Vitamin D current outlook, design and synthesis of active analogs

Vitamin D: Current Outlook, Design and Synthesis of Active Analogs

UNIVERSIDAD DE SANTIAGO DE COMPOSTELADepartamento de Química OrgánicaSantiago de Compostela E-15782, EspañaAntonio Mouriño: antonio.mourino@usc.es

Development of Active vitamin D Analogues

UNIVERSIDAD DE SANTIAGO DE COMPOSTELADepartamento de Química OrgánicaSantiago de Compostela E-15782, EspañaAntonio Mouriño: antonio.mourino@usc.es

Birmingham. DECIDE. Nov 14, 2013miércoles 27 de noviembre de 2013

miércoles 27 de noviembre de 2013

Alimentos

VIT-D3

PRE-D3

7-Deshidrocolesterol25-D3

1,25-D3

Forma Activa

80%20%

Active form 1,25D

7-Dehydrocholesterol

Vitamin D Metabolism

7-Dehydrocholesterol Previtamin D Cisoid form

Transoid form

Vitamin D

Kidney Liver

(calcitriol)

1α,25-(OH)2-D3

ICABCM

BIOLOGICALRESPONSES

1α,25-(OH)2-D3

ICABCM

DIFFERENTIATION PROLIFERATION

Miyaura et alBiochem. Biophys. Res.Commun.1981, 102, 937

BIOLOGICALRESPONSES

1α,25-(OH)2-D3

ICABCM

DIFFERENTIATION PROLIFERATION

Miyaura et alBiochem. Biophys. Res.Commun.1981, 102, 937

BONE DISEASES(OSTEOPOROSIS)

IMMUNOLOGY(TRANSPLANTATION)

PSORIASIS

CANCER

Cytoplasm

Nucleus

Mode of action of 1α,25-(OH)2-D3

Cytoplasm

Nucleus

Cytoplasm

Nucleus

Cytoplasm

Nucleus

Cytoplam

Nucleus

Mode of action of 1,25D

Cytoplam

Nucleus

Cytoplam

Nucleus

Target gene

Cytoplam

Nucleus

Target gene

Cytoplam

Nucleus

Proteins

Target gene

Cytoplam

Nucleus

Proteins

Vitamin D Nuclear Receptor (VDR)

Receptor Nuclear de la Vitamina D (VDR)

Shaffer PL, Gewirth DT.

EMBO J. 2002, 21, 2242-2252

1α,25-(OH)2-D3

Moras D. y col.Mol. Cell 2000, 5, 173-179

1α,25-(OH)2-D3

Moras D. y col.Mol. Cell 2000, 5, 173-179

Ligand Binding Domain

Ser278

2.832.86

Ser237

Ligand Binding Domain

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

Superposition of Diyne (Docking Conformation)

with 1,25D (Crystallographic Structure)

Drop containing crystals of Moras mutant VDR LBD complexed to 4cHHOHHOOH4c

Diyne-LBD(VDR)-

Complex HHO

Prof. Dino Moras (GBMC-Illkirch-Francia)

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

1,25D with a Me Group at C-12

Exploration of side

chains at C-12

Docking

Design, Syntheses and Biological Assays of

Vitamin Analogues with Side Chains at C-12.

J. Med. Chem. 2006, 49, 1509-1516

n = 1, 2, 3

1,25D Analogs with Side Chains at C-12 1,25D Analogs with Side Chains at C-12

(104%) (113%) (112%)

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

Analogs of 1,25D with Side Chains at C-18

DS-A and DS-B induced expression of the protein E-cadherin comparably to “1,25”

E-cadherin

-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

DS-B 1α,25-D3

Figure X

DS-A y DS-B Induce cell differentiation in colon

cancer cell lines (SW-480-ADH) similarly to 1,25D

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).

DS-A DS-B 1α,25-D3

Figure Z

DS-A and DS-B inhibit cell proliferation (50% vs 1,25)

Structures of Superagonists MC1288 y KH1060

Superagonists: Potent inducers of cell

differentiation

Superimposition of the crystallographic

structures of 1,25D and superagonists

KH1060 y MC1288

Moras D et al.

PNAS 2001, 98, 5491-5496

Rational Design of a New Superagonist

New Superagonist?

Isomer A induces transactivation 12 times better than

1,25D at 10-10 M, The isomer B behaves as 1,25D.

NEW SUPERAGONIST?

DESIGN OF A NEW SUPERAGONIST

2-Me-1,25D BINDS 4 TIMES BETTER TO VDR THAN 1,25D

A-MeISOMER A

Interaction Energies with the

A-Me B-Me

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

• Proliferación celular en HL-60 • Diferenciación celular en HL-60

Biological Activity Similar than 1,25D

Arg274

Gln277

Tyr147

Ser278

Ser237

Tyr143

Superimpositionof the New Metabolite with 1,25D

Prof. Román Pérez-Fernández

Vitamin D current outlook, design and synthesis of active analogs

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