Synthesis and Pharmacological Characterization of Disila‐AM80 (Disila‐tamibarotene) and Disila‐AM580, Silicon Analogues of the RARα‐Selective Retinoid Agonists AM80 (Tamibarotene) and AM580

@article{Tacke2009SynthesisAP,
  title={Synthesis and Pharmacological Characterization of Disila‐AM80 (Disila‐tamibarotene) and Disila‐AM580, Silicon Analogues of the RAR$\alpha$‐Selective Retinoid Agonists AM80 (Tamibarotene) and AM580},
  author={Reinhold Tacke and Volker Müller and Matthias W. B{\"u}ttner and W. Peter Lippert and R{\"u}diger Bertermann and J{\"u}rgen Oliver Dr. Dai{\ss} and Harshal Khanwalkar and Audrey Furst and Claudine Gaudon and Hinrich Gronemeyer},
  journal={ChemMedChem},
  year={2009},
  volume={4}
}
Retinoic acid receptors, which act as heterodimers between either one of three RARs (RARa, b, g) and RXRs (RXRa, b, g), are exciting pharmacological targets for cancer and metabolic disease therapies. Studies of the action of retinoic acid on acute promyelocytic leukemia have converted one of the worst leukemias to one that has a most favorable prognosis and might possibly be fully curable following recent advances in the field. In addition, rexinoids are clinically used for the treatment of… 
19 Citations
Novel Silicon‐Containing Analogues of the Retinoid Agonist Bexarotene: Syntheses and Biological Effects on Human Pluripotent Stem Cells
TLDR
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.
Synthesis and preliminary evaluation of affinity to retinoic acid receptors for new organosilicon-based retinoids
TLDR
The proposed silane-containing ligands ‘represent a new series of siloacetylenic aryl acids that are worth of further investigation’ and may serve as leads for the development of higher-affinity, more receptor-selective agents.
Disila-analogues of the synthetic retinoids EC23 and TTNN: synthesis, structure and biological evaluation.
TLDR
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 preliminary studies of biological activity of amino derivatives of 4-azatricyclo- [5.2.1.02,6]dec-8-ene-3,5-dione with silicon in the structure
TLDR
A series of 38 new derivatives of cyclic imides containing silicon in the structure was synthesized and characterized by 1H NMR, ESI-MS, and elemental analysis, and the compounds tested toward affinity for selected serotonin receptors showed high and moderate affinity for 5-HT1A and 5- HT7, while the antimicrobial activity of tested compounds was not significant.
Electron densities of bexarotene and disila-bexarotene from invariom application: a comparative study.
TLDR
The replacement of two carbon atoms in 1a by silicon atoms does neither influence the electronic structures nor the pharmacological properties (RXR receptor activation) significantly, and the almost completely software supported invariom formalism can yield electronic information for biologically interacting systems with moderate effort.
Effects of AM80 compared to AC261066 in a high fat diet mouse model of liver disease
TLDR
It is demonstrated that the selective RARα agonist AM80 exacerbates HFD-induced NAFLD and hyperglycemia and the findings should inform future studies examining the therapeutic potential of RAR agonists in H FD-related disorders.
Synopsis of some recent tactical application of bioisosteres in drug design.
  • N. Meanwell
  • Biology, Chemistry
    Journal of medicinal chemistry
  • 2011
TLDR
In this Perspective, some contemporary themes exploring the role of isosteres in drug design are sampled, with an emphasis placed on tactical applications designed to solve the kinds of problems that impinge on compound optimization and the long-term success of drug candidates.
...
...

References

SHOWING 1-10 OF 54 REFERENCES
Effect of Am-80, a Synthetic Derivative of Retinoid, on Experimental Arthritis in Mice
TLDR
The findings suggest that the inhibitory effect of Am-80 on CIA is partially by modulating the production of the proinflammatory cytokine, IL-6.
Synthesis, Crystal Structure Analysis, and Pharmacological Characterization of Disila-bexarotene, a Disila-Analogue of the RXR-Selective Retinoid Agonist Bexarotene
Twofold sila-substitution (C/Si exchange) in the saturated ring of the tetrahydronaphthalene skeleton of the RXR-selective retinoid agonist bexarotene (1a) leads to disila-bexarotene (1b). Compound
AM580, a stable benzoic derivative of retinoic acid, has powerful and selective cyto-differentiating effects on acute promyelocytic leukemia cells.
TLDR
It is shown here that AM580, a stable retinobenzoic derivative originally synthesized as a RAR alpha agonist, is a powerful inducer of granulocytic maturation in NB4, an APL-derived cell line, and in freshly isolated APL blasts.
Silicon Analogues of the Retinoid Agonists TTNPB and 3‐Methyl‐TTNPB, Disila‐TTNPB and Disila‐3‐methyl‐TTNPB: Chemistry and Biology
TLDR
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.
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
Effect of Am-80, a Retinoid Derivative, on 2,4-Dinitrofluorobenzene-Induced Contact Dermatitis in Mice
TLDR
Am-80 inhibited hapten-induced contact hypersensitivity through the direct inhibition of inflammatory cytokines such as IFN-γ and IL-6 through the indirect inhibition of antigen-induced production of some cytokines in vitro.
Design of selective nuclear receptor modulators: RAR and RXR as a case study
TLDR
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.
New benzoic acid derivatives with retinoid activity: lack of direct correlation between biological activity and binding to cellular retinoic acid binding protein.
TLDR
Results show that the Am- and Ch- derivatives elicit in several cell systems the same cellular responses as retinoic acid, and it is proposed that they exhibit mechanism(s) of action) similar to those of retinoids.
...
...