Silicon analogues of the retinoid agonists TTNPB and 3-methyl-TTNPB, disila-TTNPB and disila-3-methyl-TTNPB: chemistry and biology.
Twofold sila-substitution (C/Si exchange) in the saturated ring of the tetrahydronaphthalene skeleton of the retinoid agonists TTNPB (1 a) and 3-methyl-TTNPB (2 a) leads to disila-TTNPB (1 b) and disila-3-methyl-TTNPB (2 b), respectively. The silicon compounds 1 b and 2 b were synthesized in multiple steps, and their identities were established by elemental analyses, multinuclear NMR experiments, and single-crystal X-ray diffraction studies. Like TTNPB (1 a) and 3-methyl-TTNPB (2 a), the analogous silicon-based arotinoids 1 b and 2 b are strong pan-RAR agonists and display the same strong differentiation and apoptosis-inducing activity in NB4 promyelocytic leukemia cells as the parent carbon compounds. These results are in keeping with the nearly isomorphous structures of 1 a and 1 b bound to the complex of the RARbeta ligand-binding domain with the nuclear receptor (NR) box 2 peptide of the SRC-1 coactivator. The contacts within the ligand-binding pocket are identical except for helix H11, for which two turns are shifted in the disila-TTNPB (1 b) complex. This study represents the first comprehensive structure-function analysis of a carbon/silicon switch in a signaling molecule and demonstrates that silicon analogues can have the same biological functionalities and conserved structures as their parent carbon compounds, and it illustrates at the same time that silicon analogues of biologically active compounds have the potential to induce alternative allosteric effects, as in the case of helix H11, which might allow for novel options in drug design.
Büttner
Matthias W
MW
Universität Würzburg, Institut für Anorganische Chemie, Am Hubland, 97074 Würzburg, Germany.
Burschka
Christian
C
Daiss
Jürgen O
JO
Ivanova
Diana
D
Rochel
Natacha
N
Kammerer
Sabrina
S
Peluso-Iltis
Carole
C
Bindler
Audrey
A
Gaudon
Claudine
C
Germain
Pierre
P
Moras
Dino
D
Gronemeyer
Hinrich
H
Tacke
Reinhold
R
D017209:Apoptosis; D001565:Benzoates / Q000737:chemistry* / Q000494:pharmacology; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D008956:Models, Chemical; D008958:Models, Molecular; D008968:Molecular Conformation; D009281:Naphthalenes / Q000494:pharmacology; D017646:Organosilicon Compounds / Q000494:pharmacology; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D012176:Retinoids / Q000737:chemistry*; D012825:Silicon / Q000737:chemistry*
C525648:4-(2-(3,5,5,8,8-pentamethyl-5,8-disila-5,6,7,8-tetrahydro-2-naphthalenyl)-1-propenyl)benzoic acid; C525647:4-(2-(5,5,8,8-tetramethyl-5,8-disila-5,6,7,8-tetrahydro-2-naphthalenyl)-1-propenyl)benzoic acid; C525646:4-(2-(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalenyl)-1-propenyl)benzoic acid; D001565:Benzoates; D009281:Naphthalenes; D017646:Organosilicon Compounds; D012176:Retinoids; C038864:4-(2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-1-propenyl)benzoic acid; D012825:Silicon