- Lipoic acid based core cross-linked micelles for multivalent platforms: Design, synthesis and application in bio-imaging and drug delivery
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Natural lipoic acid derived small-molecule amphiphiles self-assemble into micelles in water. The presence of numerous disulfides accumulated in the core makes the micelles readily cross-linked to achieve the establishment of core cross-linked micelles (CCMs). Thanks to the inherent biocompatibility, the resulting lipoic acid based CCMs (LA-CCMs) are good multivalent platforms for biomedical applications.
- Huang, Jingsheng,Wu, Fang,Yu, Yunlong,Huang, Haolong,Zhang, Shiyong,You, Jingsong
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Read Online
- Controlled thioamide vs. amide formation in the thioacid-azide reaction under acidic aqueous conditions
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The thioacid-azide reaction and its chemoselectivity were probed with alkyl azides for a potential application to form amide bonds in aqueous solvents. Our results reveal that under acidic conditions thioamides were formed as major reaction products suggesting a competing mechanism, whereas reactions forming amides predominated at slightly higher pH values. the Partner Organisations 2014.
- Muehlberg, Michaela,Siebertz, Kristina D.,Schlegel, Brigitte,Schmieder, Peter,Hackenberger, Christian P.R.
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Read Online
- Synthesis and cation-mediated electronic interactions of two novel classes of porphyrin-fullerene hybrids
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The efficient synthesis as well as computational and photophysical studies of two novel classes of prophyrin-C6-hybrids is reported. A new synthetic methodology which can be efficaciously exploited in the construction of structurally unique con
- Baran,Monaco,Khan,Schuster,Wilson
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Read Online
- Identification of Pyruvate Carboxylase as the Cellular Target of Natural Bibenzyls with Potent Anticancer Activity against Hepatocellular Carcinoma via Metabolic Reprogramming
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Cancer cell proliferation in some organs often depends on conversion of pyruvate to oxaloacetate via pyruvate carboxylase (PC) for replenishing the tricarboxylic acid cycle to support biomass production. In this study, PC was identified as the cellular target of erianin using the photoaffinity labeling-click chemistry-based probe strategy. Erianin potently inhibited the enzymatic activity of PC, which mediated the anticancer effect of erianin in human hepatocellular carcinoma (HCC). Erianin modulated cancer-related gene expression and induced changes in metabolic intermediates. Moreover, erianin promotes mitochondrial oxidative stress and inhibits glycolysis, leading to insufficient energy required for cell proliferation. Analysis of 14 natural analogs of erianin showed that some compounds exhibited potent inhibitory effects on PC. These results suggest that PC is a cellular target of erianin and reveal the unrecognized function of PC in HCC tumorigenesis; erianin along with its analogs warrants further development as a novel therapeutic strategy for the treatment of HCC.
- Sheng, Yuwen,Chen, Yuwen,Zeng, Zhongqiu,Wu, Wenbi,Wang, Jing,Ma, Yuling,Lin, Yuan,Zhang, Jichao,Huang, Yulan,Li, Wenhua,Zhu, Qiyu,Wei, Xiao,Li, Suiyan,Wisanwattana, Wisanee,Li, Fu,Liu, Wanli,Suksamrarn, Apichart,Zhang, Guolin,Jiao, Wei,Wang, Fei
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p. 460 - 484
(2022/01/03)
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- Gold-Catalyzed Amide/Carbamate-Linked N, O-Acetal Formation with Bulky Amides and Alcohols
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A gold-catalyzed N,O-acetal formation was established to construct an amide/carbamate-linked N,O-acetal substructure with bulky alcohols. The acyliminium cation species generated from o-alkynylbenzoic acid ester in the presence of a gold catalyst is highly reactive and underwent nucleophilic attack of various bulky alcohols and phenols at room temperature under neutral conditions, leading to the corresponding N,O-acetals in yields of 34-89% with good functional group tolerance.
- Ohsawa, Kosuke,Ochiai, Shota,Kubota, Junya,Doi, Takayuki
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p. 1281 - 1291
(2021/01/14)
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- Nucleophilic transformations of azido-containing carbonyl compoundsviaprotection of the azido group
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Nucleophilic transformations of azido-containing carbonyl compounds are discussed. The phosphazide formation from azides and di(tert-butyl)(4-(dimethylamino)phenyl)phosphine (Amphos) enabled transformations of carbonyl groups with nucleophiles such as lithium aluminum hydride and organometallic reagents. The good stability of the phosphazide moiety allowed us to perform consecutive transformations of a diazide through triazole formation and the Grignard reaction.
- Aimi, Takahiro,Meguro, Tomohiro,Kobayashi, Akihiro,Hosoya, Takamitsu,Yoshida, Suguru
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supporting information
p. 6062 - 6065
(2021/06/21)
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- Sialyltransferase Inhibitors Suppress Breast Cancer Metastasis
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We report the synthesis and evaluation of a series of cell-permeable and N- versus O-selective sialyltransferase inhibitors. Inhibitor design entailed the functionalization of lithocholic acid at C(3) and at the cyclopentane ring side chain. Among the series, FCW34 and FCW66 were shown to inhibit MDA-MB-231 cell migration as effectively as ST3GALIII-gene knockdown did. FCW34 was shown to inhibit tumor growth, reduce angiogenesis, and delay cancer cell metastasis in animal models. Furthermore, FCW34 inhibited vessel development and suppressed angiogenic activity in transgenic zebrafish models. Our results provide clear evidence that FCW34-induced sialyltransferase inhibition reduces cancer cell metastasis by decreasing N-glycan sialylation, thus altering the regulation of talin/integrin/FAK/paxillin and integrin/NFκB signaling pathways.
