Vitamin D current outlook, design and synthesis of active analogs
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Vitamin D: Current Outlook, Design and Synthesis of Active Analogs
UNIVERSIDAD DE SANTIAGO DE COMPOSTELADepartamento de Química OrgánicaSantiago de Compostela E-15782, EspañaAntonio Mouriño: [email protected]
Development of Active vitamin D Analogues
UNIVERSIDAD DE SANTIAGO DE COMPOSTELADepartamento de Química OrgánicaSantiago de Compostela E-15782, EspañaAntonio Mouriño: [email protected]
Birmingham. DECIDE. Nov 14, 2013miércoles 27 de noviembre de 2013
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Alimentos
VIT-D3
PRE-D3
7-Deshidrocolesterol25-D3
1,25-D3
Forma Activa
80%20%
Active form 1,25D
Food
7-Dehydrocholesterol
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Vitamin D Metabolism
7-Dehydrocholesterol Previtamin D Cisoid form
Transoid form
Vitamin D
Kidney Liver
3
3
1,25D
(calcitriol)
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.
.
HO
OHHO
H
H
1α,25-(OH)2-D3
ICABCM
.
.
BIOLOGICALRESPONSES
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.
.
HO
OHHO
H
H
1α,25-(OH)2-D3
ICABCM
DIFFERENTIATION PROLIFERATION
Miyaura et alBiochem. Biophys. Res.Commun.1981, 102, 937
.
.
BIOLOGICALRESPONSES
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.
.
HO
OHHO
H
H
1α,25-(OH)2-D3
ICABCM
DIFFERENTIATION PROLIFERATION
Miyaura et alBiochem. Biophys. Res.Commun.1981, 102, 937
BONE DISEASES(OSTEOPOROSIS)
IMMUNOLOGY(TRANSPLANTATION)
PSORIASIS
CANCER
.
.
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DT-71
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HO
H
H
OH
OH
HO
H
H
OH
OH
HO
H
H
OH
OH
HO
H
H
OH
OH
HO
H
H
OH
OH
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HO
H
H
OH
HO
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Cytoplasm
Nucleus
Mode of action of 1α,25-(OH)2-D3
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Cytoplasm
Nucleus
Mode of action of 1α,25-(OH)2-D3
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Cytoplasm
Nucleus
Mode of action of 1α,25-(OH)2-D3
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Cytoplasm
Nucleus
Mode of action of 1α,25-(OH)2-D3
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Cytoplam
Nucleus
Mode of action of 1,25D
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Cytoplam
Nucleus
Mode of action of 1,25D
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Cytoplam
Nucleus
Mode of action of 1,25D
RXR
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Target gene
Cytoplam
Nucleus
Mode of action of 1,25D
RXR
coA
m-RNA
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Target gene
Cytoplam
Nucleus
Mode of action of 1,25D
Proteins
RXR
coA
m-RNA
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Target gene
Cytoplam
Nucleus
Mode of action of 1,25D
Proteins
RXR
coA
m-RNA
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Vitamin D Nuclear Receptor (VDR)
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Receptor Nuclear de la Vitamina D (VDR)
DNA
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Receptor Nuclear de la Vitamina D (VDR)
Shaffer PL, Gewirth DT.
