+ Site Statistics
+ Search Articles
+ PDF Full Text Service
How our service works
Request PDF Full Text
+ Follow Us
Follow on Facebook
Follow on Twitter
Follow on LinkedIn
+ Subscribe to Site Feeds
Most Shared
PDF Full Text
+ Translate
+ Recently Requested

Evaluation of O(3alpha)-, O(21)-di-(N(1)-methyloxycarbonyl-2, 4-dioxo-5-fluoropyrimidinyl) 17alpha-hydroxy-5beta-pregnan-20-one as a novel potential antiangiogenic codrug



Evaluation of O(3alpha)-, O(21)-di-(N(1)-methyloxycarbonyl-2, 4-dioxo-5-fluoropyrimidinyl) 17alpha-hydroxy-5beta-pregnan-20-one as a novel potential antiangiogenic codrug



Journal of Enzyme Inhibition and Medicinal Chemistry 20(5): 417-428



Intraocular neovascularization is a complication in a variety of eye diseases, and is a leading cause of visual loss. The purpose of this study was to design and synthesize three novel codrugs of the antiangiostatic steroid, 3alpha, 17alpha, 21-trihydroxy-5beta-pregnan-20-one (trihydroxy steroid, THS) with the cytotoxic agent 5-fluorouracil (5FU) which incorporates either one or two molecules of 5FU attached through carbonate ester linkages at positions O(3), and/or O(21) of the THS molecule. Furthermore, a kinetic study of the O(3alpha)-, O(21)-di-(N(1)-methyloxycarbonyl-2, 4-dioxo-5-fluoropyrimidinyL) 17alpha-hydroxy-5beta-pregnan-20-one (THS-BIS-5FU) codrug was carried out. The overall goal of this codrug strategy was to improve sustained drug delivery of both compounds by overcoming their individual solubility problems, and to thus enhance their bioavailability. The codrug was found to be optimal with superior angiostatic activity using the CAM assay compared to the activity of the parent compounds alone. In the hydrolysis studies 5FU was released at a faster rate than THS with an unknown intermediate observed by HPLC, a rationale and proposed structure and mechanism of the unknown THS derivative is provided.

Please choose payment method:






(PDF emailed within 0-6 h: $19.90)

Accession: 048993013

Download citation: RISBibTeXText

PMID: 16335049

DOI: 10.1080/14756360500220319


Related references

A novel chemical delivery system comprising an ocular sustained release formulation of a 3alpha, 17alpha, 21-trihydroxy-5beta-pregnan-20-one-BIS-5-fluorouracil [correction of flourouracil] codrug. Drug Development and Industrial Pharmacy 33(6): 677-682, 2007

A synthesis of 3alpha,6alpha,17alpha-trihydroxy-5beta-pregnan-20-one (triolone) from 3alpha,6alpha-dihydroxy-5beta-pregnan-20-one (diolone). Acta Poloniae Pharmaceutica 60(4): 281-284, 2004

The identification of 6alpha-hydroxytetrahydrocortisol (3alpha,6alpha,11beta,17alpha,21-pentahydroxy-5beta-pregnan-20-one) in urine. Febs Letters 88(2): 215-218, 1978

Antineophobic effect of the neuroactive steroid 3alpha-hydroxy-5beta-pregnan-20-one in male rats. Pharmacology Biochemistry and Behavior 60(1): 125-131, 1998

Steroids part 34 17beta hydroxy 5beta 14alpha 17alpha pregnan 20 one and related compounds. Journal of the Chemical Society Section C Organic Chemistry (4): 558-590, 1970

Isolation and Identification of 3alpha,17alpha,21trihydroxy-5alpha-Pregnan-20-One (Allo-Tetrahydro-Compound S) After Administration of 3beta, 17alpha,21-Trihydroxypregn-5-En-20-One(17alpha,21-Dihydroxypregnenolone). Biochemical Journal 88: 315-318, 1963

Inhibition of NMDA-induced striatal dopamine release and behavioral activation by the neuroactive steroid 3alpha-hydroxy-5beta-pregnan-20-one hemisuccinate. Journal of Neurochemistry 86(1): 92-101, 2003

Synthesis of 3alpha-hydroxy-21-(1'-imidazolyl)-3beta-methoxyl-methyl-5alpha-pregnan-20-one via lithium imidazole with 17alpha-acetylbromopregnanone. Steroids 71(1): 77-82, 2006

5beta-cholestane-3alpha, 27-diol: NAD+ oxidoreductase and 3alpha-hydroxy-5beta-cholestan-27-al; NAD+ oxidoreductase in rat liver extract. Hiroshima Journal of Medical Sciences 30(1): 1-7, 1981

5beta-Pregnan-3alpha-ol-20-one in urine. Acta Endocrinologica 41: 247-258, 1962

The synthesis of 3beta methoxy 3alpha 9alpha oxido 11alpha 20xidihydroxy 14beta o 18n epoxyethano n methylimino 5beta 17alpha pregnane 30 methyl 17alpha 20xi tetra hydro batrachotoxinin a. Helvetica Chimica Acta: 2267-2275, 1970

Actions of 3alpha - oh - 5beta - pregnan - 20 - one at recombinant GABAa receptors. Society for Neuroscience Abstract Viewer & Itinerary Planner : Abstract No 684 13, 2003

20-oxo-5beta-pregnan-3alpha-yl sulfate is a use-dependent NMDA receptor inhibitor. Journal of Neuroscience 25(37): 8439-8450, 2005

Determination of micro-amounts of 5beta-pregnan-3alpha-ol-20-one in urine using infraredspectrometry. Acta Endocrinologica 41: 234-246, 1962

Preparation and properties of steroidal 17,20- and 20,21-acetonides epimeric at C-20. I. Derivatives of 5beta-pregnan-3alpha-o1. Journal of Organic Chemistry 34(11): 3505-3512, 1969