- Fu, Chih-Wei,Tsai, Han-En,Chen, Wei-Sheng,Chang, Tzu-Ting,Chen, Chia-Ling,Hsiao, Pei-Wen,Li, Wen-Shan
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supporting information
p. 527 - 542
(2021/01/13)
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- A Reagent for Amine-Directed Conjugation to IgG1 Antibodies
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Functionalized antibodies are an indispensable resource for diagnosis, therapy and as a research tool for chemical biology. However, simpler and better methodologies are often required to improve the labeling of antibodies in terms of selectivity and scal
- M?rcher, Anders,Palmfeldt, Johan,Nisavic, Marija,Gothelf, Kurt V.
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supporting information
p. 6539 - 6544
(2021/02/09)
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- Isorhamnetin biotin probe, synthesis method and application thereof
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The invention relates to an isorhamnetin biotin probe, a synthesis method and application thereof, the probe takes isorhamnetin as a reaction group and biotin as an affinity tag, and has the structureshown as the formula in the specification, wherein X is
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- Solvent-Driven Supramolecular Wrapping of Self-Assembled Structures
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Self-assembly relies on the ability of smaller and discrete entities to spontaneously arrange into more organized systems by means of the structure-encoded information. Herein, we show that the design of the media can play a role even more important than
- Moreno-Alcántar, Guillermo,Aliprandi, Alessandro,Rouquette, Remi,Pesce, Luca,Wurst, Klaus,Perego, Claudio,Brüggeller, Peter,Pavan, Giovanni M.,De Cola, Luisa
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p. 5407 - 5413
(2021/01/26)
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- Design, synthesis and biological evaluation of a halogenated phenazine-erythromycin conjugate prodrug for antibacterial applications
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There is a significant need for new antibacterial agents as pathogenic bacteria continue to threaten human health through the acquisition of resistance and tolerance towards existing antibiotics. Over the last several years, our group has been developing
- Yang, Hongfen,Liu, Ke,Jin, Shouguang,Huigens III, Robert W.
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p. 1483 - 1487
(2021/03/01)
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- Functionalized 2-Hydroxybenzaldehyde-PEG Modules as Portable Tags for the Engagement of Protein Lysine ?-Amino Groups
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The formation of reversible-covalent interactions between a small-molecule ligand and its protein target is emerging as a general strategy to design binders with increased affinity. In this context, 2-hydroxybenzaldehyde (2HB) has been recently proposed a
- Sacco, Giovanni,Stammwitz, Simon,Belvisi, Laura,Pignataro, Luca,Dal Corso, Alberto,Gennari, Cesare
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p. 1763 - 1767
(2021/03/24)
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- Pyrene-Based “Turn-Off” Probe with Broad Detection Range for Cu2+, Pb2+ and Hg2+ Ions
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Detection of metals in different environments with high selectivity and specificity is one of the prerequisites of the fight against environmental pollution with these elements. Pyrenes are well suited for the fluorescence sensing in different media. The
- Merz, Viktor,Merz, Julia,Kirchner, Maximilian,Lenhart, Julian,Marder, Todd B.,Krueger, Anke
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p. 8118 - 8126
(2021/05/12)
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- TARGETED BIFUNCTIONAL DEGRADERS
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The present invention provides, in one aspect, bifunctional compounds that can be used to promote or enhance degradation of certain circulating proteins. In another aspect, the present invention provides bifunctional compounds that can be used to promote or enhance degradation of certain autoantibodies. In certain embodiments, treatment or management of a disease and/or disorder requires degradation, removal, or reduction in concentration of the circulating protein or the autoantibody in the subject. Thus, in certain embodiments, administration of a compound of the invention to the subject removes or reduces the circulation concentration of the circulating protein or the autoantibody, thus treating, ameliorating, or preventing the disease and/or disorder. In certain embodiments, the circulating protein is TNF.
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- Optical Manipulation of Subcellular Protein Translocation Using a Photoactivatable Covalent Labeling System
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The photoactivatable chemically induced dimerization (photo-CID) technique for tag-fused proteins is one of the most promising methods for regulating subcellular protein translocations and protein–protein interactions. However, light-induced covalent protein dimerization in living cells has yet to be established, despite its various advantages. Herein, we developed a photoactivatable covalent protein-labeling technology by applying a caged ligand to the BL-tag system, a covalent protein labeling system that uses mutant β-lactamase. We further developed CBHD, a caged protein dimerizer, using caged BL-tag and HaloTag ligands, and achieved light-induced protein translocation from the cytoplasm to subcellular regions. In addition, this covalent photo-CID system enabled quick protein translocation to a laser-illuminated microregion. These results indicate that the covalent photo-CID system will expand the scope of CID applications in the optical manipulation of cellular functions.
