53339-53-0Relevant academic research and scientific papers
Thiol-responsive pro-fluorophore labeling: Synthesis of a pro-fluorescent labeled oligonucleotide for monitoring cellular uptake
Akai, Shoji,Ohta, Takayuki,Ono, Akira,Saneyoshi, Hisao,Yamamoto, Yuta
, (2020)
Pro-fluorescent labeled oligonucleotides are potential alternative tools to classical fluorescently labeled oligonucleotides for monitoring cellular uptake. Here, we report the design and synthesis of a thiol-responsive pro-fluorophore labeled oligonucleotide, and its fluorescence responsivity to glutathione in the test tube and live cells.
Antibody drug conjugates with hydroxamic acid cargos for histone deacetylase (HDAC) inhibition
Cianferotti, Claudio,Faltoni, Valentina,Cini, Elena,Ermini, Elena,Migliorini, Francesca,Petricci, Elena,Taddei, Maurizio,Salvini, Laura,Battistuzzi, Gianfranco,Milazzo, Ferdinando Maria,Anastasi, Anna Maria,Chiapparino, Caterina,De Santis, Rita,Giannini, Giuseppe
, p. 867 - 870 (2021)
Antitumor hydroxamates SAHA and Dacinostat have been linked to cetuximab and trastuzumab through a non-cleavable linker based on thep-mercaptobenzyl alcohol structure. These antibody drug conjugates (ADCs) were able to inhibit HDAC in several tumour cell lines. The cetuximab based ADCs block human lung adenocarcinoma cell proliferation, demonstrating that bioconjugation with antibodies is a suitable approach for targeted therapy based on hydroxamic acid-containing drugs. This work also shows that ADC-based delivery might be used to overcome the classical pharmacokinetic problems of hydroxamic acids.
Investigation of the effect of different linker chemotypes on the inhibition of histone deacetylases (HDACs)
Linciano, Pasquale,Benedetti, Rosaria,Pinzi, Luca,Russo, Fabiana,Chianese, Ugo,Sorbi, Claudia,Altucci, Lucia,Rastelli, Giulio,Brasili, Livio,Franchini, Silvia
, (2020/11/24)
Histone Deacetylases (HDACs) are among the most attractive and interesting targets in anticancer drug discovery. The clinical relevance of HDAC inhibitors (HDACIs) is testified by four FDA-approved drugs for cancer treatment. However, one of the main drawbacks of these drugs resides in the lack of selectivity against the different HDAC isoforms, resulting in severe side effects. Thus, the identification of selective HDACIs represents an exciting challenge for medicinal chemists. HDACIs are composed of a cap group, a linker region, and a metal-binding group interacting with the catalytic zinc ion. While the cap group has been extensively investigated, less information is available about the effect of the linker on isoform selectivity. To this aim, in this work, we explored novel linker chemotypes to direct isoform selectivity. A small library of 25 hydroxamic acids with hitherto unexplored linker chemotypes was prepared. In vitro tests demonstrated that, depending on the linker type, some candidates selectively inhibit HDAC1 over HDAC6 isoform or vice versa. Docking calculations were performed to rationalize the effect of the novel linker chemotypes on biologic activity. Moreover, four compounds were able to increase the levels of acetylation of histone H3 or tubulin. These compounds were also assayed in breast cancer MCF7 cells to test their antiproliferative effect. Three compounds showed a significant reduction of cancer proliferation, representing valuable starting points for further optimization.
Discovery of Carbono(di)thioates as Indoleamine 2,3-Dioxygenase 1 Inhibitors
Kumazawa, Miyuki,Tejima, Manabu,Fukuda, Miwa,Takeda, Shota,Suzuki, Kenji,Mizumoto, Yukiko,Sato, Kakeru,Waki, Minoru,Miyachi, Hiroyuki,Asai, Akira,Takikawa, Osamu,Hashimoto, Tomoko,Ohno, Osamu,Matsuno, Kenji
supporting information, p. 211 - 216 (2021/02/01)
A structure-activity relationship study unexpectedly showed that carbonothioates 4a and 4b, obtained by a unique alkaline hydrolysis of 2-alkylthio-oxazolines 3a and 3b, respectively, are a novel scaffold for indoleamine 2,3-dioxygenase 1 (IDO1) inhibitors. Derivatization of the carbonothioates enhanced inhibitory activity against IDO1 and cellular kynurenine production without cytotoxicity and led to the discovery of the related scaffolds carbonodithioates 5 and cyanocarbonimidodithioates 6 as IDO1 inhibitors. Incorporation of an OH group provided the most potent analogue 5i. UV-visible absorption spectroscopy of the Soret band, as well as docking and peptide mapping studies, suggested that these molecules bind to the heme in the active site of IDO1. Our unique IDO1 inhibitors are potential leads for future development.
Reduction-responsive amphiphilic antitumor pharmic conjugate and preparation method and application thereof
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Paragraph 0040; 0044-0045; 0054, (2019/10/22)
The invention relates to a reduction-responsive amphiphilic antitumor pharmic conjugate and a preparation method and application thereof. The reduction-responsive amphiphilic antitumor pharmic conjugate has a molecular structural formula shown in a formula I, wherein ROH is a hydrophobic antitumor drug; n is 5-1000. The provided prodrug can achieve targeted drug delivery, which not only retains the advantages of a nano-drug-loading system, but also exhibits the characteristic of specific degradation of a disulfide bond at a tumor site. Compared with conventional connecting arms such as 2,2'-dithiodiacetic acid and 3,3'-dithiodipropionic acid, the anticancer drug in an original drug molecule form can be obtained without further hydrolysis.
