • Kirschke H (1977) Cathepsin H: an endoaminopeptidase. Acta Biol Med Ger 36:1547–1548

    CAS  PubMed  Google Scholar 

  • Kumar GDK, Chavarria GE, Charlton-Sevcik AK, Arispe WM, MacDonough MT, Strecker TE, Chen SE, Siim BG, Chaplin DJ, Trawick ML, Pinney KG (2010a) Design, synthesis and biological evaluation of potent thiosemicarbazone based cathepsin L inhibitors. Bioorg Med Chem Lett 20:1415–1419

    Article  Google Scholar 

  • Kumar GDK, Chavarria GE, Charlton-Sevcik AK, Yoo GK, Song J, Strecker TE, Siim BG, Chaplin DJ, Trawick ML, Pinney KG (2010b) Functionalized benzophenone, thiophene, pyridine and fluorine thiosemicarbazone derivatives as inhibitors of cathepsin L. Bioorg Med Chem Lett 20:6610–6615

    Article  CAS  PubMed  Google Scholar 

  • Lah T, Skaleric U, Babnik J, Turk V (1986) Detection of cathepsin L-like proteinase and cathepsin D in gingival fluid. J Peridontal Res 21:504–509

    Article  CAS  Google Scholar 

  • Lah TT, Kalman E, Najjar D, Gorodetsky E, Brennan P, Somers R, Daskal I (2000) cells producing cathepsins D, B, and L in human breast carcinoma and their association with prognosis. Hum Pathol 31:149–160

    Article  CAS  PubMed  Google Scholar 

  • Lankelma JM, Voorend DM, Barwari T, Koestsveld J, Vander Spek AH, De Porto AP, Van Rooijen G, Van Noorden CJ (2010) Cathepsin L, target in cancer treatment? Life Sci 86:225–233

    Article  CAS  PubMed  Google Scholar 

  • Linnerth NM, Sirbovan K, Moorehead RA (2005) Use of a transgenic mouse model to identify markers of human lung tumors. Int J Cancer 114:977–982

    Article  CAS  PubMed  Google Scholar 

  • Liu J, Sukhova GK, Yang JT, Sun J, Ma L, Ren A, Xu WH, Fu H, Dolganov GM, Hu C, Libby P, Shi GP (2006) Cathepsin L expression and regulation in human abdominal aortic aneurysm, atherosclerosis and vascular cells. Atherosclerosis 184:302–311

    Article  CAS  PubMed  Google Scholar 

  • Maciewicz RA, Etherington DJ (1988) Enzyme immunoassay for cathepsins B and L in synovial fluids from patients with arthritis. Biochem Soc Trans 16:812–813

    Article  CAS  Google Scholar 

  • Mohamed MM, Sloane BF (2006) Cysteine cathepsins: multifunctional enzymes in cancer. Nat Rev Cancer 6:764–775

    Article  CAS  PubMed  Google Scholar 

  • Mort JS, Buttle DJ (1997) Cathepsin B. Int J Biochem Cell Biol 29:715–720

    Article  CAS  PubMed  Google Scholar 

  • Nfor EN, Esemu SN, Ayimele GA, Eno EA, Iniama GE, Offiong OE (2011) Synthesis, stereochemistry and antimicrobial activity of copper(ii) and nickel(ii) complexes of 4-phenylsemicarbazones. Bull Chem Soc Ethiop 25:361–370

    Article  CAS  Google Scholar 

  • Nouh MA, Mohamed MM, EI-Shinawi M, Shaalan MA, Cavallo-Medved D, Khaled HM, Sloane BF (2011) Cathepsin B: a potential prognostic marker for inflammatory breast cancer. J Transl Med 9:1–8. doi:10.1186/1479-5876-9-1

  • Nutting CM, Van Herpen CML, Miah AB, Bhide SA, Machiels JP, Buter J, Kelly C, de Raucourt D, Harrington KJ (2009) Phase II study of 3-AP Triapine in patients with recurrent or metastatic head and neck squamous cell carcinoma. Ann Oncol 20:1275–1279

