Heparin-steroid conjugates lacking glucocorticoid or mineralocorticoid activities inhibit the proliferation of vascular endothelial cells
Autor: | Georgina A. Comin, Elaine J. Derbyshire, Philip E. Thorpe, Julian Belloir, Yong Ching Yang, Shuzhen Li |
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Rok vydání: | 1997 |
Předmět: |
DNA Replication
medicine.medical_specialty Hydrocortisone medicine.drug_class Angiogenesis medicine.medical_treatment Cortodoxone Angiogenesis inhibitor Binding Competitive Steroid Cell Line chemistry.chemical_compound Mice Adrenal Cortex Hormones Internal medicine medicine Animals Tetrahydrocortisone Molecular Biology Binding Sites Heparin-steroid conjugate Chemistry Heparin Tetrahydrocortisol Anticoagulants Cell Biology Vascular endothelial cell Angiostatic steroid Endothelial stem cell Endocrinology Mineralocorticoid Endothelium Vascular Glucocorticoid Cell Division medicine.drug |
Zdroj: | Biochimica et biophysica acta. 1310(1) |
ISSN: | 0006-3002 |
Popis: | A new class of angiogenesis inhibitors consist of a non-anticoagulating derivative of heparin, which binds to vascular endothelial cells, coupled to a steriod (e.g., cortisol) which suppresses endothelial cell division. We linked heparin to a further 10 steroids in an effort to identify ones which would yield more effective or safer angiogenesis inhibitors. Steroids having a C3 ketone group were linked by reaction with a hydrazide derivative of heparin. Steroids having a C20 ketone group and lacking a C3 ketone could not be prepared by this method, necessitating the development of alternative methods. The most efficient was to convert the steroid into a derivative having a hydrazone group at C20 and then link the steroid hydrazone to heparin. Conjugates prepared from steroids having C3 ketones were at most 6-fold more inhibitory than the free steroids to endothelial cells in tissue culture. In contrast, steroids having a C20 ketone but lacking a C3 ketone (tetrahydrocortisone, tetrahydrocortisol and tetrahydro S) became highly inhibitory to endothelial cells only after conjugation to heparin. They inhibited [3H]thymidine incorporation by 50% at a steroid concentration of 18-30 microM and by 95% at 300 microM. Since tetrahydrocortisone, tetrahydrocortisol and tetrahydro S lack glucocorticoid and mineralocorticoid activity, they may prove safer alternatives to cortisol for prolonged administration, as is likely to be necessary with anti-angiogenic therapies. |
Databáze: | OpenAIRE |
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