Inhibition of the biosynthesis of complex N-glycans in the Golgi apparatus influences progress of tumor growth and metastasis. Golgi α-mannosidase II (GMII) has become a therapeutic target for drugs with anticancer activities. One critical task for successful application of GMII drugs in medical treatments is to decrease their unwanted co-inhibition of lysosomal α-mannosidase (LMan), a weakness of all known potent GMII inhibitors. A series of novel N-substituted polyhydroxypyrrolidines was synthesized and tested with modeled GH38 α-mannosidases from Drosophila melanogaster (GMIIb and LManII). The most potent structures inhibited GMIIb (Ki =50-76 μm, as determined by enzyme assays) with a significant selectivity index of IC50 (LManII)/IC50 (GMIIb) >100. These compounds also showed inhibitory activities in in vitro assays with cancer cell lines (leukemia, IC50 =92-200 μm) and low cytotoxic activities in normal fibroblast cell lines (IC50 >200 μm). In addition, they did not show any significant inhibitory activity toward GH47 Aspergillus saitoiα1,2-mannosidase. An appropriate stereo configuration of hydroxymethyl and benzyl functional groups on the pyrrolidine ring of the inhibitor may lead to an inhibitor with the required selectivity for the active site of a target α-mannosidase.

Department of Chemistry University of Natural Resources and Life Sciences 1190 Vienna Austria

Institute of Chemistry Center for Glycomics Slovak Academy of Sciences Dúbravská cesta 9 845 38 Bratislava Slovakia

Laboratory of Experimental Medicine Institute of Molecular and Translational Medicine Faculty of Medicine and Dentistry Palacky University and University Hospital in Olomouc Puškinova 6 775 20 Olomouc Czech Republic

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Colegate SM, Dorling PR, Huxtable CR. Aust J Chem. 1979;32:2257–2264.

Dorling PR, Huxtable CR, Colegate SM. Biochem J. 1980;191:649–651. PubMed PMC

Moremen KW. Biochim Biophys Acta Gen Subj. 2002;1573:225–235. PubMed

Tulsiani DR, Harris TM, Touster O. J Biol Chem. 1982;257:7936–7939. PubMed

Cenci di Dello I, Dorling P, Winchester B. Biochem J. 1983;215:693–696. PubMed PMC

Tulsiani DR, Touster O. Arch Biochem Biophys. 1983;224:594–600. PubMed

Tulsiani DRP, Broquist HP, Touster O. Arch Biochem Biophys. 1985;236:427–434. PubMed

Goss PE, Baker MA, Carver JP, Dennis JW. Clin Cancer Res. 1995;1:935–944. PubMed

Olden K, Breton P, Grzegorzewski K, Yasuda Y, Gause BL, Oredipe OA, Newton SA, White SL. Pharmacol Ther. 1991;50:285–290. PubMed

Dennis JW, Koch K, Yousefi S, Vanderelst I. Cancer Res. 1990;50:1867–1872. PubMed

Novikoff PM, Touster O, Novikoff AB, Tulsiani DP. J Cell Biol. 1985;101:339–349. PubMed PMC

Rose DR. Curr Opin Struct Biol. 2012;22:558–562. PubMed

van den Elsen JMH, Kuntz DA, Rose DR. EMBO J. 2001;20:3008–3017. PubMed PMC

Tulsiani DRP, Opheim DJ, Touster O. J Biol Chem. 1977;252:3227–3233. PubMed

Dewald B, Touster O. J Biol Chem. 1973;248:7223–7233. PubMed

Moremen KW, Touster O, Robbins PW. J Biol Chem. 1991;266:16876–16885. PubMed

Kuntz DA, Nakayama S, Shea K, Hori H, Uto Y, Nagasawa H, Rose DR. ChemBioChem. 2010;11:673–680. PubMed

Tulsiani DRP, Touster O. J Biol Chem. 1983;258:7578–7585. PubMed

Goss PE, Reid CL, Bailey D, Dennis JW. Clin Cancer Res. 1997;3:1077–1086. PubMed

Goss JW, Baptiste J, Fernandes B, Baker M, Dennis JW. Cancer Res. 1994;54:1450–1457. PubMed

