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Discovery of PG545: A Highly Potent and Simultaneous Inhibitor of Angiogenesis, Tumor Growth, and Metastasis

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Drug Design Group, Progen Pharmaceuticals Limited, Brisbane, Queensland 4076, Australia
Clinical Pharmacology, Faculty of Medicine Mannheim, Ruprecht-Karls University of Heidelberg, Mannheim, Germany
*Phone, +617-3346 9598; fax, +617-3365 4299; e-mail, [email protected]
Cite this: J. Med. Chem. 2012, 55, 8, 3804–3813
Publication Date (Web):March 29, 2012
https://doi.org/10.1021/jm201708h
Copyright © 2012 American Chemical Society

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    Abstract

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    Increasing the aglycone lipophilicity of a series of polysulfated oligosaccharide glycoside heparan sulfate (HS) mimetics via attachment of a steroid or long chain alkyl group resulted in compounds with significantly improved in vitro and ex vivo antiangiogenic activity. The compounds potently inhibited heparanase and HS-binding angiogenic growth factors and displayed improved antitumor and antimetastatic activity in vivo compared with the earlier series. Preliminary pharmacokinetic analyses also revealed significant increases in half-life following iv dosing, ultimately supporting less frequent dosing regimens in preclinical tumor models compared with other HS mimetics. The compounds also displayed only mild anticoagulant activity, a common side effect usually associated with HS mimetics. These efforts led to the identification of 3β-cholestanyl 2,3,4,6-tetra-O-sulfo-α-d-glucopyranosyl-(1→4)-2,3,6-tri-O-sulfo-α-d-glucopyranosyl-(1→4)-2,3,6-tri-O-sulfo-α-d-glucopyranosyl-(1→4)-2,3,6-tri-O-sulfo-β-d-glucopyranoside, tridecasodium salt (PG545, 18) as a clinical candidate. Compound 18 was recently evaluated in a phase I clinical trial in cancer patients.

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    Experimental procedures and characterization data for selected compounds; tables of 1H and 13C NMR chemical shift assignments for compounds 33 and 18; plots of mean plasma concentration versus time for compounds 18, 23, and 24; 1H NMR spectra for compounds 30, 32, 33, and 18; capillary electropherograms for sulfonated test compounds. This material is available free of charge via the Internet at http://pubs.acs.org.

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    7. Mohit Chhabra, Norbert Wimmer, Qi Qi He, Vito Ferro. Development of Improved Synthetic Routes to Pixatimod (PG545), a Sulfated Oligosaccharide-Steroid Conjugate. Bioconjugate Chemistry 2021, 32 (11) , 2420-2431. https://doi.org/10.1021/acs.bioconjchem.1c00453
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    9. Zijun Wu and Jian Wang . Enantioselective Medium-Ring Lactone Synthesis through an NHC-Catalyzed Intramolecular Desymmetrization of Prochiral 1,3-Diols. ACS Catalysis 2017, 7 (11) , 7647-7652. https://doi.org/10.1021/acscatal.7b02302
    10. Eric T. Sletten, Ravi S. Loka, Fei Yu, and Hien M. Nguyen . Glycosidase Inhibition by Multivalent Presentation of Heparan Sulfate Saccharides on Bottlebrush Polymers. Biomacromolecules 2017, 18 (10) , 3387-3399. https://doi.org/10.1021/acs.biomac.7b01049
    11. Jun Zhou, Siying Lv, Dan Zhang, Fei Xia, and Wenhao Hu . Deactivating Influence of 3-O-Glycosyl Substituent on Anomeric Reactivity of Thiomannoside Observed in Oligomannoside Synthesis. The Journal of Organic Chemistry 2017, 82 (5) , 2599-2621. https://doi.org/10.1021/acs.joc.6b03017
