Disila-analogues of the synthetic retinoids EC23 and TTNN: synthesis, structure and biological evaluationElectronic supplementary information (ESI) available: Crystallographic data for compounds 5a, 5b, 8b, 15, 17, 28, 29, 33 and 34 and 1H, 13C, 15N and 29Si NMR spectra of all new compounds synthesised. CCDC 837993, 837994, 872960, 837995, 837996, 837997, 837998, 837999 and 838000. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c2ob25989c

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 RAR activation, whereas the RAR, 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 RAR,-selective retinoid. C / Si switch : Two-fold sila-substitution (C/Si exchange) in the synthetic retinoids EC23 and TTNN leads to disila-EC23 and disila-TTNN. The chemistry and biology (RAR,, activation) of these C/Si pairs and related compounds are reported.