Skip to main content
SpringerLink
Log in

Cyclic enediyne–amino acid chimeras as new aminopeptidase N inhibitors

  • Original Article
  • Published:
Amino Acids Aims and scope Submit manuscript

Abstract

Enediyne–peptide conjugates were designed with the aim to inhibit aminopeptidase N, a widespread ectoenzyme with a variety of functions, like protein digestion, inactivation of cytokines in the immune system and endogenous opioid peptides in the central nervous system. Enediyne moiety was embedded within the 12-membered ring with hydrophobic amino acid alanine, valine, leucine or phenylalanine used as carriers. Aromatic part of the enediyne bridging unit and the amino acid side chains were considered as pharmacophores for the binding to the aminopeptidase N (APN) active site. Additionally, the fused enediyne–amino acid “heads” were bound through a flexible linker to the l-lysine, an amino group donor. The synthesis included building the aromatic enediyne core at the C-terminal of amino acids and subsequent intramolecular N-alkylation. APN inhibition test revealed that the alanine-based derivative 9a inhibits the APN with IC50 of 34 ± 11 μM. Enediyne–alanine conjugate 12 missing the flexible linker was much less effective in the APN inhibition. These results show that enediyne-fused amino acids have potential as new pharmacophores in the design of APN inhibitors.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Scheme 1
Scheme 2
Fig. 2

Similar content being viewed by others

References

  • Abramić M, Vitale LJ (1992) Basic amino acids preferring broad specificity aminopeptidase from human erythrocytes. Biol Chem Hoppe-Seyler 373:375–380

    Article  PubMed  Google Scholar 

  • Abramić M, Šimaga Š, Osmak M, Čičin-Šain L, Vukelić B, Vlahoviček K, Dolovčak Lj (2004) Highly reactive cysteine residues are part of the substrate binding site of mammalian dipeptidyl peptidases III. Int J Biochem Cell Biol 36:434–446

    Article  PubMed  Google Scholar 

  • Addlagatta A, Gay L, Matthews BW (2006) Structure of aminopeptidase N from Escherichia coli suggests a compartmentalized, gated active site. Proc Natl Acad Sci USA 103:13339–13344

    Article  PubMed  CAS  Google Scholar 

  • Addlagatta A, Gay L, Matthews BW (2008) Structural basis for the unusual specificity of Escherichia coli aminopeptidase N. Biochemistry 47:5303–5311

    Article  PubMed  CAS  Google Scholar 

  • Basak A, Khatib AM, Mohottalage D, Basak S, Kolajova M, Bag SS, Basak A (2009) A novel enediynyl peptide inhibitor of furin that blocks processing of proPDGF-A, B and proVEGF-C. PLoS One 4(11):e7700

    Article  PubMed  Google Scholar 

  • Chandra K, Dutta D, Mitra A, Das AK, Basak A (2011) Design, synthesis and inhibition activity of novel cyclic enediyne amino acid conjugates against MPtpA. Bioorg Med Chem 19(10):3274–3279

    Article  PubMed  CAS  Google Scholar 

  • Chen H, Noble F, Coric P, Fournie-Zaluski MC, Roques BP (1998) Aminophosphonic inhibitors as transition state analogues of enkephalin-degrading enzymes: a class of central analgesics. Proc Natl Acad Sci USA 95:12028–12033

    Article  PubMed  CAS  Google Scholar 

  • Cheng XC, Wang Q, Fang H, Tang W, Xu WF (2008) Design, synthesis and evaluation of novel sulfonyl pyrrolidinederivatives as matrix metalloproteinase inhibitors. Bioorg Med Chem 16:5398–5404

    Article  PubMed  CAS  Google Scholar 

  • Drag M, Grembecka J, Pawełczak M, Kafarski P (2005) α-Aminoalkylphosphonates as a tool in experimental optimisation of P1 side chain shape of potential inhibitors in S1 pocket of leucine and neutral aminopeptidases. Eur J Med Chem 40:764–771

    Article  PubMed  CAS  Google Scholar 

  • Drag M, Bogyo M, Ellman JA, Salvesen GS (2010) Aminopeptidase fingerprints, an integrated approach for identification of good substrates and optimal inhibitors. J Biol Chem 285:3310–33318

    Article  PubMed  CAS  Google Scholar 

  • Dutta S, Basak A, Dasgupta S (2009) Design and synthesis of enediyne–peptide conjugates and their inhibiting activity against chymotripsin. Bioorg Med Chem 17(11):3900–3908

    Article  PubMed  CAS  Google Scholar 

  • Flipo M, Beghyn T, Charlton J, Leroux VA, Deprez BP, Deprez-Poulain RF (2007) A library of novel hydroxamic acids targeting the metallo-protease family: design, parallel synthesis and screening. Bioorg Med Chem 15:63–76

    Article  PubMed  CAS  Google Scholar 

  • Fouad FS, Wright JM, Plourde G II, Purohit AD, Wyatt JK, El-Shafey A, Hynd G, Crasto CF, Lin Y, Jones GB (2005) Synthesis and protein degradation capacity of photoactivated enediynes. J Org Chem 70:9789–9797

