Medicinal Chemistry Research

, Volume 26, Issue 7, pp 1437–1458 | Cite as

Possible anticancer agents: synthesis, pharmacological activity, and molecular modeling studies on some 5-N -Substituted-2-N-(substituted benzenesulphonyl)-L(+)Glutamines

  • Tarun Jha
  • Soumya Basu
  • Amit Kumar Halder
  • Nilanjan Adhikari
  • Soma Samanta
Original Research

Abstract

On the basis of our earlier work, fortyone 5-N-substituted-2N-(substituted benzenesulphonyl)-L(+)glutamines were synthesized and screened for cancer cell inhibitory activity. The best active compounds showed 91% tumor cell inhibition, whereas other three compounds showed more than 80% inhibition. Two-dimensional quantitative structure–activity relationship modeling and three-dimensional quantitative structure–activity relationship k-nearest neighbor molecular field analysis studies were done to get an insight into structural requirements toward further improved anticancer activity. Considering the fact that these compounds are competitive inhibitors of glutaminase, a molecular docking study followed by molecular dynamic simulation analysis were performed. The work may help to develop new anticancer agents.

Keywords

Anticancer agent Glutamine analog 2D-QSAR 3D-QSAR Docking MD simulation 

Notes

Acknowledgements

Authors are thankful to the All India Council for Technical Education (AICTE), New Delhi, Council for Scientific and Industrial Research (CSIR), New Delhi and University Grants Commission (UGC), New Delhi for providing financial support. Two authors (AKH and NA) thank Council for Scientific and Industrial Research (CSIR), New Delhi for providing a Senior Research Fellowship (SRF). We are also thankful to the authority of Jadavpur University for providing us the facility required for the work.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no competing interests.

