Synthesis and Biological Evaluation of Polysulfated Oligosaccharide Glycosides as Inhibitors of Angiogenesis and Tumor Growth

Ken D Johnstone; Tomislav Karoli; Ligong Liu; Keith Dredge; Elizabeth Copeman; Cai Ping Li; Kat Davis; Edward Hammond; Ian Bytheway; Edmund Stanley Kostewicz; Francis Chi Keung Chiu; David Shackleford; Susan Ann Charman; William Neil Charman; Job Harenberg; Thomas Gonda; Vito Ferro

doi:10.1021/jm901449m

Synthesis and Biological Evaluation of Polysulfated Oligosaccharide Glycosides as Inhibitors of Angiogenesis and Tumor Growth

Ken D Johnstone, Tomislav Karoli, Ligong Liu, Keith Dredge, Elizabeth Copeman, Cai Ping Li, Kat Davis, Edward Hammond, Ian Bytheway, Edmund Stanley Kostewicz, Francis Chi Keung Chiu, David Shackleford, Susan Ann Charman, William Neil Charman, Job Harenberg, Thomas Gonda, Vito Ferro

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Abstract

A series of polysulfated penta- and tetrasaccharide glycosides containing R(1f3)/R(1f2)-linked mannose residues were synthesized as heparan sulfate (HS) mimetics and evaluated for their ability to inhibit angiogenesis. The compounds bound tightly to angiogenic growth factors (FGF-1, FGF-2,and VEGF) and strongly inhibited heparanase activity. In addition, the compounds exhibited potent activity in cell-based and ex vivo assays indicative of angiogenesis, with tetrasaccharides exhibiting activity comparable to that of pentasaccharides. Selected compounds also showed good antitumor activity in vivo in a mouse melanoma (solid tumor) model resistant to the phase III HS mimetic 1 (muparfostat, formerly known as PI-88). The lipophilic modifications also resulted in reduced anticoagulant activity, a common side effect of HS mimetics, and conferred a reasonable pharmacokinetic profile in the rat, as exemplified by the sulfated octyl tetrasaccharide 5. The data support the further investigation of this class of compounds as potential antiangiogenic, anticancer therapeutics.

Original language	English
Pages (from-to)	1686 - 1699
Number of pages	14
Journal	Journal of Medicinal Chemistry
Volume	53
Issue number	4
DOIs	https://doi.org/10.1021/jm901449m
Publication status	Published - 2010

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10.1021/jm901449m

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Johnstone, K. D., Karoli, T., Liu, L., Dredge, K., Copeman, E., Li, C. P., Davis, K., Hammond, E., Bytheway, I., Kostewicz, E. S., Chiu, F. C. K., Shackleford, D., Charman, S. A., Charman, W. N., Harenberg, J., Gonda, T., & Ferro, V. (2010). Synthesis and Biological Evaluation of Polysulfated Oligosaccharide Glycosides as Inhibitors of Angiogenesis and Tumor Growth. Journal of Medicinal Chemistry, 53(4), 1686 - 1699. https://doi.org/10.1021/jm901449m

@article{964164e55bfe43fe9b9e2659459a1644,

title = "Synthesis and Biological Evaluation of Polysulfated Oligosaccharide Glycosides as Inhibitors of Angiogenesis and Tumor Growth",

abstract = "A series of polysulfated penta- and tetrasaccharide glycosides containing R(1f3)/R(1f2)-linked mannose residues were synthesized as heparan sulfate (HS) mimetics and evaluated for their ability to inhibit angiogenesis. The compounds bound tightly to angiogenic growth factors (FGF-1, FGF-2,and VEGF) and strongly inhibited heparanase activity. In addition, the compounds exhibited potent activity in cell-based and ex vivo assays indicative of angiogenesis, with tetrasaccharides exhibiting activity comparable to that of pentasaccharides. Selected compounds also showed good antitumor activity in vivo in a mouse melanoma (solid tumor) model resistant to the phase III HS mimetic 1 (muparfostat, formerly known as PI-88). The lipophilic modifications also resulted in reduced anticoagulant activity, a common side effect of HS mimetics, and conferred a reasonable pharmacokinetic profile in the rat, as exemplified by the sulfated octyl tetrasaccharide 5. The data support the further investigation of this class of compounds as potential antiangiogenic, anticancer therapeutics.",