- Kowada, Toshiyuki,Arai, Keisuke,Yoshimura, Akimasa,Matsui, Toshitaka,Kikuchi, Kazuya,Mizukami, Shin
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p. 11378 - 11383
(2021/04/09)
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- Synthesis of polyanionic c5-modified 2′-deoxyuridine and 2′-deoxycytidine-5′-triphosphates and their properties as substrates for dna polymerases
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Modified 2′-deoxyribonucleotide triphosphates (dNTPs) have widespread applications in both existing and emerging biomolecular technologies. For such applications it is an essential requirement that the modified dNTPs be substrates for DNA polymerases. To date very few examples of C5-modified dNTPs bearing negatively charged functionality have been described, despite the fact that such nucleotides might potentially be valuable in diagnostic applications using Si-nanowire-based detection systems. Herein we have synthesised C5-modified dUTP and dCTP nucleotides each of which are labelled with an dianionic reporter group. The reporter group is tethered to the nucleobase via a polyethylene glycol (PEG)-based linkers of varying length. The substrate properties of these modified dNTPs with a variety of DNA polymerases have been investigated to study the effects of varying the length and mode of attachment of the PEG linker to the nucleobase. In general, nucleotides containing the PEG linker tethered to the nucleobase via an amide rather than an ether linkage proved to be the best substrates, whilst nucleotides containing PEG linkers from PEG6 to PEG24 could all be incorporated by one or more DNA polymerase. The polymerases most able to incorporate these modified nucleotides included Klentaq, Vent(exo-) and therminator, with incorporation by Klenow(exo-) generally being very poor.
- Allen, Esther,Dutson, Claire,Hedley, Joseph H.,Murton, Heather E.,Thompson, Mark J.,Williams, David M.
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- ENGINEERED ANTIBODIES AS MOLECULAR DEGRADERS THROUGH CELLULAR RECEPTORS
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The present disclosure provides, in one aspect, bifunctional compounds that can be used to promote or enhance degradation of certain circulating proteins. In certain embodiments, the circulating protein mediates a disease and/or disorder in a subject, and treatment or management of the disease and/or disorder requires degradation, removal, or reduction in concentration of the circulating protein in the subject. Thus, in certain embodiments, administration of a compound of the disclosure to the subject removes or reduces the circulation concentration of the circulating protein, thus treating, ameliorating, or preventing the disease and/or disorder.
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- COMPOSITIONS AND METHODS RELATED TO MOLECULAR CONJUGATION
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The invention relates to activated Michael acceptor (AMA) compounds that can undergo conjugation with biomolecules containing Michael donor moieties, thereby providing plasma-stable antibody-drug conjugates (ADCs). Pharmaceutical compositions of the ADCs are disclosed as well. Also provided herein are a number of applications (e.g., therapeutic applications) in which the compositions are useful.
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- Supramolecular compound nano-carrier as well as preparation method and application thereof
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The invention discloses a supramolecular compound nano-carrier as well as a preparation method and application thereof, and relates to the technical field of polymer chemistry and biological detection engineering. According to the supramolecular compound nano-carrier disclosed by the invention, a two-dimensional nanosheet supramolecular structure system generated by self-assembly is driven by an anion induction effect, and a supramolecular compound nano-carrier is of a single-layer nanosheet supramolecular structure constructed by a highly-oriented one-dimensional nanorod. A hydrophobic perylene group part is used as a skeleton part for constructing the highly-oriented one-dimensional nanorod, and the charge density of a single-layer nanosheet can be regulated and controlled. The surface of the water-soluble multivalent hydrophilic part can be loaded with DNAzyme deoxyribozyme for specific detection of heavy metal ions through electrostatic interaction, and the water-soluble multivalent supramolecular compound nano sensor is constructed. Based on a fluorescence change mechanism caused by specific cutting of heavy metal ions, The fluorescence detection of the heavy metal ions in food and biological tissues is realized, and the detection effect of the heavy metal ions is greatly enhanced.
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- Synthesis of 3′-O-Alkyl Homologues and a Biotin Probe of Isorhamnetin and Evaluation of Cytotoxic Efficacy on Cancer Cells
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Isorhamnetin is a natural flavonoid which shows a variety of biological activities such as antioxidant, anti-inflammatory and antitumor. In order to identify the cellular binding protein of isorhamnetin as potential anti-cancer target, we first synthesize
- Tursumamat, Nafisa,Yang, Zhuojin,Zheng, Yi,Zhu, Mingyan
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- Facilitating functionalization of benzene-1,3,5-tricarboxamides by switching amide connectivity
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Synthetic water-compatible supramolecular polymers based on benzene-1,3,5-tricarboxamides (BTAs) have attracted a lot of interest in recent years, as they are uniquely suited to generate functional multicomponent biomaterials. Their morphologies and intrinsic dynamic behaviour mimic fibrous structures found in nature. Moreover, their modularity allows control of the density of functionalities presented on the surface of the fibres when using functionalized BTA monomers. However, such moieties generally comprise a functionality on only one of three side chains, resulting in lengthy synthetic protocols and limited yields. In this work, we avert the need for desymmetrization of the core by starting from commercially available 5-aminoisophthalic acid. This approach eliminates the statistical reactions and reduces the number of synthetic steps. It also leads to the inversion of the connectivity of one of the amides to the benzene core. By combining spectroscopy, light scattering and cryogenic transmission electron microscopy, we confirm that the inversed amide BTAs (iBTAs) form intermolecular hydrogen bonds and assemble into supramolecular polymers, like previously used symmetrical BTAs, albeit with a slight decrease in water solubility. Solubility problems were overcome by incorporating iBTAs into conventional BTA-based supramolecular polymers. These two-component mixtures formed supramolecular fibres with a morphology and dynamic behaviour similar to BTA-homopolymers. Finally, iBTAs were decorated with a fluorescent dye to demonstrate the synthesis of functional monomers, and to visualize their co-assembly with BTAs. Our results show that functionality can be introduced into supramolecular polymers with monomers that slightly differ in their core structure while maintaining the structure and dynamics of the fibres.
