Heparin-steroid conjugates lacking glucocorticoid or mineralocorticoid activities inhibit the proliferation of vascular endothelial cells

Elaine J. Derbyshire, Yong Ching Yang, Shuzhen Li, Georgina A. Comin, Julian Belloir, Philip E. Thorpe

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12 Scopus citations


A new class of angiogenesis inhibitors consist of a non-anticoagulating derivative of heparin, which binds to vascular endothelial cells, coupled to a steroid (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 μM and by 95% at 300 μM. 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.

Original languageEnglish (US)
Pages (from-to)86-96
Number of pages11
JournalBiochimica et Biophysica Acta - Molecular Cell Research
Issue number1
StatePublished - Jan 10 1996



  • Angiogenesis inhibitor
  • Angiostatic steroid
  • Heparin-steroid conjugate
  • Vascular endothelial cell

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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