EMBO J. 2002, 21, 2242-2252
DNA
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Receptor Nuclear de la Vitamina D (VDR)
1α,25-(OH)2-D3
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Receptor Nuclear de la Vitamina D (VDR)
1α,25-(OH)2-D3
Moras D. y col.Mol. Cell 2000, 5, 173-179
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Receptor Nuclear de la Vitamina D (VDR)
1α,25-(OH)2-D3
Moras D. y col.Mol. Cell 2000, 5, 173-179
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Ligand Binding Domain
H12
H11
H1
H2
H3
H4
H5
H6
H8H9
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2.81
2.82
Ser278
2.91
2.83
2.832.86
Ser237
Ligand Binding Domain
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Prof Roger Bouillon and Mieke VerstuyfLeuven University
Transactivation, Calcemic Effects, Cell Differentiation-Proliferation
Prof. Román Pérez FernándezFaculty of Medicine-USCSantiago Compostela
Transactivation, Cell Diffentiation-Proliferation(colon cancer cell lines)
Prof Alberto MuñózInstitute of Biomedical Investigations CSIC-Madrid
Transactivation, Calcemic Effects, Cell Differentiation-Proliferation
Prof. Dino Moras and Natacha RochelIGBMC-Illkirch-France Structural Studies
COLLABORATIONS
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Superposition of Diyne (Docking Conformation)
with 1,25D (Crystallographic Structure)
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Drop containing crystals of Moras mutant VDR LBD complexed to 4cHHOHHOOH4c
Diyne-LBD(VDR)-
Complex HHO
HO
OH
VDR
Prof. Dino Moras (GBMC-Illkirch-Francia)
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N Rochel, S Hourai, X Pérez, A Rumbo, A Mouriño
Arch. Biochem. Biophys. 2007, 460, 172-176
Crystallographic Structue of the Diyne superimposed with 1,25D
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HO
H
H
OH
OH
12
HO
H
H
OH
OH
12
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1,25D with a Me Group at C-12
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?
Exploration of side
chains at C-12
Docking
12
Design, Syntheses and Biological Assays of
Vitamin Analogues with Side Chains at C-12.
J. Med. Chem. 2006, 49, 1509-1516
OH
H
OHHO
H
OHHO
OH
n
n = 1, 2, 3
1,25D Analogs with Side Chains at C-12 1,25D Analogs with Side Chains at C-12
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(104%) (113%) (112%)
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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
J. Med. Chem. 2012, 55, 8642
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Analogs of 1,25D with Side Chains at C-18
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.
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DS-A and DS-B induced expression of the protein E-cadherin comparably to “1,25”
E-cadherin
VDR
-actin
Time (h)1α,25-D 3
Vehicle
Protein
1.0 1.6 6.3 1.7 4.6 0.8 1.5
DS-A DS-B 8 48 8 48 8 4848
1.0 3.4 2.1 2.4 1.6 0.9 0.8
Vehicle DS-A
48 h
DS-B 1α,25-D3
A
B
Figure X
Texto
DS-A y DS-B Induce cell differentiation in colon
cancer cell lines (SW-480-ADH) similarly to 1,25D
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5
10
15
20
25
30
VD
RE
act
ivat
ion
(fold
incr
ease
)
010- 710- 810- 9 10- 710- 810- 9 10- 710- 810- 9
DS-A DS-B 1α,25-D3
Figure Y
DS-A and DS-B activate VDR transactivation in human colon cancer cells (SW480-ADH).
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0
10
20
30
40
50
Cel
l pro
lifer
atio
n (%
inhi
bitio
n)
DS-A DS-B 1α,25-D3
Figure Z
DS-A and DS-B inhibit cell proliferation (50% vs 1,25)
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Structures of Superagonists MC1288 y KH1060
Superagonists: Potent inducers of cell
differentiation
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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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Rational Design of a New Superagonist
New Superagonist?
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54
A B
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Isomer A induces transactivation 12 times better than
1,25D at 10-10 M, The isomer B behaves as 1,25D.
A
B1,25
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58
NEW SUPERAGONIST?
29
DESIGN OF A NEW SUPERAGONIST
+ =
2-Me-1,25D BINDS 4 TIMES BETTER TO VDR THAN 1,25D
A-MeISOMER A
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Interaction Energies with the
A-Me B-Me
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TRANSACTIVATION ACTIVITY
A-Me is 13 times more potent than 1,25D and 4 times more potent than A at 10 M
A A-Me1,25D
-10
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• Proliferación celular en HL-60 • Diferenciación celular en HL-60
Biological Activity Similar than 1,25D
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Arg274
Gln277
Tyr147
Ser278
Ser237
Tyr143
W1
W2
W3
Superimpositionof the New Metabolite with 1,25D
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Prof. Román Pérez-Fernández
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