    Article  CAS  PubMed  Google Scholar 

  • Ostensen M, Morland B, Husby G (1983) Stimulation of murine macrophage cathepsin B by serum from patients with rheumatoid arthritis: an indicator of disease activity. Clin Exp Immunol 51:103–109

    CAS  PubMed  PubMed Central  Google Scholar 

  • Otto HH, Schirmeister T (1997) Cysteine proteases and their inhibitors. Chem Rev 97:133–171

    Article  CAS  PubMed  Google Scholar 

  • Podgorski I, Sloane BF (2003) Cathepsin B and its role(s) in cancer progression. Biochem Soc Symp 70:263–276

    Article  CAS  Google Scholar 

  • Puthucode RN, Pugazhenthi U, Quali JW, Stables JP, Dimmock JR (1998) Anticonvulsant activity of various aryl, arylidene and aryloxyaryl semicarbazones. Eur J Med Chem 33:595–607

    Article  Google Scholar 

  • Raghav N, Garg S (2014a) SAR studies of o-hydroxychalcones and their cyclised analogs and study them as novel inhibitors of cathepsin b and cathepsin H. Eur J Pharm Sci 60:55–63

    Article  CAS  PubMed  Google Scholar 

  • Raghav N, Garg S (2014b) N-formylpyrazolines and N-benzoylpyrazolines as novel inhibitors of mammalian cathepsin B and cathepsin H. Bioorg Chem 57:43–50

    Article  CAS  PubMed  Google Scholar 

  • Raghav N, Kaur R (2014) Synthesis and evaluation of some semicarbazone and thiosemicarbazone based cathepsin B inhibitors. Med Chem Res 23:4669–4679

    Article  CAS  Google Scholar 

  • Raghav N, Singh M (2014a) Design synthesis and docking studies of bischalcones based quinazoline-2(1H)-ones and quinazoline-2(1H)-thiones derivatives as novel inhibitors of cathepsin B and cathepsin H. Eur J Pharm Sci 54:28–39

    Article  CAS  PubMed  Google Scholar 

  • Raghav N, Singh M (2014b) Acyl hydrazide and triazoles as novel inhibitors of mammalian cathepsin B and cathepsin H. Eur J Med Chem 77:231–242

    Article  CAS  PubMed  Google Scholar 

  • Raghav N, Singh M (2014c) SAR studies of differently functionalized chalcones based hydrazones and their cyclized derivatives as inhibitors of mammalian cathepsin B and cathepsin H. Bioorg Med Chem 22:4233–45

    Article  CAS  PubMed  Google Scholar 

  • Raghav N, Singh M, Garg S, Kaur R, Jangra S, Ravish I (2015) Ion exchangers: a useful tool for separation and simultaneous purification of lysosomal cysteine proteinases, cathepsins B, H and L. Int J Pharm Sci Res 6:2944–2949

    CAS  Google Scholar 

  • Romeiro NC, Aguirre G, Hernández P, González M, Cerecetto H, Aldana I, Pérez-Silanes S, Monge A, Barreiro EJ, Lima LM (2009) Synthesis,trypanocidal activity and docking studies of novel quinoxaline-Nacylhydrazones, designed as cruzain inhibitors candidates. Bioorg Med Chem 17:641–652

    Article  CAS  PubMed  Google Scholar 

  • Sami AJ, Shakoor AR (2011) Cellulase activity inhibition and growth retardation of associated bacterial strains of Aulacophora foviecollis by two glycosylated flavonoids isolated from Mangifera indica leaves. J Med Plants Res 5:184–190

    CAS  Google Scholar 

  • Schenker P, Alfarano P, kolb P, Caflisch A, Baici A (2008) A double-headed cathepsin B inhibitor devoid of warhead. Protein Sci 17:2145–2155