Supplementary material

44_2017_1858_MOESM1_ESM.docx (27 kb)
Supplementary Information

References

  1. Adhikari N, Halder AK, Mondal C, Jha T (2013a) Exploring structural requirements of aurone derivatives as antimalarials by validated DFT-based QSAR, HQSAR, and COMFA-COMSIA approach. Med Chem Res 22:6029–6045CrossRefGoogle Scholar
  2. Adhikari N, Halder AK, Mondal C, Jha T (2013b) Ligand based validated comparative chemometric modeling and pharmacophore mapping of aurone derivatives as antimalarial agents. Curr Comput Aid Drug Des 9:417–432CrossRefGoogle Scholar
  3. Adhikari N, Halder AK, Mondal C, Jha T (2014) Structural findings of quinolone carboxylic acids in cytotoxic, antiviral, and anti-HIV-1 integrase activity through validated comparative molecular modeling studies. Med Chem Res 23:3096–3127CrossRefGoogle Scholar
  4. Adhikari N, Halder AK, Saha A, Saha KD, Jha T (2015) Structural findings of phenylindoles as cytotoxic antimitotic agents in human breast cancer cell lines through multiple validated QSAR studies. Toxicol in Vit 29:1392–1404CrossRefGoogle Scholar
  5. Adhikari N, Jana D, Halder AK, Mondal C, Maiti MK, Jha T (2012) Chemometric modeling of 5-Phenylthiophenecarboxylic acid derivatives as anti-rheumatic agents. Curr Comput Aid Drug Des 8:182–195CrossRefGoogle Scholar
  6. Bhattacharya P, Maity P (2000) Localization of phosphate dependent glutaminase in ascites fluid of ovarian cancer patient. Pathol Oncol Res 6:217–223CrossRefPubMedGoogle Scholar
  7. Chakraborty D, Maity A, Jain CK, Hazra A, Bharitkar YP, Jha T, Majumder HK, Roychoudhury S, Mondal NB (2015) Cytotoxic potential of dispirooxindolo/acenaphthoquino andrographolide derivatives against MCF-7 cell line. Med Chem Commun 6:702–707CrossRefGoogle Scholar
  8. Chakraborty D, Maity A, Jha T, Mondal NB (2014) Spermicidal and contraceptive potential of desgalactotigonin: a prospective alternative of nonoxynol-9. Plos One 9:e107164CrossRefPubMedPubMedCentralGoogle Scholar
  9. Chang WK, Yang KD, Chuang H, Jan JT, Shaio MF (2002) Glutamine protects activated human T cells from apoptosis by up-regulating glutathione and Bcl-2 levels. Clin Immunol 104:151–160CrossRefPubMedGoogle Scholar
  10. Chatterjee N, Das S, Bose D, Banerjee S, Jha T, Saha KD (2014) Leishmanial lipid suppresses the bacterial endotoxin-induced inflammatory response with attenuation of tissue injury in sepsis. J Leuk Biol. 96:325–336CrossRefGoogle Scholar
  11. Chatterjee N, Das S, Bose D, Banerjee S, Jha T, Saha KD (2015) Leishmanial lipid affords protection against oxidative stress induced hepatic injury by regulating inflammatory mediators and confining apoptosis progress. Toxicol Lett 232:499–512CrossRefPubMedGoogle Scholar
  12. Das S, Chatterjee N, Bose D, Banerjee S, Jha T, Saha KD (2015a) Leishmanial sphingolipid induces apoptosis in Sarcoma 180 cancer cells through regulation of tumour growth via angiogenic switchover. Tumor Biol 36:3109–3118CrossRefGoogle Scholar
  13. Das S, Chatterjee N, Bose D, Banerjee S, Jha T, Saha KD (2015b) Antineoplastic impact of leishmanial sphingolipid in tumour growth with regulation of angiogenic event and inflammatory response. Apoptosis 20:869–882CrossRefPubMedGoogle Scholar
  14. Das S, Chatterjee N, Bose D, Banerjee S, Pal P, Jha T, Saha KD (2014) Lipid isolated from a Leishmania donovani strain reduces Escherichia coli induced sepsis in mice through inhibition of inflammatory responses. Mediat Inflamm 2014, Article number 409694Google Scholar
  15. DeBerardinis R, Lum JJ, Hatzivassiliou G, Thompson CB (2008a) The biology of cancer: metabolic reprogramming fuels cell growth and proliferation. Cell Metabol 7:11–20CrossRefGoogle Scholar