- Dhiman, Shikha,Palmans, Anja R. A.,Schoenmakers, Sandra M. C.,Su, Lu,van den Bersselaar, Bart W. L.
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supporting information
p. 8281 - 8294
(2021/10/12)
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- An air-tolerant polymer gel-immobilized iridium photocatalyst with pumping recyclability properties
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A novel methacrylate-based cross-linked polymer gel bearing an iridium photocatalyst showed air tolerance and pumping recyclability features through its tunable swelling and deswelling ability. The photocatalytic activity of the polymer gel was demonstrated through an E-to-Z isomerisation reaction and in an azide-alkene [2+3] cycloaddition.
- Abramov, Alex,Díaz Díaz, David,Maiti, Binoy,Reiser, Oliver
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supporting information
p. 7762 - 7765
(2021/08/13)
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- PROTAC compound for targeted degradation of IDO1, and preparation method and application thereof
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The invention provides a PROTAC compound represented by formula I and used for targeted degradation of IDO1, and a pharmaceutically acceptable salt, a hydrate or a solvate thereof. In the formula I, Xrepresents -CH2 or -C = O, Y represents -CH2 or -C= O, and n is a natural number from 2 to 9. The PROTAC compound for targeted degradation of the IDO1 has efficient activity of targeted degradation of the IDO1 protein.
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- Synthesis of branched monodisperse oligoethylene glycols and 19f mri-traceable biomaterials through reductive dimerization of azides
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Multifunctionalized and branched M-OEGs represent valuable PEGylation agents, linkers, and scaffolds in biomedicine. However, the tedious synthesis limited their availability and application. We herein present an azide reductive dimerization method for the convenient synthesis of aza-M-OEGs and derivatives, which provides easy access to a variety of multifunctionalized and branched M-OEGs in one step. With this method, hexa-arm M-OEGs with 54 symmetrical fluorines were synthesized in two steps as a water-soluble, self-assemble, 19F MRI sensitive, and biocompatible dendritic biomaterial.
- Chen, Shizhen,Jiang, Zhong-Xing,Li, Yu,Yang, Hao,Yang, Zhigang,Yuan, Yuan,Zhang, Huaibin,Zhang, Jing,Zhou, Xin
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p. 6778 - 6787
(2020/06/08)
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- Vitamin-guanosine monophosphate conjugates for: In vitro transcription priming
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Expanding the catalytic repertoire of ribozymes to include vitamin synthesis requires efficient labelling of RNA with the substrate of interest, prior to in vitro selection. For this purpose, we rationally designed and synthesized six GMP-conjugates carry
- Bande, Omprakash,Groaz, Elisabetta,Herdewijn, Piet,Marlière, Philippe,Papastavrou, Nikolaos
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supporting information
p. 2787 - 2790
(2020/03/17)
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- Discovery of a new class of PROTAC BRD4 degraders based on a dihydroquinazolinone derivative and lenalidomide/pomalidomide
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BRD4 has emerged as an attractive target for anticancer therapy. However, BRD4 inhibitors treatment leads to BRD4 protein accumulation, together with the reversible nature of inhibitors binding to BRD4, which may limit the efficacy of BRD4 inhibitors. To address these problems, a protein degradation strategy based on the proteolysis targeting chimera (PROTAC) technology has been developed to target BRD4 recently. Herein, we present our design, synthesis and biological evaluation of a new class of PROTAC BRD4 degraders, which were based on a potent dihydroquinazolinone-based BRD4 inhibitor compound 6 and lenalidomide/pomalidomide as ligand for E3 ligase cereblon. Gratifyingly, several compounds showed excellent inhibitory activity against BRD4, and high anti-proliferative potency against human monocyte lymphoma cell line THP-1. Especially, compound 21 (BRD4 BD1, IC50 = 41.8 nM) achieved a submicromolar IC50 value of 0.81 μM in inhibiting the growth of THP-1 cell line, and was 4 times more potent than compound 6. Moreover, the mechanism study established that 21 could effectively induce the degradation of BRD4 protein and suppression of c-Myc. All of these results suggested that 21 was an efficacious BRD4 degrader for further investigation.