    12. Monica Gamez, Hesham E. Elhegni, Sarah Fawaz, Kwan Ho Ho, Neill W. Campbell, David A. Copland, Karen L. Onions, Matthew J. Butler, Elizabeth J. Wasson, Michael Crompton, Raina D. Ramnath, Yan Qiu, Yu Yamaguchi, Kenton P. Arkill, David O. Bates, Jeremy E. Turnbull, Olga V. Zubkova, Gavin I. Welsh, Denize Atan, Simon C. Satchell, Rebecca R. Foster. Heparanase inhibition as a systemic approach to protect the endothelial glycocalyx and prevent microvascular complications in diabetes. Cardiovascular Diabetology 2024, 23 (1) https://doi.org/10.1186/s12933-024-02133-1
    13. V. V. Malashchenko, I. A. Khlusov, K. A. Yurova, O. G. Khaziakhmatova, N. M. Todosenko, L. S. Litvinova. Potential targets of heparin during progression and metastasis of malignant neoplasms. Medical Immunology (Russia) 2024, 26 (2) , 237-252. https://doi.org/10.15789/1563-0625-PTO-2864
    14. Mihály Herczeg, Fruzsina Demeter, Tibor Nagy, Ágnes Rusznyák, Jan Hodek, Éva Sipos, István Lekli, Ferenc Fenyvesi, Jan Weber, Sándor Kéki, Anikó Borbás. Block Synthesis and Step-Growth Polymerization of C-6-Sulfonatomethyl-Containing Sulfated Malto-Oligosaccharides and Their Biological Profiling. International Journal of Molecular Sciences 2024, 25 (1) , 677. https://doi.org/10.3390/ijms25010677
    15. Pradeep Chopra, Tejabhiram Yadavalli, Francesco Palmieri, Seino A. K. Jongkees, Luca Unione, Deepak Shukla, Geert‐Jan Boons. Synthetic Heparanase Inhibitors Can Prevent Herpes Simplex Viral Spread. Angewandte Chemie 2023, 135 (41) https://doi.org/10.1002/ange.202309838
    16. Pradeep Chopra, Tejabhiram Yadavalli, Francesco Palmieri, Seino A. K. Jongkees, Luca Unione, Deepak Shukla, Geert‐Jan Boons. Synthetic Heparanase Inhibitors Can Prevent Herpes Simplex Viral Spread. Angewandte Chemie International Edition 2023, 62 (41) https://doi.org/10.1002/anie.202309838
    17. Joseph Wakpal, Vishaka Pathiranage, Alice R. Walker, Hien M. Nguyen. Rational Design and Expedient Synthesis of Heparan Sulfate Mimetics from Natural Aminoglycosides for Structure and Activity Relationship Studies. Angewandte Chemie 2023, 135 (32) https://doi.org/10.1002/ange.202304325
    18. Joseph Wakpal, Vishaka Pathiranage, Alice R. Walker, Hien M. Nguyen. Rational Design and Expedient Synthesis of Heparan Sulfate Mimetics from Natural Aminoglycosides for Structure and Activity Relationship Studies. Angewandte Chemie International Edition 2023, 62 (32) https://doi.org/10.1002/anie.202304325
    19. Yuzhao Zhang, Lina Cui. Discovery and development of small-molecule heparanase inhibitors. Bioorganic & Medicinal Chemistry 2023, 90 , 117335. https://doi.org/10.1016/j.bmc.2023.117335
    20. Yiyuan Yang, Fengyan Yuan, Huiqin Zhou, Jing Quan, Chongyang Liu, Yi Wang, Fen Xiao, Qiao Liu, Jie Liu, Yujing Zhang, Xing Yu. Potential roles of heparanase in cancer therapy: Current trends and future direction. Journal of Cellular Physiology 2023, 238 (5) , 896-917. https://doi.org/10.1002/jcp.30995
    21. Valentina Borlandelli, Zachary Armstrong, Alba Nin‐Hill, Jeroen D. C. Codée, Lluís Raich, Marta Artola, Carme Rovira, Gideon J. Davies, Herman S. Overkleeft. 4‐ O ‐Substituted Glucuronic Cyclophellitols are Selective Mechanism‐Based Heparanase Inhibitors. ChemMedChem 2023, 18 (4) https://doi.org/10.1002/cmdc.202200580
