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doi:10.1016/j.bmc.2005.09.009 
Copyright © 2005 Elsevier Ltd All rights reserved.
Versatile synthesis and biological evaluation of 1,3-diamino-substituted 1α,25-dihydroxyvitamin D3 analogues
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Daniel Ovesa, Susana Fernándeza, Miguel Ferreroa, Roger Bouillonb, Annemieke Verstuyfb and Vicente Gotora, 
, 
Received 30 May 2005;
Abstract
A concise route to 1α,3β-diamino-25-hydroxy-3-deoxyvitamin D3 (5) and 1β,3α-diamino-25-hydroxy-3-deoxyvitamin D3 (6) has been developed starting from (R)- or (S)-carvone for the construction of the modified A-ring fragments. The conversion of the hydroxyl group to amine function with complete inversion of the configuration was efficiently accomplished by Mitsunobu reaction using phthalimide as nucleophile or activation of the hydroxyl group as mesylate followed by reaction with NaN3. Diamino 5 and 6 as well as monoamino 3, 4, 30, and 31 vitamin D3 derivatives have shown poor binding to VDR compared with 1α,25-dihydroxyvitamin D3. The most active compound in the inhibition of MCF-7 cell proliferation and HL 60 cell differentiation was 1α-amino analogue 3. Also, very low in vivo calcemic effects of derivatives 3 and 4 were found.
Keywords: Calcitriol; Monoamino and diamino A-ring; Novel analogues
Article Outline
- 1. Introduction
- 2. Results and discussion
- 3. Biological evaluation
- 4. Conclusions
- 5. Experimental section
- 5.1. General spectroscopic and experimental data
- 5.2. Synthesis of 1α,3β-diamino-25-hydroxy-3-deoxyvitamin D3 (5)
- 5.3. Synthesis of 1β,3α-diamino-25-hydroxy-3-deoxyvitamin D3 (6)
- 5.4. Synthesis of (3R,5S)-3,5-dihydroxy-1-ethynyl-2-methylcyclohex-1-ene (9)
- 5.5. Synthesis of (3S,5R)-1-ethynyl-2-methyl-3,5-bis(phthalimido)cyclohex-1-ene (10)
- 5.5.1. From imide 9
- 5.5.2. From imide 12
- 5.6. Synthesis of (3S,5S)-5-acetoxy-1-ethynyl-2-methyl-3-phthalimidocyclohex-1-ene (11)
- 5.7. Synthesis of (3S,5S)-1-ethynyl-5-hydroxy-2-methyl-3-phthalimidocyclohex-1-ene (12)
- 5.8. Synthesis of (3S,5R)-3,5-bis[(tert-butoxycarbonyl)amino]-1-ethynyl-2-methylcyclohex-1-ene (13)
- 5.8.1. From diimide 10
- 5.8.2. From azide 17
- 5.9. Synthesis of (3S,5S)-3-[(tert-butoxycarbonyl)amino]-1-ethynyl-5-hydroxy-2-methylcyclohex-1-ene (14)
- 5.10. Synthesis of (3S,5R)-3-[(tert-butoxycarbonyl)amino]-1-ethynyl-2-methyl-5-phthalimidocyclohex-1-ene (15)
- 5.11. Synthesis of (3S,5S)-3-[(tert-butoxycarbonyl)amino]-1-ethynyl-5-metanesulfonyloxy-2- methylcyclohex-1-ene (16)
- 5.12. Synthesis of (3S,5R)-5-azido-3-[(tert-butoxycarbonyl)amino]-1-ethynyl-2-methylcyclohex-1-ene (17)
- 5.13. Synthesis of (3R,5R)-5-acetoxy-1-ethynyl-2-methyl-3-phthalimidocyclohex-1-ene (20)
- 5.14. Synthesis of (3R,5R)-3-[(tert-butoxycarbonyl)amino]-1-ethynyl-5-hydroxy-2-methylcyclohex-1-ene (21)
- 5.15. Synthesis of (3R,5R)-3-[(tert-butoxycarbonyl)amino]-1-ethynyl-5-metanesulfonyloxy-2-methylcyclohex-1-ene (22)
- 5.16. Synthesis of (3R,5S)-5-azido-3-[(tert-butoxycarbonyl)amino]-1-ethynyl-2-methylcyclohex-1-ene (23)
- 5.17. Synthesis of (3R,5S)-3,5-bis[(tert-butoxycarbonyl)amino]-1-ethynyl-2-methylcyclohex-1-ene (24)
- 5.18. Synthesis of 1α,3β-bis[(tert-butoxycarbonyl)amino]-25-hydroxy-6,7-didehydro-3-deoxyprevitamin D3 (26)
- 5.19. Synthesis of 1β,3α-bis[(tert-butoxycarbonyl)amino]-25-hydroxy-6,7-didehydro-3-deoxyprevitamin D3 (27)
- 5.20. Synthesis of 1α,3β-bis[(tert-butoxycarbonyl)amino]-25-hydroxy-3-deoxyprevitamin D3 (28)
- 5.21. Synthesis of 1β,3α-bis[(tert-butoxycarbonyl)amino]-25-hydroxy-3-deoxyprevitamin D3 (29)
- 5.22. Synthesis of 1α,3β-bis[(tert-butoxycarbonyl)amino]-25-hydroxy-3-deoxyvitamin D3 (30)
- 5.23. Synthesis of 1β,3α-bis[(tert-butoxycarbonyl)amino]-25-hydroxy-3-deoxyvitamin D3 (31)
- 6. In vitro and in vivo biological evaluation
- Acknowledgements
- Supplementary data
- References
); 30 (
); 31 (
).
