Disila-analogues of the synthetic retinoids EC23 and TTNN: synthesis, structure and biological evaluation.
Silicon chemistry offers the potential to tune the effects of biologically active organic molecules. Subtle changes in the molecular backbone caused by the exchange of a carbon atom for a silicon atom (sila-substitution) can significantly alter the biological properties. In this study, the biological effects of a two-fold sila-substitution in the synthetic retinoids EC23 (4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-ylethynyl)benzoic acid (4a)) and TTNN (6-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-2-naphthoic acid (7a)) as well as their corresponding analogues with an indane instead of a 1,2,3,4-tetrahydronaphthalene skeleton (compounds 5a and 8a) were investigated. Two-fold C/Si exchange in 4a, 5a, 7a and 8a leads to the silicon-analogues disila-EC23 (4b), 5b, disila-TTNN (7b) and 8b, which contain a 1,2,3,4-tetrahydro-1,4-disilanaphthalene (4b, 7b) or 1,3-disilaindane skeleton (5b, 8b). Exchange of the SiCH(2)Si moiety of 5b for an SiOSi fragment leads to the disiloxane 6 (2-oxa-1,3-disilaindane skeleton). The EC23 derivative 5a, the TTNN derivative 8a and the silicon-containing analogues 4b, 5b, 6, 7b and 8b were synthesised, and the biological properties of the C/Si pairs 4a/4b, 5a/5b, 7a/7b and 8a/8b and compound 6 were evaluated in vivo using RAR isotype-selective reporter cells. EC23 (4a) and its derivatives disila-EC23 (4b), 5a, 5b and 6 are very potent RAR agonists, which are even more potent than the powerful reference compound TTNPB. Disila-substitution of EC23 (4a) and 5a leads to a moderate decrease in RARα activation, whereas the RARβ,γ activation is almost not affected. In contrast, two-fold C/Si exchange in the weak retinoid agonist TTNN (7a) and 8a resulted in considerably different effects: a significant increase (7a→7b) and almost no change (8a→8b) in transcription activation potential for all three RAR isotypes. Disila-TTNN (7b) can be regarded as a powerful RARβ,γ-selective retinoid.
Universität Würzburg, Institut für Anorganische Chemie, Am Hubland, D-97074 Würzburg, Germany.
Josef B G
JB
Gluyas
Christian
C
Burschka
Steffen
S
Dörrich
Judith
J
Vallet
Hinrich
H
Gronemeyer
Reinhold
R
Tacke
D001565:Benzoates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D002264:Carboxylic Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D060326:Chemistry Techniques, Synthetic; D006367:HeLa Cells; D006801:Humans; D008958:Models, Molecular; D008968:Molecular Conformation; D009281:Naphthalenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D017646:Organosilicon Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D012176:Retinoids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D012825:Silicon / Q000737:chemistry*; D013764:Tetrahydronaphthalenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D015533:Transcriptional Activation / Q000187:drug effects
C577846:6-(1,1,4,4-tetramethyl-1,2,3,4-tetrahydro-1,4-disilanaphthalen-6-yl)-2-naphthoic acid; D001565:Benzoates; D002264:Carboxylic Acids; C542239:EC23 compound; D009281:Naphthalenes; D017646:Organosilicon Compounds; D012176:Retinoids; D013764:Tetrahydronaphthalenes; C085312:1-naphthoic acid; D012825:Silicon