    22. Charlotte Lemech, Keith Dredge, Darryn Bampton, Edward Hammond, Andrew Clouston, Nigel J Waterhouse, Amanda C Stanley, Lucie Leveque-El Mouttie, Grace M Chojnowski, Andrew Haydon, Nick Pavlakis, Matthew Burge, Michael P Brown, David Goldstein. Phase Ib open-label, multicenter study of pixatimod, an activator of TLR9, in combination with nivolumab in subjects with microsatellite-stable metastatic colorectal cancer, metastatic pancreatic ductal adenocarcinoma and other solid tumors. Journal for ImmunoTherapy of Cancer 2023, 11 (1) , e006136. https://doi.org/10.1136/jitc-2022-006136
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    26. Sam Spijkers‐Shaw, Katrin Campbell, Nicholas J. Shields, John H. Miller, Phillip M. Rendle, Wanting Jiao, Sarah L. Young, Olga V. Zubkova. Synthesis of Novel Glycolipid Mimetics of Heparan Sulfate and Their Application in Colorectal Cancer Treatment in a Mouse Model. Chemistry – An Asian Journal 2022, 17 (12) https://doi.org/10.1002/asia.202200228
    27. D. S.-E. Koffi Teki, B. Coulibaly, A. Bil, A. Vallin, D. Lesur, B. Fanté, V. Chagnault, J. Kovensky. Synthesis of novel S - and O -disaccharide analogs of heparan sulfate for heparanase inhibition. Organic & Biomolecular Chemistry 2022, 20 (17) , 3528-3534. https://doi.org/10.1039/D2OB00250G
    28. Alfredo Rus, Victor M. Bolanos-Garcia, Agatha Bastida, Paula Morales. Identification of Novel Potential Heparanase Inhibitors Using Virtual Screening. Catalysts 2022, 12 (5) , 503. https://doi.org/10.3390/catal12050503
    29. Mohit Chhabra, Jennifer C. Wilson, Liang Wu, Gideon J. Davies, Neha S. Gandhi, Vito Ferro. Structural Insights into Pixatimod (PG545) Inhibition of Heparanase, a Key Enzyme in Cancer and Viral Infections. Chemistry – A European Journal 2022, 28 (11) https://doi.org/10.1002/chem.202104222
    30. Mohit Chhabra, Gareth G. Doherty, Nicholas W. See, Neha S. Gandhi, Vito Ferro. From Cancer to COVID‐19: A Perspective on Targeting Heparan Sulfate‐Protein Interactions. The Chemical Record 2021, 21 (11) , 3087-3101. https://doi.org/10.1002/tcr.202100125
    31. Safa Kinaneh, Iyad Khamaysi, Tony Karram, Shadi Hamoud. Heparanase as a potential player in SARS-CoV-2 infection and induced coagulopathy. Bioscience Reports 2021, 41 (7) https://doi.org/10.1042/BSR20210290
    32. Myriam Torres-Rico, Susana Maza, José L. de Paz, Pedro M. Nieto. Synthesis, structure and midkine binding of chondroitin sulfate oligosaccharide analogues. Organic & Biomolecular Chemistry 2021, 19 (24) , 5312-5326. https://doi.org/10.1039/D1OB00882J
    33. Erika Lisztes, Erika Mező, Fruzsina Demeter, Lilla Horváth, Szilvia Bősze, Balázs István Tóth, Anikó Borbás, Mihály Herczeg. Synthesis and Cell Growth Inhibitory Activity of Six Non‐glycosaminoglycan‐Type Heparin‐Analogue Trisaccharides. ChemMedChem 2021, 16 (9) , 1467-1476. https://doi.org/10.1002/cmdc.202000917
    34. Lutan Zhou, Ronghua Yin, Na Gao, Huifang Sun, Dingyuan Chen, Ying Cai, Lin Ren, Lian Yang, Zhili Zuo, Hongbin Zhang, Jinhua Zhao. Oligosaccharides from fucosylated glycosaminoglycan prevent breast cancer metastasis in mice by inhibiting heparanase activity and angiogenesis. Pharmacological Research 2021, 166 , 105527. https://doi.org/10.1016/j.phrs.2021.105527
    35. Aikaterini Berdiaki, Monica Neagu, Eirini-Maria Giatagana, Andrey Kuskov, Aristidis M. Tsatsakis, George N. Tzanakakis, Dragana Nikitovic. Glycosaminoglycans: Carriers and Targets for Tailored Anti-Cancer Therapy. Biomolecules 2021, 11 (3) , 395. https://doi.org/10.3390/biom11030395
    36. Isabel Faria-Ramos, Juliana Poças, Catarina Marques, João Santos-Antunes, Guilherme Macedo, Celso A. Reis, Ana Magalhães. Heparan Sulfate Glycosaminoglycans: (Un)Expected Allies in Cancer Clinical Management. Biomolecules 2021, 11 (2) , 136. https://doi.org/10.3390/biom11020136