Heikinheimo P, Helland R, Leiros HKS, Leiros I, Karlsen S, Evjen G, Ravelli R, Schoehn G, Ruigrok R, Tollersrud OK, McSweeney S, et al. J Mol Biol. 2003;327:631–644. PubMed

Liao YF, Lal A, Moremen KW. J Biol Chem. 1996;271:28348–28358. PubMed

Winchester B, Aldaher S, Carpenter NC, Dibello IC, Choi SS, Fairbanks AJ, Fleet GWJ. Biochem J. 1993;290:743–749. PubMed PMC

Dibello IC, Fleet G, Namgoong SK, Tadano K, Winchester B. Biochem J. 1989;259:855–861. PubMed PMC

Bols M, Lopez O, Ortega-Caballero F. In: Comprehensive Glycoscience. 1st ed. Kamerling JP, editor. Vol. 1. Elsevier; Oxford: 2007. pp. 815–867.

Kuntz DA, Zhong W, Guo J, Rose DR, Boons GJ. ChemBioChem. 2009;10:268–277. PubMed PMC

Fiaux H, Kuntz DA, Hoffman D, Janzer RC, Gerber-Lemaire S, Rose DR, Juillerat-Jeanneret L. Bioorg Med Chem. 2008;16:7337–7346. PubMed

Siriwardena A, Strachan H, El-Daher S, Way G, Winchester B, Glushka J, Moremen K, Boons GJ. ChemBioChem. 2005;6:845–848. PubMed

Li B, Kawatkar SP, George S, Strachan H, Woods RJ, Siriwardena A, Moremen KW, Boons GJ. ChemBioChem. 2004;5:1220–1227. PubMed

George S, Li B, Strachan H, Ayres R, Collins R, Siriwardena A, Moremen KW, Boons GJ. Glycobiology. 2002;12:668–668.

Englebienne P, Fiaux H, Kuntz DA, Corbeil CR, Gerber-Lemaire S, Rose DR, Moitessier N. Proteins. 2007;69:160–176. PubMed

Fiaux H, Popowycz F, Favre S, Schutz C, Vogel P, Gerber-Lemaire S, Juillerat-Jeanneret L. J Med Chem. 2005;48:4237–4246. PubMed

Kavlekar LM, Kuntz DA, Wen X, Johnston BD, Svensson B, Rose DR, Pinto BM. Tetrahedron-Asymmetry. 2005;16:1035–1046.

Kuntz DA, Ghavami A, Johnston BD, Pinto BM, Rose DR. Tetrahedron-Asymmetry. 2005;16:25–32.

Wen X, Yuan Y, Kuntz DA, Rose DR, Pinto BM. Biochemistry. 2005;44:6729–6737. PubMed

Chen W, Kuntz DA, Hamlet T, Sim L, Rose DR, Pinto BM. Bioorg Med Chem. 2006;14:8332–8340. PubMed

Kawatkar SP, Kuntz DA, Woods RJ, Rose DR, Boons GJ. J Am Chem Soc. 2006;128:8310–8319. PubMed PMC

Poláková M, Šesták S, Lattová E, Petruš L, Mucha J, Tvaroška I, Kόňa J. Eur J Med Chem. 2011;46:944–952. PubMed

Poláková M, Stanton R, Wilson IBH, Holková I, Šesták S, Machová E, Jandová Z, Kόňa J. Carbohydr Res. 2015;406:34–40. PubMed PMC

Poláková M, Horák R, Šesták S, Holková I. Carbohydr Res. 2016;428:62–71. PubMed

Pearson WH, Guo LY. Tetrahedron Lett. 2001;42:8267–8271.

Hembre EJ, Pearson WH. Tetrahedron. 1997;53:11021–11032.

Shah R, Carver J, Marino-Albernas J, Tvaroška I, Tropper FD, Dennis J. US 2003/0236229 A1. GlycoDesign Inc; Toronto (CA): United States Patent Application Publication. 2003

Fujita T, Nagasawa H, Uto Y, Hashimoto T, Asakawa Y, Hori H. Org Lett. 2004;6:827–830. PubMed

Shah N, Kuntzt DA, Rose DR. Proc Natl Acad Sci U S A. 2008;105:9570–9575. PubMed PMC

Zhong W, Kuntz DA, Ernber B, Singh H, Moremen KW, Rose DR, Boons GJ. J Am Chem Soc. 2008;130:8975–8983. PubMed PMC

Bleriot Y, Dintinger T, Genregrandpierre A, Padrines M, Tellier C. Bioorg Med Chem Lett. 1995;5:2655–2660.