  16. DeBerardinis R, Sayed N, Ditsworth D, Thompson CB (2008b) Brick by brick: metabolism and tumor cell growth. Curr Opin Genet Dev 18:54–61CrossRefPubMedPubMedCentralGoogle Scholar
  17. Deswal S, Roy N (2006) Quantitative structure activity relationship studies of aryl heterocycle-based thrombin inhibitors. Eur J Med Chem 41:1339–1346CrossRefPubMedGoogle Scholar
  18. Dolinska M, Dybel A, Zablocka B, Albrecht J (2003) Glutamine transport in C6 glioma cells shows ASCT2 system characteristics. Neurochem Int 43:501–507CrossRefPubMedGoogle Scholar
  19. Eriksson L, Jaworska J, Worth AP, Cronin MT, McDowell RM, Gramatica P (2003) Methods for reliability and uncertainty assessment and for applicability evaluations of classification- and regression-based QSARs. Environ Health Perspect 111:1361–1375CrossRefPubMedPubMedCentralGoogle Scholar
  20. Frisch MJ, Trucks GW, Schlegel HB, Scuseria GE, Millam MA, Daniels AD, Kudin KN, Strain MC, Farkas O, Tomasi BJV, Cossi M, Cammi R, Mennucci B, Pomelli C, Adamo C, Clifford S, Ochterski J, Petersson GA, Ayala PY, Cui Q, Morokuma K, Salvador P, Dannenberg JJ, Malick DK, Rabuck AD, Raghavachari K, Foresman JB, Cioslowski J, Ortiz JV, Baboul AG, Sefanov BB, Liu G, Liashenko A, Piskorz P, Komaromi I, Gomperts R, Martin RL, Fox DJ, Keith T, A-Laham MA, Peng CY, Nanayakkara A, Challacombe M, Gill PMW, Johnson B, Chen W, Wong MW, Andes JL, Gonzalez C, Head-Gordon M, Replogle ES, Pople JA (2003) Gaussian 03-Revision B.03. Gaussian Inc, PittsburghGoogle Scholar
  21. Golbraikh A, Tropsha A (2002) Beware of q2! J Mol Graph Model 20:269–276CrossRefPubMedGoogle Scholar
  22. Gold Ver. 5.0.1, Astex technology, Cambridge, 2011. https://www.ccdc.cam.ac.uk/solutions/csd-discovery/components/gold/
  23. Halder AK, Saha A, Jha T (2013a) Exploring QSAR and pharmacophore mapping of structurally diverse selective matrix metalloproteinase-2 inhibitors. J Pharm Pharmacol 65:1541–1554CrossRefPubMedGoogle Scholar
  24. Halder AK, Saha A, Jha T (2013b) Exploration of structural and physicochemical requirements and search of virtual hits for aminopeptidase N inhibitors. Mol Divers 17:123–137CrossRefPubMedGoogle Scholar
  25. Halder AK, Saha A, Saha KD, Jha T (2015) Stepwise development of structure–activity relationship of diverse PARP-1 inhibitors through comparative and validated in silico modeling techniques and molecular dynamics simulation. J Biomol Struct Dynam 33:1756–1779CrossRefGoogle Scholar
  26. Hassanein M, Hoeksema MD, Shiota M, Qian J, Harris BK, Chen H, Clark JE, Alborn WE, Eisenberg R, Massion PP (2013) SLC1A5 mediates glutamine transport required for lung cancer cell growth and survival. Clin Cancer Res 19:560–570CrossRefPubMedGoogle Scholar
  27. Hazra A, Mondal C, Chakraborty D, Halder AK, Bharitkar YP, Mondal SK, Banerjee S, Jha T, Mondal NB (2015) Towards the development of anticancer drugs from andrographolide: semisynthesis, bioevaluation, QSAR analysis and pharmacokinetic studies. Curr Top Med Chem 15:1013–1026CrossRefPubMedGoogle Scholar
  28. Hemmateenejad B (2004) Optimal QSAR analysis of the carcinogenic activity of drugs by correlation ranking and genetic algorithm-based PCR. J Chemometr 18:475–485CrossRefGoogle Scholar
  29. Hess B, Kutzner C, van der Spoel D, Lindahl E (2008) GRGMACS 4: Algorithms for highly efficient, load balanced, and scalable molecular simulation. J Chem Theo Comput 4:435–447CrossRefGoogle Scholar
  30. Huang F, Zhao Y, Zhao J, Wu S, Jiang Y, Ma H, Zhang T (2014) Upregulated SLC1A5 promotes cell growth and survival in colorectal cancer. Int J Clin Exp Pathol 7:6006–6014PubMedPubMedCentralGoogle Scholar
  31. Huntress EH, Carten FH (1940) Identification of organic compounds. I. Chlorosulfonic acid as a reagent for the identification of Aryl Halides. J Am Chem Soc 62:511–514CrossRefGoogle Scholar