    37. Ying Wang, Xiaojuan Liu, Linling Zhu, Wendie Li, Zhizhe Li, Xiting Lu, Jie Liu, Wenjuan Hua, Yamei Zhou, Yonghui Gu, Manhui Zhu. PG545 alleviates diabetic retinopathy by promoting retinal Müller cell autophagy to inhibit the inflammatory response. Biochemical and Biophysical Research Communications 2020, 531 (4) , 452-458. https://doi.org/10.1016/j.bbrc.2020.07.134
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    39. Xuan Huang, Gina Reye, Konstantin I. Momot, Tony Blick, Thomas Lloyd, Wayne D. Tilley, Theresa E. Hickey, Cameron E. Snell, Rachel K. Okolicsanyi, Larisa M. Haupt, Vito Ferro, Erik W. Thompson, Honor J. Hugo. Heparanase Promotes Syndecan-1 Expression to Mediate Fibrillar Collagen and Mammographic Density in Human Breast Tissue Cultured ex vivo. Frontiers in Cell and Developmental Biology 2020, 8 https://doi.org/10.3389/fcell.2020.00599
    40. Kaishuo Fu, Zhifeng Bai, Lanlan Chen, Wenchong Ye, Meizhu Wang, Jiliang Hu, Chunhui Liu, Wen Zhou. Antitumor activity and structure-activity relationship of heparanase inhibitors: Recent advances. European Journal of Medicinal Chemistry 2020, 193 , 112221. https://doi.org/10.1016/j.ejmech.2020.112221
    41. Xueping Lei, Yihang Zhong, Lijuan Huang, Songpei Li, Jijun Fu, Lingmin Zhang, Yu Zhang, Qiudi Deng, Xiyong Yu. Identification of a novel tumor angiogenesis inhibitor targeting Shh/Gli1 signaling pathway in Non-small cell lung cancer. Cell Death & Disease 2020, 11 (4) https://doi.org/10.1038/s41419-020-2425-0
    42. Ievgen O. Koliesnik, Hedwich F. Kuipers, Carlos O. Medina, Svenja Zihsler, Dan Liu, Jonas D. Van Belleghem, Paul L. Bollyky. The Heparan Sulfate Mimetic PG545 Modulates T Cell Responses and Prevents Delayed-Type Hypersensitivity. Frontiers in Immunology 2020, 11 https://doi.org/10.3389/fimmu.2020.00132
    43. A. Sainio, H. Järveläinen. Extracellular matrix-cell interactions: Focus on therapeutic applications. Cellular Signalling 2020, 66 , 109487. https://doi.org/10.1016/j.cellsig.2019.109487
    44. Victoria Bendersky, Yiping Yang, Todd V. Brennan. Immunomodulatory Activities of the Heparan Sulfate Mimetic PG545. 2020, 461-470. https://doi.org/10.1007/978-3-030-34521-1_18
    45. Mohit Chhabra, Vito Ferro. PI-88 and Related Heparan Sulfate Mimetics. 2020, 473-491. https://doi.org/10.1007/978-3-030-34521-1_19
    46. Giuseppe Giannini, Gianfranco Battistuzzi, Silvia Rivara. The Control of Heparanase Through the Use of Small Molecules. 2020, 567-603. https://doi.org/10.1007/978-3-030-34521-1_23
    47. Mayank Khanna, Christopher R. Parish. Heparanase: Historical Aspects and Future Perspectives. 2020, 71-96. https://doi.org/10.1007/978-3-030-34521-1_3
    48. Liang Wu, Gideon J. Davies. An Overview of the Structure, Mechanism and Specificity of Human Heparanase. 2020, 139-167. https://doi.org/10.1007/978-3-030-34521-1_5
    49. Jicheng Zhang, Xuefei Huang. Heparin mimetics as tools for modulation of biology and therapy. 2020, 71-96. https://doi.org/10.1016/B978-0-12-816675-8.00002-6
    50. Sai-Nan Ma, Zhi-Xiang Mao, Yang Wu, Ming-Xing Liang, Dan-Dan Wang, Xiu Chen, Ping-an Chang, Wei Zhang, Jin-Hai Tang. The anti-cancer properties of heparin and its derivatives: a review and prospect. Cell Adhesion & Migration 2020, 14 (1) , 118-128. https://doi.org/10.1080/19336918.2020.1767489
    51. Deirdre R. Coombe, Neha S. Gandhi. Heparanase: A Challenging Cancer Drug Target. Frontiers in Oncology 2019, 9 https://doi.org/10.3389/fonc.2019.01316
