AC 55649

AC 55649 is a potent and selective agonist of retinoic acid receptor β2 (RARβ2) isotype with a pEC50 value of 6.9 ± 0.4 [1].

RARβ2 is a tumor suppressor gene. In several human neoplasms, it is frequently hypermethylated [2].

In MCF7 cells, AC 55649 significantly inhibited cellular growth, appeared to inhibit DNA synthesis as seen in experiments of [3H] thymidine incorporation. The extent of the inhibition was comparable to the one resulted from the presence of all-trans-retinoic acid [1]. In vitro, RARβ2 induced the neurite outgrowth in adult mouse spinal cord [3]. Before neurite outgrowth, cells were stimulated with either AC 55649 or retinoic acid for 1 week. Treatment with retinoic acid largely increased the neurite outgrowth of cells, compared with the control. This result was revealed by immunocytochemistry. AC 55649 also induced the neurite outgrowth of NTERA-2 cells. This indicated that AC 55649 mediated neuronal differentiation in a manner similar to that found with retinoic acid. Using another differentiation marker, Neurofilament L, similar results were also evident [1].

Retinoids influence both differentiation and morphogenetic events during development of the vertebrate limb. These effects are mediated by nuclear retinoid receptors. In the posterior limb bud, transcripts of RARβ2 but not RARβ1 are enriched to three-fold. Transcripts of RARβ1 are initially present throughout the limb bud ectoderm and mesenchyme, then become restricted within the loose connective tissue and perichondrial regions of the limb [4]. In Xenopus, treated with AC 55649 at 100 nM, approximately 65% of larvae survived and practically all started to form a pair of bilaterally symmetric limb buds. Treatments with AC 55649 provoked the death of larvae at the metamorphosis onset at around stage 62. Stage 62 is a stage showing peak levels of T3 and T4 thyroid hormones. Meanwhile all larvae without treatment were metamorphosed [5].

References:
[1].  Piu F, Gauthier NK, Olsson R, et al. Identification of novel subtype selective RAR agonists. Biochemical pharmacology, 2005, 71(1): 156-162.
[2].  Jerónimo C, Henrique R, Hoque MO, et al. Quantitative RARβ2 Hypermethylation A Promising Prostate Cancer Marker. Clinical Cancer Research, 2004, 10(12): 4010-4014.
[3].  Maden M, Hind M. Retinoic acid, a regeneration-inducing molecule. Developmental dynamics, 2003, 226(2): 237-244.
[4].  Cuervo R, Chimal-Monroy J. Chemical activation of RARβ induces post-embryonically bilateral limb duplication during Xenopus limb regeneration. Scientific reports, 2013, 3.
[5].  Smith SM, Kirstein IJ, Wang ZS, et al. Differential expression of retinoic acid receptor-β isoforms during chick limb ontogeny. Developmental Dynamics, 1995, 202(1): 54-66.

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.