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Design and synthesis of lupeol analogues and their in vitro PTP-1B inhibitory activity

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Abstract

Synthetic analogues of the naturally occurring triterpenoid, lupeol by modification of A-ring and isopropylene moiety with different carboxylic acid functionalities and their biological activity were investigated. The analogues were designed by considering the incorporation of ester and amide linkages in the parent molecule. They were assayed for protein tyrosine phosphatase-1B (PTP-1B) inhibitory activity. Among them, compounds 9a, 9b, 14a, 14b and 14c showed significant dose-dependant inhibition at 10 μM concentration. Our report is marked by readily accessible synthesis, excellent yield and significant PTP-1B inhibitory effect.

Graphical abstract

A synthetic approach and in vitro PTP-1B inhibition of novel analogues of lupeol are described. Compounds 9a, 9b, 14a, 14b and 14a represent a new class of PTP-1B inhibitors in type 2 diabetes

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References

  • Ali H, Houghton PJ, Soumyanath A (2006) α-Amylase inhibitory activity of some Malaysian plants used to treat diabetes; with particular reference to Phyllanthus amarus. J Ethnopharmacol 107:449–455

    Article  PubMed  Google Scholar 

  • Alonso A, Sasin J, Bottini N, Friedberg I, Osterman A, Godzik A, Hunter T, Dixon J, Mustelin T (2004) Protein tyrosine phosphatases in the human genome. Cell 117:699–711

    Article  CAS  PubMed  Google Scholar 

  • Barford D, Flint AJ, Tonks NK (1994) Crystal structure of human protein tyrosine phosphatase 1B. Science 263:1397–1404

    Article  CAS  PubMed  Google Scholar 

  • Bradford PG, Awad AB (2007) Phytosterols as anticancer compounds. Mol Nutr Food Res 51:161–170

    Article  CAS  PubMed  Google Scholar 

  • Choi JY, Na M, Hyun HI, Ho Lee S, Young Bae E, Yeon Kim B, Seog Ahn J (2009) Isolation of betulinic acid, its methyl ester and guaiane sesquiterpenoids with protein tyrosine phosphatase 1B inhibitory activity from the roots of Saussurea lappa CB Clarke. Molecules 14:266–272

    Article  CAS  PubMed  Google Scholar 

  • Cmoch P, Pakulski Z, Swaczynova J, Strnad M (2008) Synthesis of lupane-type saponins bearing mannosyl and 3, 6-branched trimannosyl residues and their evaluation as anticancer agents. Carbohydr Res 343:995–1003

    Article  CAS  PubMed  Google Scholar 

  • Combs AP (2010) Recent advances in the discovery of competitive protein tyrosine phosphatase 1B inhibitors for the treatment of diabetes, obesity, and cancer. J Med Chem 53:2333–2344

    Article  CAS  PubMed  Google Scholar 

  • Corey EJ, Suggs JW (1975) Pyridinium chlorochromate. An efficient reagent for oxidation of primary and secondary alcohols to carbonyl compounds. Tetrahedron Lett 16:2647–2650

    Article  Google Scholar 

  • Elchebly MPP, Michaliszyn E, Cromlish W, Collins S, Loy AL, Normandin D, Cheng A, Himms-Hagen J, Chan CC, Ramachandran C, Gresser MJ, Tremblay ML, Kennedy BP (1999) Increased insulin sensitivity and obesity resistance in mice lacking the protein tyrosine phosphatase-1B gene. Science 283:1544–1548

    Article  CAS  PubMed  Google Scholar 

  • Fernández MA, de las Heras B, Garcia MD, Sáenz MT, Villar A (2001) New insights into the mechanism of action of the anti-inflammatory triterpene lupeol. J Pharm Pharmacol 53:1533–1539

    Article  PubMed  Google Scholar 

  • Fonseca V (2003) Clinical significance of targeting postprandial and fasting hyperglycemia in managing type 2 diabetes mellitus. Curr Med Res Opin 19:635–641

