Silicon Analogues of the RXR‐Selective Retinoid Agonist SR11237 (BMS649): Chemistry and Biology

  title={Silicon Analogues of the RXR‐Selective Retinoid Agonist SR11237 (BMS649): Chemistry and Biology},
  author={W. Peter Lippert and Christian Burschka and Kathrin H G{\"o}tz and Martin Kaupp and Diana G. Ivanova and Claudine Gaudon and Yoshiteru Sato and Pierre Antony and Natacha Rochel and Dino Moras and Hinrich Gronemeyer and Reinhold Tacke},
C/Si switch: Twofold sila‐substitution (C/Si exchange) in the RXR‐selective retinoids 4 a (SR11237) and 5 a leads to 4 b (disila‐SR11237) and 5 b, respectively. Chemistry and biology of the C/Si pairs are reported. 
Novel Silicon‐Containing Analogues of the Retinoid Agonist Bexarotene: Syntheses and Biological Effects on Human Pluripotent Stem Cells
Preliminary evidence indicates that disila‐bexarotene and its analogues 8 and 9 may possess enhanced functions over the parent compound bexarotenes, such as induction and regulation of cell death and cell numbers.
Disila-analogues of the synthetic retinoids EC23 and TTNN: synthesis, structure and biological evaluation.
In this study, the biological effects of a two-fold sila-substitution in the synthetic retinoids EC23 and TTNN and their corresponding analogues with an indane instead of a 1,2,3,4-tetrahydronaphthalene skeleton were investigated, resulting in considerably different effects.
Synthesis and Pharmacological Characterization of Disila‐AM80 (Disila‐tamibarotene) and Disila‐AM580, Silicon Analogues of the RARα‐Selective Retinoid Agonists AM80 (Tamibarotene) and AM580
The synthesis of the silicon compounds 1 a and 2 b and the pharmacological characterization of the C/Si pairs 1 a/1 b and 2 a/ 2 b were performed as part of the systematic ACHTUNGTRENNUNGinvestigations on silicon-based drugs.
The retinoid X receptors and their ligands.
Expanding the chemical space of hydrophobic pharmacophores: the role of hydrophobic substructures in the development of novel transcription modulators
The author reviews the development of novel transcription modulators incorporating three types of substructures, i.e., silyl and germyl functionalities, hydrophobic boron clusters, and cyclopentadiene-based organometallic sandwich compounds, ashydrophobic components.
9-cis-13,14-Dihydroretinoic Acid Is an Endogenous Retinoid Acting as RXR Ligand in Mice
It is shown here that mice lacking cellular retinol binding protein (Rbp1-/-) display memory deficits reflecting compromised RXR signaling, and that 9-cis-13,14-dihydroretinoic acid (9CDHRA) acts as an RXR ligand since it binds and transactivates RXR in various assays.
Selective ligand activity at Nur/retinoid X receptor complexes revealed by dimer‐specific bioluminescence resonance energy transfer‐based sensors
Luciferase (Luc) protein complementation‐based bioluminescence resonance energy transfer (BRET) assays that can directly measure recruitment of a coactivator (CoA) motif fused to yellow fluorescent protein (YFP) by specific NR dimers are developed and optimized.
Targeting Nuclear Receptors with Marine Natural Products
The natural ligands of nuclear receptors will be described with an emphasis on their mechanisms of action and their therapeutic potentials, as well as on strategies to determine potential marine natural products as nuclear receptor modulators.


Design of selective nuclear receptor modulators: RAR and RXR as a case study
Improved understanding of the structural biology of RXRs and RARs and recent advances in the chemical synthesis of modified retinoid and rexinoid ligands should enable the rational design of more selective agents that might overcome problems of toxicity.
Silicon Analogues of the Retinoid Agonists TTNPB and 3‐Methyl‐TTNPB, Disila‐TTNPB and Disila‐3‐methyl‐TTNPB: Chemistry and Biology
This study demonstrates that silicon analogues can have the same biological functionalities and conserved structures as their parent carbon compounds, and it illustrates the potential to induce alternative allosteric effects, as in the case of helix H11, which might allow for novel options in drug design.
RAR and RXR modulation in cancer and metabolic disease
The challenges and opportunities for therapeutic strategies based on RXR and RAR modulators, with a focus on cancer and metabolic diseases such as diabetes and obesity, are discussed.
Purification and crystallization of the human RXRalpha ligand-binding domain-9-cisRA complex.
  • P. EgeaD. Moras
  • Chemistry
    Acta crystallographica. Section D, Biological crystallography
  • 2001
The purification and crystallization of the stoichiometric complex of human RXRalpha ligand-binding domain (hRXRalpha LBD) bound to its natural ligand 9- cis retinoic acid (9-cisRA) are described, which yields a pure and homogeneous complex.
Development of a New Building Block for the Synthesis of Silicon-Based Drugs and Odorants: Alternative Synthesis of the Retinoid Agonist Disila-bexarotene
With 4,4,5,5-tetramethyl-2-(3,5,5,8,8-pentamethyl-5,8-disila-5,6,7,8-tetrahydro-2-naphthyl)-1,3,2-dioxaborolane (5) a new building block for the synthesis of biologically active
Molecular recognition of agonist ligands by RXRs.
The high-resolution structures of two complexes of the human RXRalpha ligand-binding domain specifically bound to two different and chemically unrelated agonist compounds support the idea that docosa hexaenoic acid and related fatty acids could be natural agonists of RXRs and question the real nature of the endogenous ligand(s) in mammalian cells.
Synthesis and Pharmacological Characterization of Sila-panamesine, a Sila-Analogue of the σ Receptor Ligand Panamesine (EMD 57445)
Sila-substitution (C/Si exchange) at the 4-position of the piperidine skeleton of the σ receptor ligand panamesine (1a, EMD 57445) leads to sila-panamesine (1b). Compounds 1a and 1b were synthesized
The promise of retinoids to fight against cancer
Understanding of the mechanisms that underlie the anti-proliferative action of retinoids will help to exploit the beneficial aspects of this powerful class of compounds for cancer therapy and prevention.