    52. Giancarlo Ghiselli. Heparin Binding Proteins as Therapeutic Target: An Historical Account and Current Trends. Medicines 2019, 6 (3) , 80. https://doi.org/10.3390/medicines6030080
    53. Naphak Modhiran, Neha S. Gandhi, Norbert Wimmer, Stacey Cheung, Katryn Stacey, Paul R. Young, Vito Ferro, Daniel Watterson. Dual targeting of dengue virus virions and NS1 protein with the heparan sulfate mimic PG545. Antiviral Research 2019, 168 , 121-127. https://doi.org/10.1016/j.antiviral.2019.05.004
    54. Aroon Supramaniam, Helle Bielefeldt-Ohmann, Penny A. Rudd, Julie Webster, Vito Ferro, Lara J. Herrero, . PG545 treatment reduces RRV-induced elevations of AST, ALT with secondary lymphoid organ alterations in C57BL/6 mice. PLOS ONE 2019, 14 (6) , e0217998. https://doi.org/10.1371/journal.pone.0217998
    55. Chakrabhavi Dhananjaya Mohan, Swetha Hari, Habbanakuppe D. Preetham, Shobith Rangappa, Uri Barash, Neta Ilan, S. Chandra Nayak, Vijai K. Gupta, Basappa, Israel Vlodavsky, Kanchugarakoppal S. Rangappa. Targeting Heparanase in Cancer: Inhibition by Synthetic, Chemically Modified, and Natural Compounds. iScience 2019, 15 , 360-390. https://doi.org/10.1016/j.isci.2019.04.034
    56. Susana Maza, José L. de Paz, Pedro M. Nieto. Synthesis of a Fluorous-Tagged Hexasaccharide and Interaction with Growth Factors Using Sugar-Coated Microplates. Molecules 2019, 24 (8) , 1591. https://doi.org/10.3390/molecules24081591
    57. Che‐Jui Yeh, Chiao‐Chu Ku, Wei‐Chen Lin, Chiao‐Yuan Fan, Medel Manuel L. Zulueta, Yoshiyuki Manabe, Koichi Fukase, Yaw‐Kuen Li, Shang‐Cheng Hung. Single‐Step Per‐O‐Sulfonation of Sugar Oligomers with Concomitant 1,6‐Anhydro Bridge Formation for Binding Fibroblast Growth Factors. ChemBioChem 2019, 20 (2) , 237-240. https://doi.org/10.1002/cbic.201800464
    58. Edward Hammond, Nicole M. Haynes, Carleen Cullinane, Todd V. Brennan, Darryn Bampton, Paul Handley, Tomislav Karoli, Fleur Lanksheer, Liwen Lin, Yiping Yang, Keith Dredge. Immunomodulatory activities of pixatimod: emerging nonclinical and clinical data, and its potential utility in combination with PD-1 inhibitors. Journal for ImmunoTherapy of Cancer 2018, 6 (1) https://doi.org/10.1186/s40425-018-0363-5
    59. Valentina Masola, Gloria Bellin, Giovanni Gambaro, Maurizio Onisto. Heparanase: A Multitasking Protein Involved in Extracellular Matrix (ECM) Remodeling and Intracellular Events. Cells 2018, 7 (12) , 236. https://doi.org/10.3390/cells7120236
    60. Cinzia Lanzi, Giuliana Cassinelli. Heparan Sulfate Mimetics in Cancer Therapy: The Challenge to Define Structural Determinants and the Relevance of Targets for Optimal Activity. Molecules 2018, 23 (11) , 2915. https://doi.org/10.3390/molecules23112915
    61. Mohit Chhabra, Vito Ferro. The Development of Assays for Heparanase Enzymatic Activity: Towards a Gold Standard. Molecules 2018, 23 (11) , 2971. https://doi.org/10.3390/molecules23112971
    62. Anil Kumar Gorle, Samantha J. Katner, Wyatt E. Johnson, Daniel E. Lee, A. Gerard Daniel, Eric P. Ginsburg, Mark von Itzstein, Susan J. Berners‐Price, Nicholas P. Farrell. Substitution‐Inert Polynuclear Platinum Complexes as Metalloshielding Agents for Heparan Sulfate. Chemistry – A European Journal 2018, 24 (25) , 6606-6616. https://doi.org/10.1002/chem.201706030
    63. Keith Dredge, Todd V. Brennan, Edward Hammond, Jason D. Lickliter, Liwen Lin, Darryn Bampton, Paul Handley, Fleur Lankesheer, Glynn Morrish, Yiping Yang, Michael P. Brown, Michael Millward. A Phase I study of the novel immunomodulatory agent PG545 (pixatimod) in subjects with advanced solid tumours. British Journal of Cancer 2018, 118 (8) , 1035-1041. https://doi.org/10.1038/s41416-018-0006-0
