A comparative assessment of α-lipoic acid N-phenylamides as non-steroidal androgen receptor antagonists both on and off gold nanoparticles

Henderson, Luke C.; Altimari, Jarrad M.; Dyson, Gail; Servinis, Linden; Niranjan, Birunthi; Risbridger, Gail P.

doi:10.1016/j.bioorg.2011.11.007

Cited by 16 publications

(9 citation statements)

References 35 publications

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“…This size range was chosen because it was small enough for imaging purposes, and similarly sized AuNPs have shown slower kinetics of cellular uptake than larger particles [24]. The anchor point of the tethered GPCR ligands consisted of a TA moiety containing two thiol groups to achieve a relatively stable bond with the nanoparticle [37]. A segment of ten PEG units attached to the carboxylic group of the thioctic acid contributed to water solubility and was intended to allow the interaction of the immobilized GPCR ligand with the adaptable binding site of the GPCR.…”

Section: Design and Chemical Synthesismentioning

confidence: 99%

Modulation of G protein-coupled adenosine receptors by strategically functionalized agonists and antagonists immobilized on gold nanoparticles

Jayasekara

Phan

Tosh

et al. 2012

Purinergic Signalling

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Gold nanoparticles (AuNPs) allow the tuning of pharmacokinetic and pharmacodynamic properties by active or passive targeting of drugs for cancer and other diseases. We have functionalized gold nanoparticles by tethering specific ligands, agonists and antagonists, of adenosine receptors (ARs) to the gold surface as models for cell surface interactions with G protein-coupled receptors (GPCRs). The AuNP conjugates with chain-extended AR ligands alone (PEGylated nucleosides and nonnucleosides, anchored to the Au via thioctic acid) were found to be insoluble in water due to hydrophobic entities in the ligand. Therefore, we added a second, biologically inactive pendant moiety to increase the water solubility, consisting of a PEGylated chain terminating in a carboxylic or phosphate group. The purity and stability of the immobilized biologically active ligand were examined by ultrafiltration and HPLC. Pharmacological receptor binding studies on these GPCR ligand-derivatized AuNPs (2-5 nm in diameter), performed using membranes of mammalian cells stably expressing human A 1 , A 2A , and A 3 ARs, showed that the desired selectivity was retained with K i values (nanomolar) of A 3 AR agonist 21b and A 2A AR antagonists 24 and 26a of 14 (A 3 ), 34 (A 2 A ), and 69 (A 2 A ), respectively. The corresponding monomers displayed K i values of 37, 61, and 1,420 nM, respectively. In conclusion, we have synthesized stable, water-soluble AuNP derivatives of tethered A 3 and A 2A AR ligands that retain the biological properties of their monomeric ligands and are intended for therapeutic and imaging applications. This is the first prototypical application to gold carriers of small molecule (nonpeptide) GPCR ligands, which are under investigation for treatment of cancer and inflammatory diseases.

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Section: Design and Chemical Synthesismentioning

confidence: 99%

Modulation of G protein-coupled adenosine receptors by strategically functionalized agonists and antagonists immobilized on gold nanoparticles

Jayasekara

Phan

Tosh

et al. 2012

Purinergic Signalling

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“…The synthesis of 1,2,3-triazoles via copper mediated 1,3-dipolar reactions has become one of the most widely used methodologies to tether molecules together or to a surface (Bock et al, 2006;Irie et al, 2012). Electronically deactivated N-phenyl-1,2,3-triazoles have been employed in several areas such as the combinatorial development of kinase inhibitors (Jia & Zhu, 2010) in the development of monoamine oxidase inhibitors, androgen receptor antagonists (Henderson et al, 2012) and as GABA receptor antagonists (Alam et al, 2006;Alam et al, 2007). This compound provides an aryl chloride moiety in the para-position relative to the triazole ring providing a synthetic handle for further structural elaboration.…”

Section: S1 Commentmentioning

confidence: 99%

1-[4-Chloro-3-(trifluoromethyl)phenyl]-4-phenyl-1H-1,2,3-triazole

Altimari¹,

Healy²,

Henderson³

2012

Acta Cryst E

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“…Lipoic acid was reported to be employed in the treatment of liver cirrhosis, mushroom poisoning, and heavy metal intoxication and also in the treatment of diabetic polyneuropathy . Keeping in view of the pharmacological actions of lipoic acid, several hybrid molecules have been reported with the aim to provide the beneficial effects of both lipoic acid and the conjugate involved . A recent report on the lipoic acid analogs based on the condensation of amino acids with carboxylic acid group of lipoic acid showed potential application of lipoic acid based peptides in the treatment of cellular ischemia‐reperfusion injury .…”

Section: Introductionmentioning

confidence: 99%

Enzymatic synthesis and characterization of 1‐lipoyl‐2‐palmitoyl phosphatidylcholine: A novel phospholipid containing lipoic acid

Kaki

Balakrishna

2014

Euro J Lipid Sci & Tech

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Bioorganic synthesis of a novel phospholipid, 1-lipoyl-2-palmitoyl phosphatidylcholine (LPPC) was carried out using dipalmitoylphosphotidylcholine (DPPC) and lipoic acid as substrates via lipase catalyzed transesterification reaction at controlled water activity. A high lipoic acid concentration and low water activity were necessary for the enzymatic acidolysis reaction in an organic solvent medium at ambient temperature. Four immobilized lipases were examined for the incorporation of lipoic acid into DPPC. The transesterification reaction resulted in formation of the desired product along with the lyso PC as a by-product at controlled water activity of 0.11 in 96 h using Lipozyme RM IM lipase. The composition of the modified PC showed that 41.07 mol% of lipoic acid was incorporated into DPPC. The transesterification was regioselective with nearly 91% incorporation of lipoic acid in the sn-1 position with about 4% incorporation in the sn-2 position in the product PC. The prepared LPPC can have applications as a lipid based prodrug of lipoic acid and also can have potential applications in drug solubilization and release studies.Practical applications: Novel phospholipid bearing lipoic acid as an active ingredient is synthesized via enzymatic route. It is a smart combination of two biologically active molecules with proven activities. The prepared phospholipid can have potential applications in nutraceuticals, cosmetics, and biomedical fields. This molecule can help to address the bioavailability issues of lipoic acid. The product can have applications in controlled release of lipoic acid due to incorporation into a phospholipid.

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A comparative assessment of α-lipoic acid N-phenylamides as non-steroidal androgen receptor antagonists both on and off gold nanoparticles

Cited by 16 publications

References 35 publications

Modulation of G protein-coupled adenosine receptors by strategically functionalized agonists and antagonists immobilized on gold nanoparticles

Modulation of G protein-coupled adenosine receptors by strategically functionalized agonists and antagonists immobilized on gold nanoparticles

1-[4-Chloro-3-(trifluoromethyl)phenyl]-4-phenyl-1H-1,2,3-triazole

Enzymatic synthesis and characterization of 1‐lipoyl‐2‐palmitoyl phosphatidylcholine: A novel phospholipid containing lipoic acid

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