- Advanced aqueous-phase phosphoramidation reactions for effectively synthesizing peptide-oligonucleotide conjugates trafficked into a human cell line
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Peptide-oligonucleotide conjugates (POCs) have held promise as effective therapeutic agents in treating microbial infections and human genetic diseases including cancers. In clinical applications, POCs are especially useful to circumvent cellular delivery and specificity problems of oligonucleotides. We previously reported that nucleic acid phosphoramidation reactions performed in aqueous solutions have the potential for facile POC synthesis. Here, we carried out further studies to significantly improve aqueous-phase two-step phosphoramidation reaction yield. Optimized reactions were employed to effectively synthesize POCs for delivery into human A549 cells. We achieved optimization of aqueous-phase two-step phosphoramidation reaction and improved reaction yield by (1) determining appropriate co-solutes and co-solute concentrations to acquire higher reaction yields, (2) exploring a different nucleophilicity of imidazole and its derivatives to stabilize essential nucleic acid phosphorimidazolide intermediates prior to POC formation, and (3) enhancing POC synthesis by increasing reactant nucleophilicity. The advanced two-step phosphoramidation reaction was exploited to effectively conjugate a well-studied cell penetrating peptide, the Tat48-57 peptide, with oligonucleotides, bridged by either no linkers or a disulfide-containing linker, to have the corresponding POC yields of 47-75%. Phosphoramidation-synthesized POCs showed no cytotoxicity to human A549 cells at studied POC concentrations after 24 h inoculation and were successfully trafficked into the human A549 cell line as demonstrated by flow cytometry, fluorescent microscopy, and confocal laser scanning microscopy study. The current report provides insight into aqueous-phase phosphoramidation reactions, the knowledge of which was used to develop effective strategies for synthesizing POCs with crucial applications including therapeutic agents for medicine.
- Wang, Tzu-Pin,Ko, Ni Chien,Su, Yu-Chih,Wang, Eng-Chi,Severance, Scott,Hwang, Chi-Ching,Shih, Ying Ting,Wu, Min Hui,Chen, Yen-Hsu
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- Conjugation between maleimide-containing Pt(IV) prodrugs and furan or furan-containing drug delivery vectors via Diels-Alder cycloaddition
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Pt(IV) complexes are considered to act as antitumor prodrugs and their in vivo activity can be improved exploiting drug targeting and delivery strategies. With a view to such applications, the maleimide-containing ligand 2-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)acetic acid was used to produce the cisplatin-based Pt(IV) complexes (OC-6-44)-diamminedichlorido(ethanolato)(2-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)acetato)platinum(IV) and (OC-6-44)-acetatodiamminedichlorido(2-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)acetato)platinum(IV). These complexes underwent Diels-Alder reaction with furan, used as a model molecule to set up the experimental conditions, at ambient temperature up to 50 h, with limited decomposition. Finally, the reaction between the maleimide-containing Pt(IV) complexes and silica nanoparticles decorated with furan were successfully used as a proof-of-concept to demonstrate the clickability of functionalized vectors for drug delivery.
- Gabano, Elisabetta,Perin, Elena,Bonzani, Diego,Ravera, Mauro
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- The stereodynamics of macrocyclic succinimide-thioethers
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Maleimide-thiol coupling is a popular bioconjugation strategy, but little is known about the stereoselectivity and the stereodynamics of the succinimide thioether formed in a biopolymer environment. We used thiol 1,4-addition for the macrocyclisation of 5 designed pentapeptides with the ringsize of hexapeptides because they incorporate the succinimide thioether (4-8). Both succinimide diastereomers are observed in the constrained macrocyclic rings in each case. In spite of the low diastereoselectivity of the macrocyclisation reaction, there is a significant influence of the amino acid environment on the epimerization rate of the succinimide. Its half life can be as short as several hours at room temperature when Gly is the amino acid following the succinimide (peptide 8). On the contrary, no epimerization is detectable even after several weeks in the case of d-Phe C-terminal to the succinimide in peptide 4. Already the small selection of examples shows how big the differences in epimerization rates can be and that the local environment has a significant influence. The variation of amino acids in the vicinity of the ligation site points the way towards the synthesis of bioconjugates which are obtained as stable and separable diastereomers.