- Zhang, Fangqing,Wu, Zhenwei,Chen, Pan,Zhang, Jian,Wang, Tao,Zhou, Jinpei,Zhang, Huibin
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- Development of small-molecule BRD4 degraders based on pyrrolopyridone derivative
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Bromodomain-containing protein 4 (BRD4) plays a crucial role in the epigenetic regulation of gene transcription and some BRD4 inhibitors have been advanced to clinical trials. Nevertheless, the clinical application of BRD4 inhibitors could be limited by drug resistance. As an alternative strategy, the emerging Proteolysis Targeting Chimeras (PROTACs) technology has the potential to overcome the drug resistance of traditional small-molecule drugs. Based on PROTACs approaches, several BRD4 degraders were developed and have been proved to degrade BRD4 protein and inhibit tumor growth. Herein, we present the design, synthesis, and biological evaluation of pyrrolopyridone derivative-based BRD4 degraders. Four synthesized compounds displayed comparative potence against BRD4 BD1 with IC50 at low nanomolar concentrations. Anti-proliferative activity of 32a against BxPC3 cell line (IC50 = 0.165 μM) was improved by about 7-fold as compared to the BRD4 inhibitor ABBV-075. Furthermore, degrader 32a potently induced the degradation of BRD4 and inhibited the expression of c-Myc in BxPC3 cell line in a time-dependent manner. The exploration of intracellular antitumor mechanism showed 32a induced cell cycle arrest and apoptosis effectively. All the results demonstrated that compound 32a could be considered as a potential BRD4 degrader for further investigation.
- Chen, Pan,Wang, Lixun,Wang, Tao,Xu, Changliang,Zhang, Huibin,Zhang, Jian,Zheng, Peiyuan,Zhou, Jinpei,Zhu, Peiyu
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- BIVALENT TARGETED CONJUGATES
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The invention provides conjugates that comprise a bivalent targeting moiety, a nucleic acid, and optional linking groups as well as synthetic intermediates and synthetic methods useful for preparing the conjugates, compositions comprising the bidentate targeting ligands and the conjugates, as well as methods for targeting therapeutic nucleic acids with the bidentate conjugates. The conjugates are useful to target therapeutic nucleic acids.
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- THERAPEUTIC METHODS
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The invention provides methods and compositions for delivering a nucleic acid to a cell or the cytosol of the target cell. The method includes contacting the cell with, 1) a membrane-destabilizing polymer; and 2) a nucleic acid conjugate. The nucleic acid conjugate includes a targeting ligand bound to an optional linker and a nucleic acid.
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- Synthesis of Tryptophan-Folate Conjugates
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A mild protocol for the synthesis of folate-peptide/protein conjugates targeting tryptophan residues is described. This synthetic protocol is advantageous for homogeneous conjugation of chemically sensitive folates to biomolecules, with potential applications in cancer therapy and diagnostics.
- Kanai, Motomu,Konoue, Natsuki,Malawska, Katarzyna Joanna,Maruyama, Katsuya,Oisaki, Kounosuke
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p. 784 - 787
(2020/05/19)
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- Optimization of IEDDA bioorthogonal system: Efficient process to improve trans-cyclooctene/tetrazine interaction
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The antibody pretargeting approach for radioimmunotherapy (RIT) using inverse electron demand Diels-Alder cycloaddition (IEDDA) constitutes an emerging theranostic approach for solid cancers. However, IEDDA pretargeting has not reached clinical trial. The major limitation of the IEDDA strategy depends largely on trans-cyclooctene (TCO) stability. Indeed, TCO may isomerize into the more stable but unreactive cis-cyclooctene (CCO), leading to a drastic decrease of IEDDA efficiency. We have thus developed both efficient and reproducible synthetic pathways and analytical follow up for (PEGylated) TCO derivatives, providing high TCO isomeric purity for antibody modification. We have set up an original process to limit the isomerization of TCO to CCO before the mAbs’ functionalization to allow high TCO/tetrazine cycloaddition.
- Béquignat, Jean-Baptiste,Boucheix, Claude,Canitrot, Damien,Chezal, Jean-Michel,Degoul, Fran?oise,Miot-Noirault, Elisabeth,Moreau, Emmanuel,Navarro-Teulon, Isabelle,Quintana, Mercedes,Rondon, Aurélie,Taiariol, Ludivine,Ty, Nancy
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- PYRIDAZINE DERIVATIVES AS SMARCA2/4 DEGRADERS
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The present invention provides pyridazine derivatives of formula (I), which are therapeutically useful as SMARCA2/4 degraders. These compounds are useful in the treatment and/or prevention of diseases or disorders dependent upon SMARCA2/4 in a mammal. The present invention also provides preparation of the compounds and pharmaceutical compositions comprising at least one of the pyridazine derivatives of formula (I) or a pharmaceutically acceptable salt, or a stereoisomer thereof.
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Page/Page column 106; 106
(2019/11/12)
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- A MedChem toolbox for cereblon-directed PROTACs
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A modular chemistry toolbox was developed for cereblon-directed PROTACs. A variety of linkers was attached to a CRBN ligand via the 4-amino position of pomalidomide. We used linkers of different constitution to modulate physicochemical properties. We equipped one terminus of the linker with a set of functional groups, e.g. protected amines, protected carboxylic acids, alkynes, chloroalkanes, and protected alcohols, all of which are considered to be attractive for PROTAC design. We also highlight different opportunities for the expansion of the medicinal chemists' PROTAC toolbox towards heterobifunctional molecules, e.g. with biotin, fluorescent, hydrophobic and peptide tags.