Heck MP, Vincent SP, Murray BW, Bellamy F, Wong CH, Mioskowski C. J Am Chem Soc. 2004;126:1971–1979. PubMed

Kuntz DA, Tarling CA, Withers SG, Rose DR. Biochemistry. 2008;47:10058–10068. PubMed

Kumar NS, Kuntz DA, Wen X, Pinto BM, Rose DR. Proteins. 2008;71:1484–1496. PubMed

Sladek V, Kόňa J, Tokiwa H. Phys Chem Chem Phys. 2017;19:12527–12537. PubMed

Rabouille C, Kuntz DA, Lockyer A, Watson R, Signorelli T, Rose DR, van den Heuvel M, Roberts DB. J Cell Sci. 1999;112:3319–3330. PubMed

Nemčovičová I, Šesták S, Rendić D, Plšková M, Mucha J, Wilson IBH. Glycoconjugate J. 2013;30:899–909. PubMed

Kumar BSG, Pohlentz G, Schulte M, Mormann M, Kumar NS. Glycobiology. 2014;24:252–261. PubMed

Howard S, Braun C, McCarter J, Moremen KW, Liao YF, Withers SG. Biochem Biophys Res Commun. 1997;238:896–898. PubMed

Kuntz DA, Rose DR. Golgi Mannosidase II in complex with swainsonine at 1.3 Angstrom. The Research Collaboratory for Structural Bioinformatics (RCSB): RCSB-Rutgers, RCSB-San Diego Supercomputer Center, and University of Wisconsin-Madison; [Accessed June 04, 2012]. PDB ID: 3BLB. http://www.rcsb.org.

Bobovská A, Tvaroška I, Kóňa J. J Mol Graph Model. 2016;66:47–57. PubMed

Vamshikrishna K, Srihari P. Tetrahedron. 2012;68:1540–1546.

Cho JH, Bernard DL, Sidwell RW, Kern ER, Chu CK. J Med Chem. 2006;49:1140–1148. PubMed

Furst R, Lentsch C, Rinner U. Eur J Org Chem. 2013:2293–2297. PubMed PMC

Kim DK, Kim GH, Kim YW. J Chem Soc Perkin Trans. 1996;1:803–808.

Mercer TB, Jenkinson SF, Bartholomew B, Nash RJ, Miyauchi S, Kato A, Fleet GWJ. Tetrahedron-Asymmetry. 2009;20:2368–2373.

Corsi M, Bonanni M, Catelani G, D'Andrea F, Gragnani T, Bianchini R. Int J Org Chem. 2013;3:41–48.

Vallee F, Yip P, Lipari F, Sleno B, Romero P, Karaveg K, Moremen K, Herscovics A, Howell PL. Glycobiology. 2000;10:1141–1141.

Legler G. In: Inimosugars as Glycosidase Inhibitors: Nojirimycin and beyond. Stütz AE, editor. Wiley-VCH Verlag GmbH; Weinheim: 1999. pp. 31–67.

Lopez O, Qing FL, Pedersen CM, Bols M. Bioorg Med Chem. 2013;21:4755–4761. PubMed

De-Freitas-Junior JCM, Bastos LG, Freire-Neto CA, Du Rocher B, Abdelhay ESFW, Morgado-Diaz JA. J Cell Biochem. 2012;113:2957–296. PubMed

Paschinger K, Hykollari A, Razzazi-Fazeli E, Greenwell P, Leitsch D, Walochnik J, Wilson IBH. Glycobiology. 2012;22:300–313. PubMed PMC

Nosková V, Džubák P, Kuzmina G, Ludková A, Stehlik D, Trojanec R, Janošťáková A, Kořínková G, Mihal V, Hajduch M. Neoplasma. 2002;49:418–425. PubMed

Perlíková P, Rylová G, Nauš P, Elbert T, Tloušťová E, Bourderioux A, Slavětínská LP, Motyka K, Doležal D, Znojek P, Nová A, et al. Mol Cancer Ther. 2016;15:922–937. PubMed

Friesner RA, Banks JL, Murphy RB, Halgren TA, Klicic JJ, Mainz DT, Repasky MP, Knoll EH, Shelley M, Perry JK, Shaw DE, et al. J Med Chem. 2004;47:1739–1749. PubMed

Glide, version 7.0. Schrödinger, LLC; New York, NY: 2016.

