AC 261066

AC 261066 is an agonist of retinoic acid receptor subtype β isoform 2 (RARβ2) [1] [2]. It is also called UVI2062 [3]. AC 261066 exhibited good oral bioavailability in rats (Foral= 52%) [4]. The IC50 of AC 261066 to AKR1B10 is 51 ± 7µM. No inhibition of AC 261066 to AKR1B1 was detected when using up to 100 µM AC 261066 in the enzymatic assay [3].

Retinoic acid receptors (RARs, subtypes α, β, γ) form heterodimeric complexes with retinoid X receptors (RXR α, β, γ) to orchestrate complex events, such as organ homoeostasis, immune function, development and reproduction [1]. RARβ2 is an isoform of subtype β of retinoic acid receptor, its affinity to retinoids and biological functions are different from other isoforms [2].

AC 261066 did not induce the cell adhesion of RPMI 8866 B cells to the ADAM28 disintegrin-like domain and did not block the atRA-induced adhesion [5].

AC 261066-treatment significantly inhibited the tail regeneration process in N. viridescens compared to DMSO controls. When these AC 261066-treated newts were removed from AC 261066 at 21 days (time of analysis) and then placed back into normal pond water, tail regeneration commenced. Five weeks after removal from the AC 26l066, the tail had regenerated, albeit with an alteration in the dorsal-ventral patterning compared to a normal tail regenerate [6].

References:
[1].  Albane le Maire, Susana Álvarez, Pattabhiraman Shankaranarayanan, et al. Retinoid Receptors and Therapeutic Applications of RAR/RXR Modulators. Current Topics in Medicinal Chemistry, 2012, 12: 505-527.
[2].  Christopher R. Gardner, Belamy B. Cheung, Jessica Koach, et al. Synthesis of retinoid enhancers based on 2-aminobenzothiazoles for anti-cancer therapy. Bioorg. Med. Chem., 2012, 20: 6877-6884.
[3].  Sergio Porté, Joan Giménez, Marta Dominguez, et al. Aldo–keto reductases in retinoid metabolism: Search for substrate specificity and inhibitor selectivity. Chemico-Biological Interactions, 2013, 202(1-3):186-94.
[4].  Birgitte W. Lund, Fabrice Piu, Natalie K. Gauthier, et al. Discovery of a Potent, Orally Available, and Isoform-Selective Retinoic Acid β2 Receptor Agonist. J. Med. Chem., 2005, 48: 7517-7519.
[5].  Jarrett T. Whelan, Lei Wang, Jianming Chen, et al. Retinoids induce integrin-independent lymphocyte adhesion through RAR-α nuclear receptor activity. Biochemical and Biophysical Research Communications, 2014, 454: 537-542.
[6].  Christopher J. Carter. Identification of novel retinoid receptors and their roles in vertebrate and invertebrate nervous systems [D]. St. Catharines: Brock University, 2011.

Reducing mass peak instability caused by the phase changes of RF and AC signals in a rectilinear ion-trap analyzer.[Pubmed:28372366]

Rev Sci Instrum. 2017 Mar;88(3):034103.

For an ion trap with resonance ejection, peak intensity and peak position of the acquired mass spectra are affected by the phase difference between the radio frequency (RF) and auxiliary alternating current (AC) potentials. To ensure measurement stability, RF and AC phase-locking is commonly used in commercial ion trap mass spectrometers. In this study, a compact electronic control system was developed to accurately regulate the RF and AC phases and was employed in a photoionization rectilinear ion trap (RIT) mass spectrometer. We found that the phase-locking method was defective in multicomponent analysis because the optimal RF and AC phase difference was usually different for different m/z peaks. After studying and characterizing the relationship between the peaks and the RF and AC phases, a correction method based on data processing was used to improve the peaks' stability and accuracy. The results show that the fluctuations of both peak intensity and peak position were significantly reduced and that the instrument presented satisfying reproducibility and quantitative ability.

Multi-isotope SPECT imaging of the (225)Ac decay chain: feasibility studies.[Pubmed:28362640]

Phys Med Biol. 2017 Jun 7;62(11):4406-4420.

Effective use of the [Formula: see text] decay chain in targeted internal radioimmunotherapy requires the retention of both [Formula: see text] and progeny isotopes at the target site. Imaging-based pharmacokinetic tests of these pharmaceuticals must therefore separately yet simultaneously image multiple isotopes that may not be colocalized despite being part of the same decay chain. This work presents feasibility studies demonstrating the ability of a microSPECT/CT scanner equipped with a high energy collimator to simultaneously image two components of the [Formula: see text] decay chain: [Formula: see text] (218 keV) and [Formula: see text] (440 keV). Image quality phantoms were used to assess the performance of two collimators for simultaneous [Formula: see text] and [Formula: see text] imaging in terms of contrast and noise. A hotrod resolution phantom containing clusters of thin rods with diameters ranging between 0.85 and 1.70 mm was used to assess resolution. To demonstrate ability to simultaneously image dynamic [Formula: see text] and [Formula: see text] activity distributions, a phantom containing a [Formula: see text] generator from [Formula: see text] was imaged. These tests were performed with two collimators, a high-energy ultra-high resolution (HEUHR) collimator and an ultra-high sensitivity (UHS) collimator. Values consistent with activity concentrations determined independently via gamma spectroscopy were observed in high activity regions of the images. In hotrod phantom images, the HEUHR collimator resolved all rods for both [Formula: see text] and [Formula: see text] images. With the UHS collimator, no rods were resolvable in [Formula: see text] images and only rods 1.3 mm were resolved in [Formula: see text] images. After eluting the [Formula: see text] generator, images accurately visualized the reestablishment of transient equilibrium of the [Formula: see text] decay chain. The feasibility of evaluating the pharmacokinetics of the [Formula: see text] decay chain in vivo has been demonstrated. This presented method requires the use of a high-performance high-energy collimator.

