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Vitamin D current outlook, design and synthesis of active analogs
1. UNIVERSIDAD DE SANTIAGO DE COMPOSTELA
Departamento de Química Orgánica
Santiago de Compostela E-15782, España
Antonio Mouriño: antonio.mourino@usc.es
Vitamin D: Current Outlook, Design
and Synthesis of Active Analogs
Development of Active vitamin D Analogues
Birmingham. DECIDE. Nov 14, 2013
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35. COLLABORATIONS
Prof Roger Bouillon and Mieke Verstuyf
Leuven University
Transactivation, Calcemic Effects,
Cell Differentiation-Proliferation
Prof Alberto Muñóz
Institute of Biomedical Investigations
CSIC-Madrid
Transactivation,
Cell Diffentiation-Proliferation
(colon cancer cell lines)
Prof. Román Pérez Fernández
Faculty of Medicine-USC
Santiago Compostela
Transactivation, Calcemic Effects,
Cell Differentiation-Proliferation
Prof. Dino Moras and Natacha Rochel
IGBMC-Illkirch-France
Structural Studies
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44. Drop containing crystals of Moras mutant VDR LBD complexed to 4c
Prof. Dino Moras (GBMC-Illkirch-Francia)
HO
Diyne-LBD(VDR)Complex
HO
H
OH
VDR
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45. Crystallographic Structue of the Diyne
superimposed with 1,25D
N Rochel, S Hourai, X Pérez, A Rumbo, A Mouriño
Arch. Biochem. Biophys. 2007, 460, 172-176
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50. Design, Syntheses and Biological Assays of
1,25D Analogs with Side Chains at C-12
1,25D Analogs with Side Chains at C-12.
Vitamin Analogues with Side Chains atC-12
J. Med. Chem. 2006, 49, 1509-1516
OH
OH
n
Exploration of side
chains at C-12
n = 1, 2, 3
?
H
HO
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OH
12
H
Docking
HO
OH
55. J. Med. Chem. 2012, 55, 8642
in silico LBD(VDR)
100
104
113
112
Affinity for hVDR
100
17
22
13
Transactivation (10-9 M)
100
40
36
57
Ca Effects
100
0
18
1
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56. Analogs of 1,25D with Side Chains at C-18
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59. comparably to “1,25”
DS-A y DS-B Induce cell differentiation in colon
cancer cell lines (SW-480-ADH) similarly to 1,25D
A
48 h
Vehicle
1α,25-D3
DS-A
DS-B
le 5-D 3
ic ,2
eh 1α
V
DS-A DS-B
B
Time (h)
48
8
1.0
1.6
48
8
48
8
48
E-cadherin
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6.3 1.7 4.6 0.8 1.5
60. DS-A and DS-B activate VDR transactivation in
human colon cancer cells (SW480-ADH).
VDRE activation (fold increase)
30
25
20
15
10
5
0
10- 9 10- 8 10- 7 10- 9 10- 8 10- 7 10- 9 10- 8 10- 7
1α,25-D3
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DS-A
DS-B
61. DS-A and DS-B inhibit cell proliferation (50% vs 1,25)
Cell proliferation (% inhibition)
50
40
30
20
10
0
1α,25-D3 DS-A
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DS-B
62. Structures of Superagonists MC1288 y KH1060
Superagonists: Potent inducers of cell
differentiation
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63. Superimposition of the crystallographic
structures of 1,25D and superagonists
KH1060 y MC1288
Moras D et al.
PNAS 2001, 98, 5491-5496
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64. Rational Design of a New Superagonist
New Superagonist?
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70. 58
DESIGN OF A NEW SUPERAGONIST
+
ISOMER A
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=
2-Me-1,25D
BINDS 4 TIMES
BETTER TO VDR
THAN 1,25D
A-Me
NEW
SUPERAGONIST?
29
73. TRANSACTIVATION ACTIVITY
A-Me is 13 times more potent than 1,25D and 4
times more potent than A at 10-10 M
1,25D
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A
A-Me