    Article  PubMed  CAS  Google Scholar 

  • Fukasawa K, Fujii H, Saitoh Y, Koizumi K, Aozuka Y, Sekine K, Yamada M, Saiki I, Nishikawa K (2006) Aminopeptidase N (APN/CD13) is selectively expressed in vascular endothelial cells and plays multiple roles in angiogenesis. Cancer Lett 243(1):135–143

    Article  PubMed  CAS  Google Scholar 

  • Gabrilovac J, Breljak D, Čupić B, Ambriović-Ristov A (2005) Regulation of aminopeptidase N (EC 3.4.11.2; APN; CD13) by interferon-γ on the HL-60 cell line. Life Sci 76:2681–2697

    Article  PubMed  CAS  Google Scholar 

  • Gao JJ, Gao ZH, Zhao CR, Yuan Y, Cui SX, Zhang XF, Cheng YN, Xu WF, Tang W, Qu XJ (2011) LYP, a novel bestatin derivative, inhibits cell growth and suppresses APN/CD13 activity in human ovarian carcinoma cells more potently than bestatin. Invest New Drugs 29(4):574–582

    Article  PubMed  CAS  Google Scholar 

  • Gredičak M, Jerić I (2009) The Sonogashira cross-coupling reaction of alkenyl chlorides with aliphatic acetylenes. Synlett 7:1063–1066

    Google Scholar 

  • Gredičak M, Kolonić A, Jerić I (2008) Novel chloroenyne-modified amino acid derivatives. Amino Acids 35:185–194

    Article  PubMed  Google Scholar 

  • Gredičak M, Matanović I, Zimmermann B, Jerić I (2010) Bergman cyclization of acyclic amino acid derived enediynes leads to the formation of 2,3-dihydrobenzo[f]isoindoles. J Org Chem 75:6219–6228

    Article  PubMed  Google Scholar 

  • Grzywa R, Oleksyszyn J (2008) First synthesis of α-aminoalkyl-(N-substituted)thiocarbamoyl-phosphinates: inhibitors of aminopeptidase N (APN/CD13) with the new zinc-binding group. Bioorg Med Chem Lett 18:3734–3736

    Article  PubMed  CAS  Google Scholar 

  • Grzywa R, Oleksyszyn J, Salvesen GS, Drag M (2010) Identification of very potent inhibitor of human aminopeptidase N (CD13). Bioorg Med Chem Lett 20:2497–2499

    Article  PubMed  CAS  Google Scholar 

  • Hirayama Y, Sakamaki S, Takayanagi N, Tsuji Y, Sagawa T, Chiba C, Matsunaga T, Niitsu Y (2003) Chemotherapy with ubenimex corresponding to patient age and organ disorder for 18 causes of acute myelogeneous leukemia in elderly patients—effects, complications and long term survival. Cancer Chemother 30(8):1113–1118

    Google Scholar 

  • Ito K, Nakajima Y, Onohara Y, Takeo M, Nakashima K, Matsubara F, Ito T, Yoshimoto T (2006) Crystal structure of aminopeptidase N (proteo bacteria alanyl aminopeptidase) from Escherichia coli and conformational change of methionine 260 involved in substrate recognition. J Biol Chem 281:33664–33676

    Article  PubMed  CAS  Google Scholar 

  • Jones RR, Bergman RG (1972) p-Benzyne. Generation as an intermediate in a thermal isomerization reaction and trapping evidence for the 1,4-benzenediyl structure. J Am Chem Soc 94:660–661

    Article  CAS  Google Scholar 

  • Joshi MC, Bisht GS, Rawat DS (2007) Syntheses and antibacterial activity of phendioxy substituted cyclic enediynes. Bioorg Med Chem Lett 17:3226–3230

    Article  PubMed  CAS  Google Scholar 

  • Lee J, Shim JS, Jung SA, Lee ST, Kwon HJ (2005) N-hydroxy-2-(naphtalene-ylsulfanyl)-acetamide, a novel hydroxamic acid-based inhibitor of aminopeptidase N and its anti-angiogenic activity. Bioorg Med Chem 15:181–183

    Article  CAS  Google Scholar 

  • Li Q, Fang H, Xu W (2007) Novel 3-galloylamido-N′-substituted-2,6-piperidinedione-N-acetamide peptidomimetics as metalloproteinase inhibitors. Bioorg Med Chem Lett 17:2935–2938

    Article  PubMed  CAS  Google Scholar 

  • Li X, Wang Y, Wu J, Yonggang L, Wang Q, Xu W (2009) Novel aminopeptidase N inhibitors derived from antineoplaston AS2–5 (Part II). Bioorg Med Chem 17:3061–3071

    Article  PubMed  CAS  Google Scholar 

  • Lin CF, Hsieh PC, Lu WD, Chiu HF, Wu MJ (2001) A series of enediynes as novel inhibitors of topoisomerase I. Bioorg Med Chem 9(7):1707–1711