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Schweiger A, Christensen IJ, Nielsen HJ, Sorensen S, Brunner N, Kos J (2004) Serum cathepsin H as a potential prognostic marker in patients with colorectal cancer. Int J Biol Markers 19:289–294

    Article  CAS  PubMed  Google Scholar 

  • Selzer PM, Pingel S, Hsieh I, Ugele B, Chan VJ, Engel JC, Bogyo M, Russell DG, Sakanari JA, Mckerrow JH (1999) Cysteine protease inhibitors as chemotherapy: lessons from a parasite target. Proc Natl Acad Sci 96:11015–11022

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Steverding D (2011) The Cathepsin B-selective inhibitors CA-074 and CA-074Me inactivate Cathepsin L under reducing conditions. Open Enzyme Inhib J 4:11–16

    Article  CAS  Google Scholar 

  • Swathi K, Sarangapani M (2014) Synthesis and anti-inflammatory activity of a novel series of isatin hydrazone & isatin thiosemicarbazone derivatives. World J Pharm Pharm Sci 3(2014):2070–2078

    Google Scholar 

  • Tenorio RP, Carvalho CS, Pessanha CS, de Lima JG, de Faria AR, Alves AJ, de Melo EJT, Goes AJS (2005) Synthesis of thiosemicarbazone and 4-thiazolidinone derivatives and their in vitro anti-toxoplasma gondii activity. Bioorg Med Chem Lett 15:2575–2578

    Article  CAS  PubMed  Google Scholar 

  • Toomes C, James J, Wood AJ, Wu CL, Mccormlck D, Lench N, Hewitt C, Moynlnam L, Roberts E, Woods CG, Markham A, Wong M, Widmer R, Ghaffar KA, Pemberton M, Husseln IR, Temtamy SA, Davles R, Read AP, Sloan P, Dixon MJ, Thakker NS (1999) Loss of function mutations in the cathepsin C gene result in periodontal disease and palmoplantar keratosis. Nat Genet 23:421–424

    Article  CAS  PubMed  Google Scholar 

  • Turk V, Turk B, Guncar G, Turk D, Kos J (2002) Lysosomal cathepsins: structure, role in antigen processing and presentation and cancer. Adv Enzyme Regul 42(2002):285–303

    Article  CAS  PubMed  Google Scholar 

  • Van der Stappen WJJos, Paraskeva C, Williams AC, Hague A, Maciewicz RA (1991) Relationship between the secretion of cysteine proteinases and their inhibitors and malignant potential. Biochem Soc Trans 19:362S

    Article  PubMed  Google Scholar 

  • Waghray A, Keppler D, Sloane BF, Schuger L, Chen YQ (2002) Analysis of a truncated form of cathepsin H in human prostate tumor cells. J Biol Chem 277:11533–11538

    Article  CAS  PubMed  Google Scholar 

  • Warren JD, Woodward DL, Hargreaves RT (1977) 4-Substituted semicarbazones of mono and dichlorobenzaldehydes as antihypertensive agents. J Med Chem Res 20:1520–1521

    Article  CAS  Google Scholar 

  • Wolters PJ, Chapman HA (2000) Importance of lysosomal cysteine proteases in lung disease. Respir Res 1:170–177

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgement

Among the authors, Ravinder Kaur acknowledges Kurukshetra University, Kurukshetra for providing URS and other lab facilities.

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  1. Department of Chemistry, Kurukshetra University, Kurukshetra, Haryana, 132116, India

    Neera Raghav & Ravinder Kaur

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  1. Neera Raghav
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  2. Ravinder Kaur
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Correspondence to Neera Raghav.

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Raghav, N., Kaur, R. A comparative account of sar studies of semicarbazones and thiosemicarbazones on cathepsins H and L. Med Chem Res 26, 1723–1734 (2017). https://doi.org/10.1007/s00044-017-1826-9

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  • DOI: https://doi.org/10.1007/s00044-017-1826-9

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