author = "Johnstone, {Ken D} and Tomislav Karoli and Ligong Liu and Keith Dredge and Elizabeth Copeman and Li, {Cai Ping} and Kat Davis and Edward Hammond and Ian Bytheway and Kostewicz, {Edmund Stanley} and Chiu, {Francis Chi Keung} and David Shackleford and Charman, {Susan Ann} and Charman, {William Neil} and Job Harenberg and Thomas Gonda and Vito Ferro",

year = "2010",

doi = "10.1021/jm901449m",

language = "English",

volume = "53",

pages = "1686 -- 1699",

journal = "Journal of Medicinal Chemistry",

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publisher = "American Chemical Society",

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Johnstone, KD, Karoli, T, Liu, L, Dredge, K, Copeman, E, Li, CP, Davis, K, Hammond, E, Bytheway, I, Kostewicz, ES, Chiu, FCK, Shackleford, D , Charman, SA, Charman, WN, Harenberg, J, Gonda, T & Ferro, V 2010, 'Synthesis and Biological Evaluation of Polysulfated Oligosaccharide Glycosides as Inhibitors of Angiogenesis and Tumor Growth', Journal of Medicinal Chemistry, vol. 53, no. 4, pp. 1686 - 1699. https://doi.org/10.1021/jm901449m

TY - JOUR

T1 - Synthesis and Biological Evaluation of Polysulfated Oligosaccharide Glycosides as Inhibitors of Angiogenesis and Tumor Growth

AU - Johnstone, Ken D

AU - Karoli, Tomislav

AU - Liu, Ligong

AU - Dredge, Keith

AU - Copeman, Elizabeth

AU - Li, Cai Ping

AU - Davis, Kat

AU - Hammond, Edward

AU - Bytheway, Ian

AU - Kostewicz, Edmund Stanley

AU - Chiu, Francis Chi Keung

AU - Shackleford, David

AU - Charman, Susan Ann

AU - Charman, William Neil

AU - Harenberg, Job

AU - Gonda, Thomas

AU - Ferro, Vito

PY - 2010

Y1 - 2010

N2 - A series of polysulfated penta- and tetrasaccharide glycosides containing R(1f3)/R(1f2)-linked mannose residues were synthesized as heparan sulfate (HS) mimetics and evaluated for their ability to inhibit angiogenesis. The compounds bound tightly to angiogenic growth factors (FGF-1, FGF-2,and VEGF) and strongly inhibited heparanase activity. In addition, the compounds exhibited potent activity in cell-based and ex vivo assays indicative of angiogenesis, with tetrasaccharides exhibiting activity comparable to that of pentasaccharides. Selected compounds also showed good antitumor activity in vivo in a mouse melanoma (solid tumor) model resistant to the phase III HS mimetic 1 (muparfostat, formerly known as PI-88). The lipophilic modifications also resulted in reduced anticoagulant activity, a common side effect of HS mimetics, and conferred a reasonable pharmacokinetic profile in the rat, as exemplified by the sulfated octyl tetrasaccharide 5. The data support the further investigation of this class of compounds as potential antiangiogenic, anticancer therapeutics.

AB - A series of polysulfated penta- and tetrasaccharide glycosides containing R(1f3)/R(1f2)-linked mannose residues were synthesized as heparan sulfate (HS) mimetics and evaluated for their ability to inhibit angiogenesis. The compounds bound tightly to angiogenic growth factors (FGF-1, FGF-2,and VEGF) and strongly inhibited heparanase activity. In addition, the compounds exhibited potent activity in cell-based and ex vivo assays indicative of angiogenesis, with tetrasaccharides exhibiting activity comparable to that of pentasaccharides. Selected compounds also showed good antitumor activity in vivo in a mouse melanoma (solid tumor) model resistant to the phase III HS mimetic 1 (muparfostat, formerly known as PI-88). The lipophilic modifications also resulted in reduced anticoagulant activity, a common side effect of HS mimetics, and conferred a reasonable pharmacokinetic profile in the rat, as exemplified by the sulfated octyl tetrasaccharide 5. The data support the further investigation of this class of compounds as potential antiangiogenic, anticancer therapeutics.

U2 - 10.1021/jm901449m

DO - 10.1021/jm901449m

M3 - Article

SN - 0022-2623

VL - 53

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JO - Journal of Medicinal Chemistry

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ER -