  32. Jones G, Willet P, Glen RC (1995) Molecular recognition of receptor sites using a genetic algorithm with a description of desolvation. J Mol Biol 245:43–53CrossRefPubMedGoogle Scholar
  33. Jones G, Willet P, Glen RC, Leach AR, Taylor R (1997) Development and validation of a genetic algorithm for flexible docking. J Mol Biol 267:727–748CrossRefPubMedGoogle Scholar
  34. Klimberg VS, McClellan JL (1996) Claude H. Organ, Jr. Honorary Lectureship. Glutamine, cancer, and its therapy. Am J Surg 172:418–424CrossRefPubMedGoogle Scholar
  35. Krogsgaard-Larsen P, Liljefors T, Madsen ULF (2002) Text book of drug design & discovery. Taylor & Francis, LondonGoogle Scholar
  36. Kumar A, Chowdhury SR, Chakrabarti T, Majumder HK, Jha T, Mukhopadhyay S (2014) A new ellagic acid glycoside and DNA topoisomerase IB inhibitory activity of saponins from Putranjiva roxburghii. Nat. Prod. Commun 9:675–677PubMedGoogle Scholar
  37. Kumar A, Chowdhury SR, Jatte KK, Chakrabarti T, Majumder HK, Jha T, Mukhopadhyay S (2015) Anthocephaline, a new indole alkaloid and cadambine, a potent inhibitor of DNA topoisomerase IB of Leishmania donovani (LdTOP1LS), isolated from Anthocephalus cadamba. Nat Prod Commun 10:297–299PubMedGoogle Scholar
  38. Leach, AR (2001) Molecular modeling principles and applications, 2nd edn. Prentice Hall, EnglandGoogle Scholar
  39. Lu W, Pelicano H, Huang P (2010) Cancer metabolism: is glutamine sweeter than glucose? Cancer Cell 18:199–200CrossRefPubMedPubMedCentralGoogle Scholar
  40. Marquez J, Sanchez-Jimenez FM, Medina A, Quesada AR, Nunez de Castro I (1989) Nitrogen metabolism in tumor bearing mice. Arch Biochem Biophys 268:667–675CrossRefPubMedGoogle Scholar
  41. Martin M, Beauvoit B, Voisin PJ, Canoini P, Guerin B, Rigoulet M (1998) Energetic and morphological plasticity of C6 glioma cells grown on 3-D support; effect of transient glutamine deprivation. J Bioenerg Biomembr 30:565–578CrossRefPubMedGoogle Scholar
  42. Massiere F, Badet-Denisot MA (1998) The mechanism of glutamine-dependent amidotransferases. Cell Mol Life Sci 54:205–222CrossRefPubMedGoogle Scholar
  43. Matsuno T, Hirai H (1989) Glutamine synthetase and glutaminase activities in various hepatoma cells. Biochem Int 19:219–225PubMedGoogle Scholar
  44. Mondal C, Halder AK, Adhikari N, Jha T (2013) Cholesteryl ester transfer protein inhibitors in coronary heart disease: Validated comparative QSAR modeling of N, N-disubstituted trifluoro-3-amino-2-propanols. Comp Biol Med 43:1545–1555CrossRefGoogle Scholar
  45. Mondal C, Halder AK, Adhikari N, Jha T (2014) Structural findings of cinnolines as anti-schizophrenic PDE10A inhibitors through comparative chemometric modeling. Mol Divers 18:655–671CrossRefPubMedGoogle Scholar
  46. Mondal C, Halder AK, Adhikari N, Saha A, Saha KD, Gayen S, Jha T (2015) Comparative validated molecular modeling of p53-HDM2 inhibitors as antiproliferative agents. Eur J Med Chem 90:860–875CrossRefPubMedGoogle Scholar
  47. Nargotra A, Koul S, Sharma S, Khan IA, Kumar A, Thota N, Koul JL, Taneja SC, Qazi GN (2009) Quantitative structure-activity relationship (QSAR) of aryl alkenyl amides/imines for bacterial efflux pump inhibitors. Eur J Med Chem 44:229–238CrossRefPubMedGoogle Scholar
  48. Newsholme P, Procopio J, Ramos Lima MS, Pithon-Curi TC, Curi R (2003) Glutamine and glutamate--their central role in cell metabolism and function. Cell Biochem Funct 21:1–9CrossRefPubMedGoogle Scholar
  49. Ogura M, Takarada T, Nakamichi N, Kawagoe H, Sako A, Nakazato R, Yoneda Y (2011) Exacerbated vulnerability to oxidative stress in astrocytic C6 glioma cells with stable overexpression of the glutamine transporter slc38a1. Neurochem Int 58:504–511CrossRefPubMedGoogle Scholar