    Article  PubMed  Google Scholar 

  • Fotie J, Scott BD, Leimanis ML, Georges E, Rukunga G, Augustin EN (2006) Lupeol long-chain fatty acid esters with antimalarial activity from Holarrhena floribunda. J Nat Prod 69:62–67

    Article  CAS  PubMed  Google Scholar 

  • Geetha T, Varalakshmi P, Latha RM (1998) Effect of triterpenes from Crataeva Nurvala stem bark on lipid peroxidation in adjuvant induced arthritis in rats. Pharmacol Res 37:191–195

    Article  CAS  PubMed  Google Scholar 

  • Gutiérrez-Nicolás F, Gordillo-Román B, Oberti JC, Estévez-Braun A, Ravelo ÁG, Joseph-Nathan P (2012) Synthesis and anti-HIV activity of lupane and olean-18-ene derivatives. Absolute configuration of 19, 20-epoxylupanes by VCD. J Nat Prod 75:669–676

    Article  PubMed  Google Scholar 

  • Hernández-Pérez M, López-García RE, Rabanal RM, Darias V, Arias A (1994) Antimicrobial activity of Visnea mocanera leaf extracts. J Ethnopharmacol 41:115–119

    Article  PubMed  Google Scholar 

  • Hsia SH, Davidson MB (2002) Established therapies for diabetes mellitus. Curr Med Res Opin 18(Suppl 1):s13–s21

    Article  PubMed  Google Scholar 

  • Jenkins DJ, Kendall CW, Nguyen TH, Marchie A, Faulkner DA, Ireland C, Josse AR, Vidgen E, Trautwein EA, Lapsley KG (2008) Effect of plant sterols in combination with other cholesterol-lowering foods. Metabolism 57:130–139

    Article  CAS  PubMed  Google Scholar 

  • Neises B, Steglich W (1978) Simple method for the esterification of carboxylic acids. Angew Chem Int Ed 17:522–524

    Article  Google Scholar 

  • Nikiema J, Vanhaelen-Fastré R, Vanhaelen M, Fontaine J, De Graef C, Heenen M (2001) Effects of antiinflammatory triterpenes isolated from Leptadenia hastata latex on keratinocyte proliferation. Phytother Res 15:131–134

    Article  CAS  PubMed  Google Scholar 

  • Pereira FBM, Domingnes FMJ, Silva AMS (1996) Triterpenes from Acacia dealbata. Nat Prod Lett 8:97–103

    Article  CAS  Google Scholar 

  • Porte D, Schwartz MW (1996) Diabetes complications: why is glucose potentially toxic? Science 272:1861

    Article  Google Scholar 

  • Preetha SP, Kanniappan M, Selvakumar E, Nagaraj M, Varalakshmi P (2006) Lupeol ameliorates aflatoxin B1-induced peroxidative hepatic damage in rats. Comp Biochem Physiol C Toxicol Pharmacol 143:333–339

    Article  CAS  PubMed  Google Scholar 

  • Qian S, Li HJ, Chen Y, Zhang WY, Yang SY, Wu Y (2010) Synthesis and biological evaluation of oleanolic acid derivatives as inhibitors of protein tyrosine phosphatase 1B. J Nat Prod 73:1743–1750

    Article  CAS  PubMed  Google Scholar 

  • Qiu WW, Shen Q, Yang F, Wang B, Zou H, Li JY, Li J, Tang J (2009) Synthesis and biological evaluation of heterocyclic ring-substituted maslinic acid derivatives as novel inhibitors of protein tyrosine phosphatase 1B. Bioorg Med Chem Lett 19:6618–6622

    Article  CAS  PubMed  Google Scholar 

  • Rendell M (2004) The role of sulphonylureas in the management of type 2 diabetes mellitus. Drugs 64:1339–1358

