132307-50-7Relevant articles and documents
An Eighteen-Membered Macrocyclic Ligand for Actinium-225 Targeted Alpha Therapy
Thiele, Nikki A.,Brown, Victoria,Kelly, James M.,Amor-Coarasa, Alejandro,Jermilova, Una,MacMillan, Samantha N.,Nikolopoulou, Anastasia,Ponnala, Shashikanth,Ramogida, Caterina F.,Robertson, Andrew K. H.,Rodríguez-Rodríguez, Cristina,Schaffer, Paul,Williams, Clarence,Babich, John W.,Radchenko, Valery,Wilson, Justin J.
, p. 14712 - 14717 (2017)
The 18-membered macrocycle H2macropa was investigated for 225Ac chelation in targeted alpha therapy (TAT). Radiolabeling studies showed that macropa, at submicromolar concentration, complexed all 225Ac (26 kBq) in 5 min at RT. [225Ac(macropa)]+ remained intact over 7 to 8 days when challenged with either excess La3+ ions or human serum, and did not accumulate in any organ after 5 h in healthy mice. A bifunctional analogue, macropa-NCS, was conjugated to trastuzumab as well as to the prostate-specific membrane antigen-targeting compound RPS-070. Both constructs rapidly radiolabeled 225Ac in just minutes at RT, and macropa-Tmab retained >99 % of its 225Ac in human serum after 7 days. In LNCaP xenograft mice, 225Ac-macropa-RPS-070 was selectively targeted to tumors and did not release free 225Ac over 96 h. These findings establish macropa to be a highly promising ligand for 225Ac chelation that will facilitate the clinical development of 225Ac TAT for the treatment of soft-tissue metastases.
Fluorescent Probes for Single-Step Detection and Proteomic Profiling of Histone Deacetylases
Xie, Yusheng,Ge, Jingyan,Lei, Haipeng,Peng, Bo,Zhang, Huatang,Wang, Danyang,Pan, Sijun,Chen, Ganchao,Chen, Lanfang,Wang, Yi,Hao, Quan,Yao, Shao Q.,Sun, Hongyan
, p. 15596 - 15604 (2016)
Histone deacetylases (HDACs) play important roles in regulating various physiological and pathological processes. Developing fluorescent probes capable of detecting HDAC activity can help further elucidate the roles of HDACs in biology. In this study, we first developed a set of activity-based fluorescent probes by incorporating the Kac residue and the O-NBD group. Upon enzymatic removal of the acetyl group in the Kac residue, the released free amine reacted intramolecularly with the O-NBD moiety, resulting in turn-on fluorescence. These designed probes are capable of detecting HDAC activity in a continuous fashion, thereby eliminating the extra step of fluorescence development. Remarkably, the amount of turn-on fluorescence can be as high as 50-fold, which is superior to the existing one-step HDAC fluorescent probes. Inhibition experiments further proved that the probes can serve as useful tools for screening HDAC inhibitors. Building on these results, we moved on and designed a dual-purpose fluorescent probe by introducing a diazirine photo-cross-linker into the probe. The resulting probe was not only capable of reporting enzymatic activity but also able to directly identify and capture the protein targets from the complex cellular environment. By combining a fluorometric method and in-gel fluorescence scanning technique, we found that epigenetic readers and erasers can be readily identified and differentiated using a single probe. This is not achievable with traditional photoaffinity probes. In light of the prominent properties and the diverse functions of this newly developed probe, we envision that it can provide a robust tool for functional analysis of HDACs and facilitate future drug discovery in epigenetics.
MACROCYCLIC COMPLEXES OF ALPHA-EMITTING RADIONUCLIDES AND THEIR USE IN TARGETED RADIOTHERAPY OF CANCER
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Paragraph 0286-0287, (2020/06/08)
The present technology provides compounds as well as compositions including such compounds useful in targeted radiotherapy of cancer and/or mammalian tissue overexpressing prostate specific membrane antigen (“PSMA”) where the compounds are represented by
Site-Specific Incorporation of Multiple Thioamide Substitutions into a Peptide Backbone via Solid Phase Peptide Synthesis
Yang, Jinhua,Wang, Changliu,Yao, Chaochao,Chen, Chunqiu,Hu, Yafang,He, Guifeng,Zhao, Junfeng
, p. 1484 - 1494 (2020/01/02)
Among various peptide modification strategies, thioamide substitution by replacing the carbonyl oxygen atom of an amide bond with a sulfur atom constitutes an invaluable tool for chemical biology, for use in peptide drug discovery and protein structure-fu
Modified hydrophobic auxiliary material as well as preparation method and application thereof
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Paragraph 0073; 0077; 0081; 0087, (2020/12/31)
The invention relates to preparation of novel pharmaceutic auxiliary materials and drug-loaded fat emulsions, and provides a hydrophobic auxiliary material, the molecular formula of which is as follows: R is a hydrophobic natural compound or synthetic compound with one to three hydroxyl groups (n= 1-3); R1 is an alpha-amino protecting group, R2 is an amino acid side chain, m is equal to 0, and atthe moment, R reacts with the amino acid derivative with the protecting group through esterification to form a hydrophobic auxiliary material carrying the amino acid derivative with the protecting group; or m is equal to 1, at the moment, an amino acid connecting arm (l being equal to 1, 2, 4, and 6) with different chain lengths is introduced into R through an ester group, then an amino acid derivative with a protective group is introduced, and the hydrophobic auxiliary material carrying the amino acid derivative polypeptide with the protective group is formed. According to the method, the amino acid derivative with the aromatic or alkoxycarbonyl or acyl amino protecting group is introduced to the hydrophobic auxiliary material, so that the solubility of the drug in the hydrophobic auxiliary material is increased, and the stability of the drug-loaded fat emulsion is improved.