    64. Aroon Supramaniam, Xiang Liu, Vito Ferro, Lara J. Herrero. Prophylactic Antiheparanase Activity by PG545 Is Antiviral In Vitro and Protects against Ross River Virus Disease in Mice. Antimicrobial Agents and Chemotherapy 2018, 62 (4) https://doi.org/10.1128/AAC.01959-17
    65. Susana Maza, Noel Gandia-Aguado, José L. de Paz, Pedro M. Nieto. Fluorous-tag assisted synthesis of a glycosaminoglycan mimetic tetrasaccharide as a high-affinity FGF-2 and midkine ligand. Bioorganic & Medicinal Chemistry 2018, 26 (5) , 1076-1085. https://doi.org/10.1016/j.bmc.2018.01.022
    66. Mugunthan Govindarajan. Amphiphilic glycoconjugates as potential anti-cancer chemotherapeutics. European Journal of Medicinal Chemistry 2018, 143 , 1208-1253. https://doi.org/10.1016/j.ejmech.2017.10.015
    67. Shifaza Mohamed, Deirdre Coombe. Heparin Mimetics: Their Therapeutic Potential. Pharmaceuticals 2017, 10 (4) , 78. https://doi.org/10.3390/ph10040078
    68. Argyris Spyrou, Soumi Kundu, Lulu Haseeb, Di Yu, Tommie Olofsson, Keith Dredge, Edward Hammond, Uri Barash, Israel Vlodavsky, Karin Forsberg-Nilsson. Inhibition of Heparanase in Pediatric Brain Tumor Cells Attenuates their Proliferation, Invasive Capacity, and In Vivo Tumor Growth. Molecular Cancer Therapeutics 2017, 16 (8) , 1705-1716. https://doi.org/10.1158/1535-7163.MCT-16-0900
    69. Zhi-Peng Yu, Na Liu, Ya-Lan Lin, Jian Huang, Hui-Qing Wang, Zong-Quan Wu. Synthesis and chiroptical properties of helical polyallenes bearing chiral cholesteryl pendant groups. Journal of Polymer Science Part A: Polymer Chemistry 2017, 55 (13) , 2227-2233. https://doi.org/10.1002/pola.28609
    70. Anna Alekseeva, Giulia Mazzini, Giuseppe Giannini, Annamaria Naggi. Structural features of heparanase-inhibiting non-anticoagulant heparin derivative Roneparstat. Carbohydrate Polymers 2017, 156 , 470-480. https://doi.org/10.1016/j.carbpol.2016.09.032
    71. Ravi S. Loka, Fei Yu, Eric T. Sletten, Hien M. Nguyen. Design, synthesis, and evaluation of heparan sulfate mimicking glycopolymers for inhibiting heparanase activity. Chemical Communications 2017, 53 (65) , 9163-9166. https://doi.org/10.1039/C7CC04156J
    72. Ryan J. Weiss, Jeffrey D. Esko, Yitzhak Tor. Targeting heparin and heparan sulfate protein interactions. Organic & Biomolecular Chemistry 2017, 15 (27) , 5656-5668. https://doi.org/10.1039/C7OB01058C
    73. Shadi Hamoud, Rabia Shekh Muhammad, Niroz Abu-Saleh, Ahmad Hassan, Yaniv Zohar, Tony Hayek. Heparanase Inhibition Reduces Glucose Levels, Blood Pressure, and Oxidative Stress in Apolipoprotein E Knockout Mice. BioMed Research International 2017, 2017 , 1-9. https://doi.org/10.1155/2017/7357495
    74. Wenbo Zhou, Wenshu Tang, Zhenliang Sun, Yunqi Li, Yanmin Dong, Haixiang Pei, Yangrui Peng, Jinhua Wang, Ting Shao, Zhenran Jiang, Zhengfang Yi, Yihua Chen. Discovery and Optimization of N-Substituted 2-(4-pyridinyl)thiazole carboxamides against Tumor Growth through Regulating Angiogenesis Signaling Pathways. Scientific Reports 2016, 6 (1) https://doi.org/10.1038/srep33434
    75. Soumi Kundu, Anqi Xiong, Argyris Spyrou, Grzegorz Wicher, Voichita D. Marinescu, Per-Henrik D. Edqvist, Lei Zhang, Magnus Essand, Anna Dimberg, Anja Smits, Neta Ilan, Israel Vlodavsky, Jin-Ping Li, Karin Forsberg-Nilsson. Heparanase Promotes Glioma Progression and Is Inversely Correlated with Patient Survival. Molecular Cancer Research 2016, 14 (12) , 1243-1253. https://doi.org/10.1158/1541-7786.MCR-16-0223
