Azacitidine
From The Cure For The Needy
Contents |
Azacitidine (5-azacytidine, Vidaza)
Effective Against
Myelodysplastic syndrome (MDS)
In treating myleodysplastic syndrome, azacitidine works by helping the bone marrow to produce normal blood cells and by killing abnormal cells in the bone marrow. Specifically, Cells in the presence of azacitidine incorporate it into DNA during replication and RNA during transcription. The incorporation of azacitidine into DNA or RNA inhibits methyltransferase thereby causing demethylation in that sequence, affecting the way that cell regulation proteins are able to bind to the DNA/RNA substrate. Inhibition of DNA methylation occurs through the formation of stable complexes between the molecule and with DNA methyltransferases, thereby saturating the cells methylation machinery.
Cost
Cost of molecule from Sigma-Aldrich: 231 USD (1g)
Reported Routes of Synthesis
The reaction of 1,2,3,5-tetra-O-acetyl-beta-D-ribofuranose (I) with dry HCl in ether-acetic anhydride gives 1-chloro-2,3,5-tri-O-acetyl-beta-D-ribofuranose (II), which by reaction with silver isocyanate in dry xylene is converted into 2,3,5-tri-O-acetyl-beta-D-ribofuranosylisocyanate (III). The reaction of (III) with 2-methylisourea (IV) in dry CHCl3 affords 1-(2,3,5-tri-O-acetyl-3-D-ribofuranosyl)-4-methylisobiuret (V), which is cyclized by reaction with ethyl orthoformate at 135 C yielding 1-(2,3,5-tri-O-acetyl-beta-D-ribofuranosyl)-4-methoxy-2-oxo-1,2-dihydro-1,3,5-triazine (VI). Finally, this compound is treated with ammonia in dry methanol.
Von Hoff, D.D. Azacitidine. Drugs Fut 1980, 5(8): 392
Cost of Starting Materials and Selected Reagents:
Starting Material β-D-Ribofuranose 1,2,3,5-tetraacetate from Sigma-Aldrich: 31.7 USD (1 g)
Hydrochloric acid from Sigma-Aldrich: 46.5 USD (100 mL)
Silver isocyanate pricing not available from Sigma-Aldrich
O-Methylisourea hemisulfate salt from Sigma-Aldrich: 168.5 USD (100 g)
Triethyl orthoformate from Sigma-Aldrich: 47.8 USD (250 mL)
Ammonia solution (2 M in methanol) from Sigma-Aldrich: 57.8 USD (100 mL)
The protection of 5-aza-cytosine (I) by means of HMDS and ammonium sulfate gives N,O-bis(trimethylsilyl)-5-azacytosine (II), which is condensed with 1,2,3,5-tetra-O-acetyl-beta-D-ribofuranose (III) to yield 1',2',3',5'-tetra-O-acetyl-N-trimethylsilyl-5-azacytidine (IV). Finally, this compound is deprotected by means of NaOMe in methanol to obtain the target 5-aza-cytidine.
Synthesis of 5-azacytidine. Ash Stevens,Inc. US 2004186283, WO 2004082618, US 7038038
Cost of Starting Materials and Selected Reagents:
Starting Material 5-azocytosine from Sigma-Aldrich: 38.7 USD (5 g)
Hexamethyldisilazane from Sigma-Aldrich: 39.1 USD (50 mL)
Chlorotrimethylsilane from Sigma-Aldrich: 48.7 USD (100 mL)
Trimethylsilyl trifluoromethanesulfonate from Sigma-Aldrich: 28.1 USD (10 mL)