Tumor-targeted polypeptide drug conjugate and preparation method and application thereof
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Paragraph 0043; 0047-0048; 0057, (2019/10/22)
The invention relates to a tumor-targeted polypeptide drug conjugate and a preparation method and application thereof. The tumor-targeted polypeptide drug conjugate has the molecular structural formula shown in the formula I, wherein Aaa1 is L-Lys or D-Lys; Aaa2 is L-Lys or D-Lys or L-Arg or D-Arg; X is L-Cys-Ac or D-Cys-Ac; ROH is a hydrophobic anti-tumor drug. By means of the tumor-targeted polypeptide drug conjugate, targeted drug delivery can be achieved, the tumor-targeted polypeptide drug conjugate can be assembled into nano-micelles, the in-vivo circulation time is prolonged, the targeted polypeptide can deliver the anti-tumor drug to specific tumor cells, after the drug enters the tumor cells, the characteristic that disulfide bonds are specifically degraded at the tumor site is exerted, the anti-tumor drug is quickly released, compared with 2,2'-thiodiacetic acid, 3,3'-dithiodipropionic acid and other conventional connecting arms, the anti-tumor drug in an original medicine molecular form can be obtained without further hydrolysis, the drug therapeutic effect is improved, and the toxic and side effects on normal cells are reduced.
Compound, fluorescence-labeled-introducing agent, and introducing fluorescent labeling method (by machine translation)
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Paragraph 0084, (2020/01/07)
[Problem] no fluorescence whereas the extracellular, intracellular fluorescence of fluorescently labeled compound is incorporated, and such fluorescent labeling for introducing fluorescent labeling agent is introduced. (1) A compound represented by general formula [a] is used. In the general formula (1), the A, biological material or derivatives thereof may be incorporated into the cell through a cell membrane structure 1 comprises a divalent group, the FL, fluorescent light having a fluorescent unit which exhibits cyclic backbone nitrogen atom, L is, a monovalent group FL A coupling 2, the X, a single bond or O - (=O) a - C, wavy lines represent bonds, the nitrogen atom is bound to a FL included, the Ar, para or ortho position of the aromatic ring which has a valence bond 2, R is, nitro or - S e S a-R1 And, R1 Is, a monovalent group, n the, an integer of 1 - 3. [Drawing] no (by machine translation)
HSP90-TARGETING CONJUGATES AND FORMULATIONS THEREOF
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Paragraph 0343; 0352, (2019/07/19)
Conjugates of an active agent attached to a targeting moiety, such as an HSP90 binding moiety, via a linker, and particles comprising such conjugates have been designed. Such conjugates and particles can provide improved temporospatial delivery of the active agent, improved biodistribution and penetration in tumor, and/or decreased toxicity. Methods of making the conjugates, the particles, and the formulations thereof are provided. Methods of administering the formulations to a subject in need thereof are provided, for example, to treat or prevent cancer.
Stabilizing p-Dithiobenzyl Urethane Linkers without Rate-Limiting Self-Immolation for Traceless Drug Release
Zheng, Yiwu,Shen, Yang,Meng, Xiaoting,Wu, Yaqi,Zhao, Yibing,Wu, Chuanliu
, p. 1196 - 1203 (2019/05/28)
Exploiting the redox sensitivity of disulfide bonds is a prevalent strategy in targeted prodrug designs. In contrast to aliphatic disulfides, p-thiobenzyl-based disulfides have rarely been used for prodrug designs, given their intrinsic instability caused by the low pKa of aromatic thiols. Here, we examined the interplay between steric hindrance and the low-pKa effect on thiol–disulfide exchange reactions and uncovered a new thiol–disulfide exchange process for the self-immolation of p-thiobenzyl-based disulfides. We observed a central leaving group shifting effect in the α,α-dimethyl-substituted p-dithiobenzyl urethane linkers (DMTB linkers), which leads to increased disulfide stability by more than two orders of magnitude, an extent that is significantly greater than that observed with typical aliphatic disulfides. In particular, the DMTB linkers display not only high stability, but also rapid self-immolation kinetics due to the low pKa of the aromatic thiol, which can be used as a general and robust linkage between targeting reagents and cytotoxic drugs for targeted prodrug designs. The unique and promising stability characteristics of the present DMTB linker will likely inspire the development of novel targeted prodrugs to achieve traceless release of drugs into cells.
HDAC INHIBITORS-BASED ANTIBODY DRUG CONJUGATES (ADCs) AND USE IN THERAPY
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Page/Page column 86-88, (2018/10/25)
The present invention relates to novel Histone Deacetylase Inhibitors (HDACi)- based antibody drug conjugates particularly with antibodies directed to ErbB1, ErbB2 and ErbB3 receptors, pharmaceutical compositions comprising said antibodies as well as to their use in the treatment of cancer or tumor and other diseases where a modulation of one or more histone deacetylase isoforms can be effective for therapeutic interventions.