- Steinebach, Christian,Sosi?, Izidor,Lindner, Stefanie,Bricelj, Ale?a,Kohl, Franziska,Ng, Yuen Lam Dora,Monschke, Marius,Wagner, Karl G.,Kr?nke, Jan,Gütschow, Michael
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supporting information
p. 1037 - 1041
(2019/06/27)
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- Monodisperse polyethylene glycol “brushes” with enhanced lipophilicity, and thermo and plasma stability
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A convenient strategy was developed for highly branched and multifunctionalized peptidic monodisperse polyethylene glycol “brushes”, which exhibit remarkable physicochemical and biological properties and potential as versatile biomaterials.
- Li, Yu,Wang, Xuemeng,Chen, Yongping,Yang, Zhigang,Jiang, Zhong-Xing
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p. 1895 - 1898
(2019/05/02)
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- Combretastatin A4-camptothecin micelles as combination therapy for effective anticancer activity
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Cancer is a major worldwide health problem, for which chemotherapy is a common treatment option. However drug toxicity and the development of resistance to chemotherapy are two main challenges associated with the traditional anticancer drugs. Combined pharmacological therapy based on different mechanisms might be an effective strategy in cancer treatment, and could exhibit a synergistic therapeutic efficacy. Herein, we aim to combine combretastatin A4 (CA4) and camptothecin (Cpt) chemically into a codrug through two hydrophilic linkers utilizing click chemistry to improve their water solubility and anticancer activity. The synthesized amphiphilic structure could self-assemble into a micelle structure as confirmed by atomic force microscopy (AFM) and dynamic light scattering (DLS), which showed a high stability and improved water solubility at pH 7.4, with a low critical micelle concentration (CMC) value of 0.9 mM. Moreover, in vitro hydrolysis was observed upon incubation of the hybrid compound with an esterase enzyme, which suggested a complete disassembly into the starting active drugs. Finally, cytotoxicity studies on HeLa cancer cells showed that the codrug demonstrated an enhanced (five fold) cytotoxicity as compared with the free drugs. In addition the combination index (CI) was 1, which suggests a synergistic activity for the codrug. Moreover, the tested concentrations of the codrug were not significantly cytotoxic to a noncancerous fibroblast cell line. The imaging of HeLa cells treated with FITC-loaded micelles showed a rapid internalization. In conclusion, the codrug of CA4 and Cpt might be a potential novel anticancer drug as it demonstrated a synergistic cytotoxic activity that might spare noncancerous cells.
- Assali, Mohyeddin,Kittana, Naim,Qasem, Sahar Alhaj,Adas, Raghad,Saleh, Doaa,Arar, Asala,Zohud, Osayd
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p. 1055 - 1061
(2019/01/18)
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- Set of Highly Stable Amine- and Carboxylate-Terminated Dendronized Au Nanoparticles with Dense Coating and Nontoxic Mixed-Dendronized Form
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The synthesis of a novel poly(propyleneimine) (PPI) dendron in gram scale as well as its use in the formation of a highly stable, dendronized gold nanoparticle (AuNP)-based drug delivery platform is described herein. The AuNP-based platform is composed of three complementary parts: (i) a 15 nm AuNP core, (ii) a heterofunctional thioctic acid-terminated tetraethylene glycol spacer, and (iii) a third-generation PPI dendron with a unique protonation profile and diverse end-group functionalization that allows for further derivatization. The prepared dendronized AuNPs are able to withstand several rounds of lyophilization cycles with no sign of aggregation, are stable in phosphate-buffered saline and Hanks' buffer as well as in serum, and are resistant to degradation by glutathione exchange reactions. This nanocarrier platform displays a dense coating, with >1400 dendrons/AuNPs, which will enable very high payload. Furthermore, while amine-terminated AuNPs expectedly showed cytotoxicity against the MCF-7 breast cancer cell line from a NP concentration of 1 nM, the mixed monolayer AuNPs (coated with 40/60 amine/carboxylate dendrons) interestingly did not exhibit any sign of toxicity at concentrations as high as 15 nM, similar to the carboxylate-terminated AuNPs. The described dendronized AuNPs address the current practical need for a stable NP-based drug delivery platform which is scalable and easily conjugable, has long-term stability in solution, and can be conveniently formulated as a powder and redispersed in desired buffer or serum.
- Saha Ray, Arunendra,Ghann, William E.,Tsoi, Phoebe S.,Szychowski, Brian,Dockery, Lance T.,Pak, Yewon J.,Li, Wenjing,Kane, Maureen A.,Swaan, Peter,Daniel, Marie-Christine
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p. 3391 - 3403
(2019/03/07)
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- METHODS FOR TREATING HEPATITIS B INFECTIONS
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Certain embodiments of the invention provide a method for identifying a patient that has a higher likelihood of responding to an HBV antigen inhibitor, such a method comprising detecting a hepatitis B virus (HBV) infected patient's genotype at one or more of the IL28B/A associated SNPs described herein, wherein the relevant genotype(s) described herein are indicative of a patient that has a higher likelihood of responding to an HBV antigen inhibitor as compared to an HBV infected patient having different genotypes at these locations.
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- GALNAC DERIVATIVES
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Modified oligonucleotides comprising a GalNAc moiety of the present disclosure along with methods of making and use, e.g., against HBV are disclosed.