    Article  CAS  PubMed  Google Scholar 

  • Saleem M (2009) Lupeol, a novel anti-inflammatory and anti-cancer dietary triterpene. Cancer Lett 285:109–115

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Saleem M, Alam A, Arifin S, Shah MS, Ahmed B, Sultana S (2001) Lupeol, a triterpene, inhibits early responses of tumor promotion induced by benzoyl peroxide in murine skin. Pharmacol Res 43:127–134

    Article  CAS  PubMed  Google Scholar 

  • Stein CJ, Colditz GA (2004) The epidemic of obesity. J Clin Endocrinol Metab 89:2522–2525

    Article  CAS  PubMed  Google Scholar 

  • Sudhahar V, Kumar SA, Varalakshmi P, Sujatha V (2008) Protective effect of lupeol and lupeol linoleate in hypercholesterolemia associated renal damage. Mol Cell Biochem 317:11–20

    Article  CAS  PubMed  Google Scholar 

  • Suksamrarn A, Tanachatchairatana T, Kanokmedhakul S (2003) Antiplasmodial triterpenes from twigs of Gardenia saxatilis. J Ethnopharmacol 88:275–277

    Article  CAS  PubMed  Google Scholar 

  • Taniguchi CM, Emanuelli B, Kahn CR (2006) Critical nodes in signalling pathways: insights into insulin action. Nat Rev Mol Cell Biol 7:85–96

    Article  CAS  PubMed  Google Scholar 

  • Tanitame A, Oyamada Y, Ofuji K, Terauchi H, Kawasaki M, Wachi M, Yamagishi JI (2005) Synthesis and antibacterial activity of a novel series of DNA gyrase inhibitors: 5-[(E)-2-arylvinyl]pyrazoles. Bioorg Med Chem Lett 15:4299–4303

    Article  CAS  PubMed  Google Scholar 

  • Wild S, Roglic G, Green A, Sicree R, King H (2004) Global prevalence of diabetes estimates for the year 2000 and projections for 2030. Diabetes Care 27:1047–1053

    Article  PubMed  Google Scholar 

  • Zhang ZY, Thieme-Sefler AM, Maclean D, McNamara DJ, Dobrusin EM, Sawyer TK, Dixon JE (1993) Substrate specificity of the protein tyrosine phosphatases. Proc Natl Acad Sci USA 90:4446–4450

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Zhang W, Hong D, Zhou Y, Zhang Y, Shen Q, Li JY, Hu LH, Li J (2006) Ursolic acid and its derivative inhibit protein tyrosine phosphatase 1B, enhancing insulin receptor phosphorylation and stimulating glucose uptake. Biochim Biophys Acta 1760:1505–1512

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

Authors are very thankful to UGC and CSIR, New Delhi for financial assistance as senior and junior research fellowships. M. F. K. is also acknowledging to SAIF division, CDRI for providing NMR and MASS spectral data as well as S. C. Tiwari for his technical assistance. CDRI communication number is 8633.

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Authors and Affiliations

  1. Medicinal and Process Chemistry Division, CSIR-Central Drug Research Institute, Lucknow, 226031, India

    Mohammad F. Khan, Devendra P. Mishra, E. Ramakrishna & Rakesh Maurya

  2. Biochemistry Division, CSIR-Central Drug Research Institute, Lucknow, 226031, India

    Arun K. Rawat, Akansha Mishra & Arvind K. Srivastava

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  1. Mohammad F. Khan
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  2. Devendra P. Mishra
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  3. E. Ramakrishna
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  7. Rakesh Maurya
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Correspondence to Rakesh Maurya.

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Khan, M.F., Mishra, D.P., Ramakrishna, E. et al. Design and synthesis of lupeol analogues and their in vitro PTP-1B inhibitory activity. Med Chem Res 23, 4156–4166 (2014). https://doi.org/10.1007/s00044-014-0984-2

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  • DOI: https://doi.org/10.1007/s00044-014-0984-2

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