    76. Silvia Rivara, Ferdinando M Milazzo, Giuseppe Giannini. Heparanase: A Rainbow Pharmacological Target Associated to Multiple Pathologies Including Rare Diseases. Future Medicinal Chemistry 2016, 8 (6) , 647-680. https://doi.org/10.4155/fmc-2016-0012
    77. Joanna S. Said, Edward Trybala, Staffan Görander, Maria Ekblad, Jan-Åke Liljeqvist, Eva Jennische, Stefan Lange, Tomas Bergström. The Cholestanol-Conjugated Sulfated Oligosaccharide PG545 Disrupts the Lipid Envelope of Herpes Simplex Virus Particles. Antimicrobial Agents and Chemotherapy 2016, 60 (2) , 1049-1057. https://doi.org/10.1128/AAC.02132-15
    78. Tadas Rimkus, Richard Carpenter, Shadi Qasem, Michael Chan, Hui-Wen Lo. Targeting the Sonic Hedgehog Signaling Pathway: Review of Smoothened and GLI Inhibitors. Cancers 2016, 8 (2) , 22. https://doi.org/10.3390/cancers8020022
    79. Marina Weissmann, Gil Arvatz, Netanel Horowitz, Sari Feld, Inna Naroditsky, Yi Zhang, Mary Ng, Edward Hammond, Eviatar Nevo, Israel Vlodavsky, Neta Ilan. Heparanase-neutralizing antibodies attenuate lymphoma tumor growth and metastasis. Proceedings of the National Academy of Sciences 2016, 113 (3) , 704-709. https://doi.org/10.1073/pnas.1519453113
    80. J. L. de Paz, P. M. Nieto. Improvement on binding of chondroitin sulfate derivatives to midkine by increasing hydrophobicity. Organic & Biomolecular Chemistry 2016, 14 (14) , 3506-3509. https://doi.org/10.1039/C6OB00389C
    81. Todd V. Brennan, Liwen Lin, Joshua D. Brandstadter, Victoria R. Rendell, Keith Dredge, Xiaopei Huang, Yiping Yang. Heparan sulfate mimetic PG545-mediated antilymphoma effects require TLR9-dependent NK cell activation. Journal of Clinical Investigation 2015, 126 (1) , 207-219. https://doi.org/10.1172/JCI76566
    82. Anna Shteingauz, Ilanit Boyango, Inna Naroditsky, Edward Hammond, Maayan Gruber, Ilana Doweck, Neta Ilan, Israel Vlodavsky. Heparanase Enhances Tumor Growth and Chemoresistance by Promoting Autophagy. Cancer Research 2015, 75 (18) , 3946-3957. https://doi.org/10.1158/0008-5472.CAN-15-0037
    83. Wei Gao, Heungnam Kim, Mitchell Ho, . Human Monoclonal Antibody Targeting the Heparan Sulfate Chains of Glypican-3 Inhibits HGF-Mediated Migration and Motility of Hepatocellular Carcinoma Cells. PLOS ONE 2015, 10 (9) , e0137664. https://doi.org/10.1371/journal.pone.0137664
    84. Boris Winterhoff, Luisa Freyer, Edward Hammond, Shailendra Giri, Susmita Mondal, Debarshi Roy, Attila Teoman, Sally A. Mullany, Robert Hoffmann, Antonia von Bismarck, Jeremy Chien, Matthew S. Block, Michael Millward, Darryn Bampton, Keith Dredge, Viji Shridhar. PG545 enhances anti-cancer activity of chemotherapy in ovarian models and increases surrogate biomarkers such as VEGF in preclinical and clinical plasma samples. European Journal of Cancer 2015, 51 (7) , 879-892. https://doi.org/10.1016/j.ejca.2015.02.007
    85. Vaibhav Tiwari, Morgan Tarbutton, Deepak Shukla. Diversity of Heparan Sulfate and HSV Entry: Basic Understanding and Treatment Strategies. Molecules 2015, 20 (2) , 2707-2727. https://doi.org/10.3390/molecules20022707
    86. Rami A. Al-Horani, Rajesh Karuturi, Stephen Verespy, Umesh R. Desai. Synthesis of Glycosaminoglycan Mimetics Through Sulfation of Polyphenols. 2015, 49-67. https://doi.org/10.1007/978-1-4939-1714-3_7
    87. Kwok-Kong Tony Mong, Kai-Sheng Shiau, Yu Hsien Lin, Kuang-Chun Cheng, Chun-Hung Lin. A concise synthesis of single components of partially sulfated oligomannans. Organic & Biomolecular Chemistry 2015, 13 (47) , 11550-11560. https://doi.org/10.1039/C5OB01786F