    Article  PubMed  CAS  Google Scholar 

  • Luan YP, Wang QA, Liu N, Mou JJ, Jiao XJ, Fang H, Li MY, Xu WF (2011) Synthesis and activity evaluation of a new bestatin derivative LYP2 as an aminopeptidase N inhibitor. Anticancer Drugs 22:99–103

    Article  PubMed  CAS  Google Scholar 

  • Maiereanu C, Schmitt C, Schifano-Faux N, Le Nouen D, Defoin A, Tarnus C (2011) A novel amino-benzosuberone derivative is a picomolar inhibitor of mammalian aminopeptidase N/CD13. Bioorg Med Chem 19:5716–5733

    Article  PubMed  CAS  Google Scholar 

  • Mitsunobu O, Yamada M (1967) Preparation of esters of carboxylic and phosphoric acid via quaternary phosphonium salts. Bull Chem Soc Jpn 40:2380–2382

    Article  CAS  Google Scholar 

  • Nicolaou KC, Dai W-M (1991) Chemistry and biology of the enediyne anticancer antibiotics. Angew Chem Int Ed 30(11):1387–1416

    Article  Google Scholar 

  • Nicolaou KC, Zuccarello G, Riemer C, Estevez VA, Dai W-M (1992) Design, synthesis, and study of simple monocyclic conjugated enediynes. The 10-membered ring enediyne moiety of the enediyne anticancer antibiotics. J Am Chem Soc 114:7360–7371

    Article  CAS  Google Scholar 

  • Nicolaou KC, Smith AL, Yue EW (1993) Chemistry and biology of natural and designed enediynes. Proc Natl Acad Sci USA 90:5881–5888

    Article  PubMed  CAS  Google Scholar 

  • Noble F, Roques BP (2007) Protection of endogenous enkephalin catabolism as natural approach to novel analgesic and antidepressant drugs. Expert Opin Ther Targets 11:145–159

    Article  PubMed  CAS  Google Scholar 

  • Petrovic N, Schacke W, Shapiro LH (2004) CD13/Aminopeptidase N in tumor growth and angiogenesis. In: Hooper NM, Lendeckel U (eds) Aminopeptidases in biology and disease. Kluwer Academic/Plenum Publishers, New York, pp 179–200

    Chapter  Google Scholar 

  • Rao M, Li QS, Feng L, Xia X, Ruan LJ, Sheng XF, Ge M (2011) A new aminopeptidase inhibitor from Streptomyces strain HCCB10043 found by UPLC–MS. Anal Bioanal Chem 401:699–706

    Article  PubMed  CAS  Google Scholar 

  • Smith AL, Nicolaou KC (1996) The enediyne antibiotics. J Med Chem 39:2103–2117

    Article  PubMed  CAS  Google Scholar 

  • Sonogashira K, Tohda Y, Hagihara N (1975) A convenient synthesis of acetylenes: catalytic substitutions of acetylenic hydrogen with bromoalkenes, iodoarenes and bromopyridines. Tetrahedron Lett 16(50):4467–4470

    Article  Google Scholar 

  • Taylor A (1993) Aminopeptidases: towards a mechanism of action. Trends Biochem Sci 18:167–171

    PubMed  CAS  Google Scholar 

  • Turner AJ (2004) Membrane alanyl aminopeptidase. In: Barrett AJ, Rawlings ND, Woessner JF (eds) Handbook of Proteolytic Enzymes, vol 1. Elsevier Academic Press, Amsterdam, pp 289–294

    Google Scholar 

  • Wang Q, Chen MY, Zhu HW, Zhang J, Fang H, Wang BH, Xu WF (2008) Design, synthesis and QSAR studies of novel lysine derivatives as amino-peptidase N/CD13 inhibitors. Bioorg Med Chem 10:5473–5481

    Article  Google Scholar 

  • Zhang X, Xu W (2008) Aminopeptidase N (APN/CD13) as a target for anti-cancer agent design. Curr Med Chem 15:2850–2865

    Article  PubMed  CAS  Google Scholar 

  • Zhang X, Fang H, Yuan Y, Xu W (2011) Recent advances in aminopeptidase N (APN/CD13) inhibitor research. Curr Med Chem 18:5011–5021

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This research has been supported by the Croatian Ministry of Science, Education and Sports, Grant Nos. 098-0982933-2936 and 098-1191344-2938.

Author information

Authors and Affiliations

  1. Division of Organic Chemistry and Biochemistry, Ruđer Bošković Institute, Bijenička cesta 54, HR-10002, Zagreb, Croatia

    Matija Gredičak, Marija Abramić & Ivanka Jerić

Authors
  1. Matija Gredičak
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Marija Abramić
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ivanka Jerić
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ivanka Jerić.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Gredičak, M., Abramić, M. & Jerić, I. Cyclic enediyne–amino acid chimeras as new aminopeptidase N inhibitors. Amino Acids 43, 2087–2100 (2012). https://doi.org/10.1007/s00726-012-1292-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00726-012-1292-0

Keywords

Search

Navigation