Response of phenolic metabolism to cadmium and phenanthrene and its influence on pollutant translocations in the mangrove plant Aegiceras corniculatum (L.) Blanco (Ac).[Pubmed:28363172]

Ecotoxicol Environ Saf. 2017 Jul;141:290-297.

Polyphenolic compounds are abundant in mangrove plants, playing a pivotal role in the detoxification of pollutants extruded from surrounding environments into plant tissues. The present study aimed to examine the variations of phenolic compounds, namely total polyphenolics, soluble tannins, condensed tannins and lignin, in the mangrove plant Aegiceras corniculatum (L.) due to the presence of exogenous cadmium and phenanthrene and to explore the influence of phenolic metabolism on biological translocation of these pollutants from roots to leaves. After a 6-week exposure to cadmium and phenanthrene, significant accumulations of both pollutants were observed. All determined phenolic compounds in both leaves and roots at high dosage levels were enhanced compared to the uncontaminated plant. Elevations of polyphenols in both treatments are possibly a result of stimulation in the activity of phenylalanine ammonia-lyase (PAL) and the enrichment of soluble sugar. Additionally, a significantly positive dosage relationship between polyphenolic metabolism intensity and phenanthrene contamination levels was found, while the trend observed in cadmium treatment was weak since cadmium at high levels inhibited phenolic production. The enrichment of polyphenols led to a decline in the biological translocation of these pollutants from roots to leaves. The immobilization of pollutants in the plant roots is possibly linked to the adsorption potential of polyphenols. These results will improve the understanding of the tolerance of mangrove plants to exogenous pollutants and will guide the selection of plants in phytoremediation because of the variability of polyphenol concentrations among species.

Investigation of ac-magnetic field stimulated nanoelectroporation of magneto-electric nano-drug-carrier inside CNS cells.[Pubmed:28374799]

Sci Rep. 2017 Apr 4;7:45663.

In this research, we demonstrate cell uptake of magneto-electric nanoparticles (MENPs) through nanoelectroporation (NEP) using alternating current (ac)-magnetic field stimulation. Uptake of MENPs was confirmed using focused-ion-beam assisted transmission electron microscopy (FIB-TEM) and validated by a numerical simulation model. The NEP was performed in microglial (MG) brain cells, which are highly sensitive for neuro-viral infection and were selected as target for nano-neuro-therapeutics. When the ac-magnetic field optimized (60 Oe at 1 kHz), MENPs were taken up by MG cells without affecting cell health (viability > 92%). FIB-TEM analysis of porated MG cells confirmed the non-agglomerated distribution of MENPs inside the cell and no loss of their elemental and crystalline characteristics. The presented NEP method can be adopted as a part of future nanotherapeutics and nanoneurosurgery strategies where a high uptake of a nanomedicine is required for effective and timely treatment of brain diseases.

Design, synthesis, and structure-activity analysis of isoform-selective retinoic acid receptor beta ligands.[Pubmed:19239230]

J Med Chem. 2009 Mar 26;52(6):1540-5.

We recently discovered the isoform selective RAR beta 2 ligand 4'-octyl-4-biphenylcarboxylic acid (3, AC-55649). Although 3 is highly potent at RAR beta 2 and displays excellent selectivity, solubility issues make it unsuitable for drug development. Herein we describe the exploration of the SAR in a biphenyl and a phenylthiazole series of analogues of 3. This ultimately led to the design of 28, a novel, orally available ligand with excellent isoform selectivity for the RAR beta 2.

Discovery of a potent, orally available, and isoform-selective retinoic acid beta2 receptor agonist.[Pubmed:16302793]

J Med Chem. 2005 Dec 1;48(24):7517-9.

4'-Octyl-4-biphenylcarboxylic acid (1g, AC-55649) was identified as a highly isoform-selective agonist at the human RARbeta2 receptor in a functional intact cell-based screening assay. The subsequent hit to lead optimization transformed the lipophilic, poorly soluble hit into a more potent and orally available compound (2, AC-261066) with retained beta2 selectivity and greatly improved physiochemical properties. Being an isoform-selective RARbeta2 receptor agonist that discriminates between nuclear receptor isoforms having identical ligand binding domains, 2 will be useful as a pharmacological research tool but also a valuable starting point for drug development.

AC-261066 is a potent, orally available and isoform-selective retinoic acid beta2 (RARbeta2) receptor agonist, with a pEC50 of 8.0.

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