TUNABLE FLUORESCENCE USING CLEAVABLE LINKERS
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Paragraph 0077, (2014/11/11)
The invention relates to cleavable chemistry in general, and in particular, to tunable fluoresence using cleavable linkers present in fluorochrome-quencher conjugates.
Stepwise orthogonal click chemistry toward fabrication of paclitaxel/galactose functionalized fluorescent nanoparticles for hepg2 cell targeting and delivery
Lai, Chian-Hui,Chang, Tsung-Che,Chuang, Yung-Jen,Tzou, Der-Lii,Lin, Chun-Cheng
, p. 1698 - 1709 (2013/11/06)
In this report, we used stepwise orthogonal click chemistry (SOCC) involving strain-promoted azide-alkyne cycloaddition (SPAAC) and microwave-assisted Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC) to assemble an anticancer drug (paclitaxel, PTX) and
Mechanism-based affinity capture of sirtuins
Cen, Yana,Falco, Jessica N.,Xu, Ping,Youn, Dou Yeon,Sauve, Anthony A.
supporting information; experimental part, p. 987 - 993 (2011/04/15)
The ability to probe for catalytic activities of enzymes and to detect their abundance in complex biochemical contexts has traditionally relied on a combination of kinetic assays and techniques such as western blots that use expensive reagents such as antibodies. The ability to simultaneously detect activity and isolate a protein catalyst from a mixture is even more difficult and currently impossible in most cases. In this manuscript we describe a chemical approach that achieves this goal for a unique family of enzymes called sirtuins using novel chemical tools, enabling rapid detection of activity and isolation of these protein catalysts. Sirtuin deacetylases are implicated in the regulation of many physiological functions including energy metabolism, DNA-damage response, and cellular stress resistance. We synthesized an aminooxy-derivatized NAD+ and a pan-sirtuin inhibitor that reacts on sirtuin active sites to form a chemically stable complex that can subsequently be crosslinked to an aldehyde-substituted biotin. Subsequent retrieval of the biotinylated sirtuin complexes on streptavidin beads followed by gel electrophoresis enabled simultaneous detection of active sirtuins, isolation and molecular weight determination. We show that these tools are cross reactive against a variety of human sirtuin isoforms including SIRT1, SIRT2, SIRT3, SIRT5, SIRT6 and can react with microbial derived sirtuins as well. Finally, we demonstrate the ability to simultaneously detect multiple sirtuin isoforms in reaction mixtures with this methodology, establishing proof of concept tools for chemical studies of sirtuins in complex biological samples.
A facile synthesis and crystallographic analysis of N-protected β-amino alcohols and short peptaibols
Jadhav, Sandip V.,Bandyopadhyay, Anupam,Benke, Sushil N.,Mali, Sachitanand M.,Gopi, Hosahudya N.
supporting information; experimental part, p. 4182 - 4187 (2011/06/28)
A facile, efficient and racemization-free method for the synthesis of N-protected β-amino alcohols and peptaibols using N-hydroxysuccinimide active esters is described. Using this method, dipeptide, tripeptide and pentapeptide alcohols were isolated in high yields. The conformations in crystals of β-amino alcohol, dipeptide and tripeptide alcohols were analysed, with a well-defined type III β-turn being observed in the tripeptide alcohol crystals. This method is found to be compatible with Fmoc-, Boc- and other side-chain protecting groups.
Hydrogelation and self-assembly of Fmoc-tripeptides: Unexpected influence of sequence on self-assembled fibril structure, and hydrogel modulus and anisotropy
Cheng,Castelletto,Moulton,Newby,Hamley
experimental part, p. 4990 - 4998 (2010/11/18)
The self-assembly and hydrogelation properties of two Fmoc-tripeptides [Fmoc = N-(fluorenyl-9-methoxycarbonyl)] are investigated, in borate buffer and other basic solutions. A remarkable difference in self-assembly properties is observed comparing Fmoc-VLK(Boc) with Fmoc-K(Boc)LV, both containing K protected by Nε-tert-butyloxycarbonate (Boc). In borate buffer, the former peptide forms highly anisotropic fibrils which show local alignment, and the hydrogels show flow-aligning properties. In contrast, Fmoc-K(Boc)LV forms highly branched fibrils that produce isotropic hydrogels with a much higher modulus (G′ > 104 Pa), and lower concentration for hydrogel formation. The distinct self-assembled structures are ascribed to conformational differences, as revealed by secondary structure probes (CD, FTIR, Raman spectroscopy) and X-ray diffraction. Fmoc-VLK(Boc) forms well-defined β-sheets with a cross-β X-ray diffraction pattern, whereas Fmoc-KLV(Boc) forms unoriented assemblies with multiple stacked sheets. Interchange of the K and V residues when inverting the tripeptide sequence thus leads to substantial differences in self-assembled structures, suggesting a promising approach to control hydrogel properties.