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- COMPOSITIONS AND METHODS FOR DELIVERY OF MACROMOLECULES
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The present disclosure provides endosomal disruptors, which are useful for facilitating delivery of a macromolecule to the cytoplasm of a cell. The present disclosure provides compositions comprising an endosomal disruptor and a macromolecule. The present disclosure provides methods of delivering a macromolecule to the cytoplasm of a cell.
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- Naphthalimide/benzimide-based excited-state intramolecular proton transfer active luminogens: Aggregation-induced enhanced emission and potential for chemical modification
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Fluorescent organic particles are important in a number of areas, including medical imaging; hence, the development of organic materials that exhibit aggregation-induced emissions is an important objective. To that end, we report the synthesis of naphthalimide- and benzimide-based 2-(2-hydroxyphenyl)benzothiazole (HBT) derivatives (HNIBT and HPIBT, respectively) that exhibit aggregation-induced emission enhancement (AIEE), in contrast to most naphthalimide- or benzimide-based derivatives that are prone to aggregation-induced quenching. Experimental studies like single-crystal X-ray diffraction analysis and theoretical calculations demonstrate that the ability to undergo excited-state intramolecular proton transfer is pivotal for AIEE. Further studies revealed that a terminal alkynyl chain at the N-imide site of HPIBT has little impact on the emission behavior of the resultant compound (HPIBT-yl). HPIBT-Pe, an amphiphilic molecule obtained through the click reaction of HPIBT-yl and a tetraethylene-glycol-derived azide, self-assembled to form highly photostable particles that have long-term fluorescence imaging potential in cellular environments.
- Wang, Rong,Ding, Ju,Zhang, Yanrong
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p. 9152 - 9161
(2019/06/17)
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- TRIPODAL SQUARAMIDE-BASED MONOMERS
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The present invention relates to a tripodal squaramide-based monomer based monomer according to formula (I) for the formation of supramolecular polymers: wherein T represents a central atom; n is an integer of from 4 to 12; and R1 is a group ac
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- IRAK DEGRADERS AND USES THEREOF
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The present invention provides compounds, compositions thereof, and methods of using the same.
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- BI-FUNCTIONAL MOLECULES TO DEGRADE CIRCULATING PROTEINS
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The present invention is directed to bi-functional compounds which find use as pharmaceutical agents in the treatment of disease states and/or conditions which are through.macrophage migration inhibitory factor (MIF) or immunoglubin G (IgG). The present invention is also directed to pharmaceutical compositions which comprise these bi- functional compounds as well as methods for treating disease states and/or conditions which are mediated through MIF/lgG or where MIF/lgG is a contributing factor to the development and perpetuation of diseases and/or conditions, especially including autoimmune diseases and cancer, among others. The purpose of the present invention is to provide a molecular strategy to lower plasma MIF/lgG level in patients with autoimmune diseases or certain types of cancers. The b.i -functional molecule construct is comprised of a MIF/IgQ-targeting motif, that is derived from small molecule MIF/lgG ligands, and an ASGPr- targeting motif that binds to hepatocyte asialoglycoprotein receptor { ASGPr). The compounds selectively bind MIF or IgG in plasma and subsequently engage the endo-lysosomal pathway of hepatocytes through ASGPr. As a consequence, MIF/igG is internalized and degraded by hepatocytes, thus resulting in potential attenuation of corresponding disease symptoms which are modulated through MIF/igG.
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- Bladder Cancer Photodynamic Therapeutic Agents with Off-On Magnetic Resonance Imaging Enhancement
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Provided herein are porphyrinato-lanthanide complexes useful as theranostic agents and methods of preparation and use thereof. The porphyrinato-lanthanide complexes are useful in the treatment and imaging of cancer.
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- COMPOSITIONS AND METHODS CONCERNING IMMUNE TOLERANCE
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The present disclosure provides compositions comprising mannose-fused antigens to target mannose receptors. The compositions may be used to prevent immunity or reduce an immune response protein-based drugs that would otherwise elicit an immune response.
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- BIFUNCTIONAL SMALL MOLECULES TO TARGET THE SELECTIVE DEGRADATION OF CIRCULATING PROTEINS
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The present invention is directed to bifunctional small molecules which contain a circulating protein binding moiety (CPBM) linked through a linker group to a cellular receptor binding moiety (CRBM) which is a membrane receptor of degrading cell such as a hepatocyte or other degrading cell. In embodiments, the (CRBM) is a moiety which binds to asialoglycoprotein receptor (an asialoglycoprotein receptor binding moiety, or ASGPRBM) of a hepatocyte. In additional embodiments, the (CRBM) is a moiety which binds to a receptor of other cells which can degrade proteins, such as a LRP1, LDLR, FcyRI, FcRN, Transferrin or Macrophage Scavenger receptor. Pharmaceutical compositions based upon these bifunctional small molecules represent an additional aspect of the present invention. These compounds and/or compositions may be used to treat disease states and conditions by removing circulating proteins through degradation in the hepatocytes or macrophages of a patient or subject in need of therapy. Methods of treating disease states and/or conditions in which circulating proteins are associated with the disease state and/or condition are also described herein.