Zhao Y, Truhlar DG. Theor Chem Res. 2008;120:215–241.

Murphy RB, Philipp DM, Friesner RA. J Comput Chem. 2000;21:1442–1457.

Qsite. Schrödinger, LLC; New York, NY: 2016.

Jaguar, version 9.1. Schrödinger, LLC; New York, NY: 2016.

Maestro, version 10.5. Schrödinger, LLC; New York, NY: 2016.

Klicic JJ, Friesner RA, Liu SY, Guida WC. J Phys Chem A. 2002;106:1327–1335.

Li H, Robertson AD, Jensen JH. Proteins. 2005;61:704–721. PubMed

Bas DC, Rogers DM, Jensen JH. Proteins. 2008;73:765–783. PubMed

Wadt WR, Hay PJ. J Chem Phys. 1985;82:284–298.

Hay PJ, Wadt WR. J Chem Phys. 1985;82:270–283.

Kaminski GA, Friesner RA, Tirado-Rives J, Jorgensen WL. J Phys Chem B. 2001;105:6474–6487.

Fedorov DG, Nagata T, Kitaura K. Phys Chem Chem Phys. 2012;14:7562–7577. PubMed

Tanaka S, Mochizuki Y, Komeiji Y, Okiyama Y, Fukuzawa K. Phys Chem Chem Phys. 2014;16:10310–10344. PubMed

Fedorov DG, Kitaura K. The Fragnemt Molecular Orbital Method - Practical Applications to Large Molecular Systems. CRC Press, Taylor and Francis Group; 2009.

Gordon MS, Fedorov DG, Pruitt SR, Slipchenko LV. Chem Rev. 2012;112:632–672. PubMed

Arulmozhiraja S, Matsuo N, Ishitsubo E, Okazaki S, Shimano H, Tokiwa H. PLoS One. 2016:11. PubMed PMC

Sriwilaijaroen N, Magesh S, Imamura A, Ando H, Ishida H, Sakai M, Ishitsubo E, Hori T, Moriya S, Ishikawa T, Kuwata K, et al. J Med Chem. 2016;59:4563–4577. PubMed

Boys SF, Bernardi F. Mol Phys. 1970;19:553–566.

Sheng XW, Mentel L, Gritsenko OV, Baerends EJ. J Comput Chem. 2011;32:2896–2901. PubMed

Fukuzawa K, Watanabe C, Kurisaki I, Taguchi N, Mochizuki Y, Nakano T, Tanaka S, Komeiji Y. Comput Theor Chem. 2014;1034:7–16.

Schmidt MW, Baldridge KK, Boatz JA, Elbert ST, Gordon MS, Jensen JH, Koseki S, Matsunaga N, Nguyen KA, Su SJ, Windus TL, et al. J Comput Chem. 1993;14:1347–1363.

Gordon MS, Schmidt MW. Theory and Applications of Computational Chemistry. Elsevier; 2005.

Weigend F. Phys Chem Chem Phys. 2006;8:1057–1065. PubMed

Weigend F, Ahlrichs R. Phys Chem Chem Phys. 2005;7:3297–3305. PubMed

Ren XG, Rinke P, Blum V, Wieferink J, Tkatchenko A, Sanfilippo A, Reuter K, Scheffler M. New J Phys. 2012;14:053020.

Green MC, Fedorov DG, Kitaura K, Francisco JS, Slipchenko LV. J Chem Phys. 2013;138 PubMed

Fedorov DG, Kitaura K. J Comput Chem. 2007;28:222–237. PubMed

Sladek V, Tvaroška I. J Phys Chem B. 2017;121:6148–6162. PubMed