  50. Roy PP, Roy K (2008) On some aspects of variable selection for partial least squares regression models. QSAR Comb Sci 27:302–313CrossRefGoogle Scholar
  51. Samanta S, Srikanth K, Banerjee S, Debnath B, Gayen S, Jha T (2004) 5-N-Substituted-2-(substituted benzenesulphonyl) glutamines as antitumor agents. Part II: synthesis, biological activity and QSAR study. Bioorg Med Chem 12:1413–1423CrossRefPubMedGoogle Scholar
  52. Snedecor GW, Cochran WG (1967) Statistical methods. Oxford & IBH, New DelhiGoogle Scholar
  53. Van Der Spoel D, Lindahl B, Hess B, Groenhof G, Mark AE (2005) GROMACS: Fast, flexible, and free. J Comput Chem 26:1701–1718CrossRefGoogle Scholar
  54. Szeliga M, Obara-Michlewska M (2009) Glutamine in neoplastic cells: focus on the expression and roles of glutaminases. Neurochem Int 55:71–75CrossRefPubMedGoogle Scholar
  55. Tetko IV, Tanchuk VY, Villa AE (2001) Prediction of n-octanol/water partition coefficients from PHYSPROP database using artificial neural networks and E-state indices. J Chem Inf Comput Sci 41:1407–1421CrossRefPubMedGoogle Scholar
  56. Topliss RP, Edwards P (1979) Chance factors in studies of quantitative structure-activity relationships. J Med Chem 22:1238–1244CrossRefPubMedGoogle Scholar
  57. Tropsha A (2003) Recent trends in quantitative structure-activity relationships. In: Abraham DJ (ed) Burger’s medicinal chemistry and drug discovery, vol 1. 6th edn. Wiley, New York, p 49–75Google Scholar
  58. Tropsha A, Gramatica P, Gomber VK (2003) The Importance of Being Earnest: Validation is the Absolute Essential for Successful Application and Interpretation of QSPR Models. QSAR Comb Sci 22:69–77CrossRefGoogle Scholar
  59. Turner A, McGivan JD (2003) Glutaminase isoform expression in cell lines derived from human colorectal adenomas and carcinomas. Biochem J 370:403–408CrossRefPubMedPubMedCentralGoogle Scholar
  60. Venkatachalam CM, Jiang X, Oldfield T, Waldman M (2003) LigandFit: a novel method for the shape-directed rapid docking of ligands to protein active sites. J Mol Graph Model 21:289–307CrossRefPubMedGoogle Scholar
  61. VLife (2011) QSAR Plus 1.0 is a molecular modelling software of VLife Sciences and Technologies, Pune, India. www.vlifesciences.com
  62. Walker JD, Jaworska J, Comber MH, Schultz TW, Dearden JC (2003) Guidelines for developing and using quantitative structure-activity relationships. Environ Toxicol Chem 22:1653–1665CrossRefPubMedGoogle Scholar
  63. Wasa M, Bode BP, Abcouwer SF, Collins CL, Tanabe KK, Souba WW (1996) Glutamine as a regulator of DNA and protein biosynthesis in human solid tumor cell lines. Ann Surg 224:189–197CrossRefPubMedPubMedCentralGoogle Scholar
  64. Wasa M, Wang HS, Okada A (2002) Characterization of L-glutamine transport by a human neuroblastoma cell line. Am J Physiol Cell Physiol 282:C1246–C1253CrossRefPubMedGoogle Scholar
  65. Witte D, Ali N, Carlson N, Younes M (2002) Overexpression of the neutral amino acid transporter ASCT2 in human colorectal adenocarcinoma. Anticancer Res 22:2555–2557PubMedGoogle Scholar
  66. Xie J, Li P, Gao HF, Qian JX, Yuan LY, Wang JJ (2014) Overexpression of SLC38A1 is associated with poorer prognosis in Chinese patients with gastric cancer. BMC Gastroenterol. 14:70Google Scholar
  67. Zalkin H, Smith JL (1998) Enzymes utilizing glutamine as an amide donor. Adv Enzymol Relat Areas Mol Biol 72:87–144PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2017

Authors and Affiliations

  • Tarun Jha
    • 1
  • Soumya Basu
    • 1
  • Amit Kumar Halder
    • 1
  • Nilanjan Adhikari
    • 1
  • Soma Samanta
    • 1
  1. 1.Natural Science Laboratory, Division of Medicinal and Pharmaceutical Chemistry, Department of Pharmaceutical TechnologyJadavpur UniversityKolkataIndia

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