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- Chemical Genetics Reveals a Role of dCTP Pyrophosphatase 1 in Wnt Signaling
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Cell-based screening is a powerful approach to identify novel chemical modulators and biological components of relevant biological processes. The canonical Wnt pathway is essential for normal embryonic development and tissue homeostasis, and its deregulation plays a crucial role in carcinogenesis. Therefore, the identification of new pathway members and regulators is of significant interest. By means of a cell-based assay monitoring Wnt signaling we identified the pyrrolocoumarin Pyrcoumin as inhibitor of canonical Wnt signaling. Target identification and validation revealed that Pyrcoumin is a competitive inhibitor of dCTP pyrophosphatase 1 (dCTPP1). We demonstrate a yet unknown interaction of dCTPP1 with ubiquitin carboxyl-terminal hydrolase (USP7) that is counteracted by dCTPP1 inhibitors. These findings indicate that dCTPP1 plays a role in regulation of Wnt/β-catenin signaling most likely through a direct interaction with USP7.
- Friese, Alexandra,Kapoor, Shobhna,Schneidewind, Tabea,Vidadala, Srinivasa Rao,Sardana, Juhi,Brause, Alexandra,F?rster, Tim,Bischoff, Matthias,Wagner, Jessica,Janning, Petra,Ziegler, Slava,Waldmann, Herbert
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supporting information
p. 13009 - 13013
(2019/07/15)
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- Y-TYPE DISCRETE POLYETHYLENE GLYCOL DERIVATIVE AND PREPARATION METHOD THEREOF
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The present invention discloses a Y-type discrete polyethylene glycol derivative and a preparation method thereof, which has the advantages of determined molecular weights and the number of chain segments, and can avoid the defect of heterogeneity of a PEG derivative, meanwhile the preparation method has simple steps, mild conditions, without need for strictly anhydrous environment or performing protection and deprotection steps. In addition, the Y-type discrete polyethylene glycol derivative of the present invention may increase the water solubility of the discrete polyethylene glycol, and solve the problem of insufficient water solubility of the discrete polyethylene glycol-modified insoluble drug caused by an increase of the loading capacity.
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Paragraph 0061; 0080; 0083
(2018/03/09)
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- A Ratiometric Acoustogenic Probe for in Vivo Imaging of Endogenous Nitric Oxide
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Photoacoustic (PA) imaging is an emerging imaging modality that utilizes optical excitation and acoustic detection to enable high resolution at centimeter depths. The development of activatable PA probes can expand the utility of this technology to allow for detection of specific stimuli within live-animal models. Herein, we report the design, development, and evaluation of a series of Acoustogenic Probe(s) for Nitric Oxide (APNO) for the ratiometric, analyte-specific detection of nitric oxide (NO) in vivo. The best probe in the series, APNO-5, rapidly responds to NO to form an N-nitroso product with a concomitant 91 nm hypsochromic shift. This property enables ratiometric PA imaging upon selective irradiation of APNO-5 and the corresponding product, tAPNO-5. Moreover, APNO-5 displays the requisite photophysical characteristics for in vivo PA imaging (e.g., high absorptivity, low quantum yield) as well as high biocompatibility, stability, and selectivity for NO over a variety of biologically relevant analytes. APNO-5 was successfully applied to the detection of endogenous NO in a murine lipopolysaccharide-induced inflammation model. Our studies show a 1.9-fold increase in PA signal at 680 nm and a 1.3-fold ratiometric turn-on relative to a saline control.
- Reinhardt, Christopher J.,Zhou, Effie Y.,Jorgensen, Michael D.,Partipilo, Gina,Chan, Jefferson
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p. 1011 - 1018
(2018/02/07)
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- BIFUNCTIONAL ANTIFUNGAL AGENTS AND METHODS OF TREATING FUNGAL INFECTION
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The present invention is directed to bifunctional compounds which are useful in the treatment of fungal infections. The present compounds contains at least one fungal binding moiety (FBM) which is linked to at least one antibody binding moiety (ΑB/s
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- ANTIBODY-DRUG CONJUGATES
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An antibody-drug conjugate (ADC) has a structure represented by Formula (I): [in-line-formulae][D2-L2-Cn2?yG2-Ab-Sg1?G1-L1-D1]x?? Formula (I)[/in-line-formulae]or a pharmaceutically acceptable salt thereof, wherein Ab is an antibody without glycans (i.e., the protein portion of an antibody);G1 and G2 are glycan moieties, which may be the same or different;Cn1 and Cn2 are conjugation moieties, which may be the same or different;L1 and L2 are linker moieties, which may be the same or different;D1 and D2 are drug units which may be the same or different; andx and y are independently an integer from 0 to 8, provided that x+y≠0.
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- HETEROBIFUNCTIONAL LINKER
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The present disclosure relates generally to heterobifunctional linkers.
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- FUSOGENIC LIPOSOMES, COMPOSITIONS, KITS AND USE THEREOF FOR TREATING CANCER
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A fusogenic liposome comprising a lipid bilayer comprising a plurality of lipid molecules having 14 to 24 carbon atoms, wherein at least one of said lipid molecules is functionalised with a first functional group of a specific binding pair capable of binding to a complementary second functional group of said binding pair; and optionally further comprising an immune system activating agent functionalised with a complementary second functional group of said binding pair bound to said first functional group is provided. Methods of treatment of cancer using the fusogenic liposome are also provided.
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