    88. Luning Zu, Yisheng Zhao, Guofeng Gu. Recent Development in the Synthesis of Natural Saponins and Their Derivatives. Journal of Carbohydrate Chemistry 2014, 33 (6) , 269-297. https://doi.org/10.1080/07328303.2014.957387
    89. Ann-Kathrin Schoenfeld, Simone Vierfuß, Susanne Lühn, Susanne Alban. Testing of potential glycan-based heparanase inhibitors in a fluorescence activity assay using either bacterial heparinase II or human heparanase. Journal of Pharmaceutical and Biomedical Analysis 2014, 95 , 130-138. https://doi.org/10.1016/j.jpba.2014.02.021
    90. Claudio Pisano, Israel Vlodavsky, Neta Ilan, Franco Zunino. The potential of heparanase as a therapeutic target in cancer. Biochemical Pharmacology 2014, 89 (1) , 12-19. https://doi.org/10.1016/j.bcp.2014.02.010
    91. Alessia Coletti, Stefano Elli, Eleonora Macchi, Patrizia Galzerano, Leila Zamani, Marco Guerrini, Giangiacomo Torri, Elena Vismara. Conformational changes of 1-4-glucopyranosyl residues of a sulfated CC linked hexasaccharide. Carbohydrate Research 2014, 389 , 134-140. https://doi.org/10.1016/j.carres.2014.02.009
    92. Hong‐Ling Wang, Nan Qin, Jia Liu, Mei‐Na Jin, Xiang Zhang, Mei‐Hua Jin, Dexin Kong, Shen‐De Jiang, Hong‐Quan Duan. Synthesis and Antimetastatic Effects of E ‐Salignone Amide Derivatives. Drug Development Research 2014, 75 (2) , 76-87. https://doi.org/10.1002/ddr.21157
    93. Marta Correia-da-Silva, Emília Sousa, Madalena M. M. Pinto. Emerging Sulfated Flavonoids and other Polyphenols as Drugs: Nature as an Inspiration. Medicinal Research Reviews 2014, 34 (2) , 223-279. https://doi.org/10.1002/med.21282
    94. Vladimir Berezin, Peter S. Walmod, Mikhail Filippov, Alexander Dityatev. Targeting of ECM molecules and their metabolizing enzymes and receptors for the treatment of CNS diseases. 2014, 353-388. https://doi.org/10.1016/B978-0-444-63486-3.00015-3
    95. Jennifer C. Wilson, Andrew Elohim Laloo, Sanjesh Singh, Vito Ferro. 1H NMR spectroscopic studies establish that heparanase is a retaining glycosidase. Biochemical and Biophysical Research Communications 2014, 443 (1) , 185-188. https://doi.org/10.1016/j.bbrc.2013.11.079
    96. Yury N. Kotovshchikov, Gennadij V. Latyshev, Nikolay V. Lukashev, Irina P. Beletskaya. Synthesis of novel 1,2,3-triazolyl derivatives of pregnane, androstane and d -homoandrostane. Tandem “click” reaction/Cu-catalyzed d -homo rearrangement. Org. Biomol. Chem. 2014, 12 (22) , 3707-3720. https://doi.org/10.1039/C4OB00404C
    97. Ana Marta Matos, Ana Paula Francisco. Targets, Structures, and Recent Approaches in Malignant Melanoma Chemotherapy. ChemMedChem 2013, 8 (11) , 1751-1765. https://doi.org/10.1002/cmdc.201300248
    98. Steen U. Hansen, Gavin J. Miller, Claire Cole, Graham Rushton, Egle Avizienyte, Gordon C. Jayson, John M. Gardiner. Tetrasaccharide iteration synthesis of a heparin-like dodecasaccharide and radiolabelling for in vivo tissue distribution studies. Nature Communications 2013, 4 (1) https://doi.org/10.1038/ncomms3016
    99. Margien G.S. Boels, Dae Hyun Lee, Bernard M. van den Berg, Martijn J.C. Dane, Johan van der Vlag, Ton J. Rabelink. The endothelial glycocalyx as a potential modifier of the hemolytic uremic syndrome. European Journal of Internal Medicine 2013, 24 (6) , 503-509. https://doi.org/10.1016/j.ejim.2012.12.016
    100. Vito Ferro. Heparan sulfate inhibitors and their therapeutic implications in inflammatory illnesses. Expert Opinion on Therapeutic Targets 2013, 17 (8) , 965-975. https://doi.org/10.1517/14728222.2013.811491
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