- Lenz, Stefan,Horx, Philip,Geyer, Armin
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- Incorporating 131I into a PAMAM (G5.0) dendrimer-conjugate: design of a theranostic nanosensor for medullary thyroid carcinoma
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We report the synthesis and purification of a targeting probe for Medullary Thyroid Carcinoma (MTC) by incorporating 131I into PAMAM (G5.0) dendrimers. Both the 131I labeled control dendrimer (131I-PAMAM (G5.0) without attached targeting peptide) and the MTC-targeting dendrimer (131I-PAMAM (G5.0) attached to VTP (vascular targeting peptide)) were labeled with the radioisotope 131I by applying the iodogen method. The resulting G5.0 dendrimers were purified by means of ultracentrifugation. The labelling efficiencies and radiochemical purities vs. time were determined by paper chromatography. The radiolabeling efficiencies of 131I-PAMAM (G5.0) and 131I-PAMAM (G5.0) were 93 ± 1% and 85 ± 2%, respectively. 131I-PAMAM (G5.0) did exhibit small, but significant changes in radiochemical purity as a function of time after labelling. The highest observed highest purity was 82 ± 2%. 131I-PAMAM (G5.0)-VTP did display larger changes in radiochemical purity as a function of time after labelling, maximally 80 ± 2%. The stability of the two probes and their binding behavior to the human medullary thyroid cancer cell line (TT) were observed in vitro. Compared to the negative control group (consisting of Na131I), the TT cell binding rate of 131I-PAMAM (G5.0)-VTP was significantly increased at 48 h and 72 h (P 131I-PAMAM (G5.0)-VTP at 48 h and 72 h was not significantly different when compared to the positive control group (131I-PAMAM (G5.0) group) (P > 0.05). These findings have been confirmed by performing MTT assays. These results confirm earlier findings, which demonstrated fast uptake of PAMAM (G5.0) by various cell types.
- He,Wang,Su,Chen,Xie,Chen,Yu,Toledo,Abayaweera,Zhu,Bossmann
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- A simple network of synthetic replicators can perform the logical or operation
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Figure presented A small network of synthetic replicators is capable of responding to instructional inputs such that the output of the network is an excess of one of the replicators whenever the input contains either or both of the replicators, mirroring
- Allen, Victoria C.,Robertson, Craig C.,Turega, Simon M.,Philp, Douglas
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- Structural and thermodynamic studies of simple aldose reductase-inhibitor complexes
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The competitive inhibition constants of series of inhibitors related to phenylacetic acid against both wild-type and the doubly mutanted C298A/W219Y aldose reductase have been measured. Van't Hoff analysis shows that these acids bind with an enthalpy near -6.8 kcal/mol derived from the electrostatic interactions, while the 100-fold differences in binding affinity appear to be largely due to entropic factors that result from differences in conformational freedom in the unbound state. These temperature studies also point out the difference between substrate and inhibitor binding. X-ray crystallographic analysis of a few of these inhibitor complexes both confirms the importance of a previously described anion binding site and reveals the hydrophobic nature of the primary binding site and its general plasticity. Based on these results, N-glycylthiosuccinimides were synthesized to demonstrate their potential in studies that probe distal binding sites. Reduced α-lipoic acid, an anti-oxidant and therapeutic for diabetic complications, was shown to bind aldose reductase with a binding constant of 1 μM.
- Brownlee, June M.,Carlson, Erik,Milne, Amy C.,Pape, Erika,Harrison, David H.T.
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- Synthesis of functionalized copillar[4+1]arenes and rotaxane as heteromultivalent scaffolds
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In this study, novel copillar[4+1]arenes were used as central heteromultivalent scaffolds via orthogonal couplings with a series of biologically relevant molecules such as carbohydrates, α-amino acids, biotin and phenylboronic acid. Further modifications by introducing maleimides or cyclooctyne groups provided molecular probes adapted to copper-free click chemistry. An octa-azidated fluorescent rotaxane bearing two distinct ligands was also generated in a fully controlled manner.
- Chen, Wenzhang,Mohy Ei Dine, Tharwat,Vincent, Stéphane P.
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supporting information
p. 492 - 495
(2021/01/25)
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- Synthesis and Biological Evaluation of Shishijimicin A Type LinkerDrugs and Antibodya'Drug Conjugates
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Our previous studies with shishijimicin A resulted in the total synthesis of this scarce marine natural product and a number of its simpler analogues endowed with picomolar potencies against certain cancer cell lines. Herein, we describe the design, synthesis, and biological evaluation of four linker-drugs, anticipating the construction of antibodya'drug conjugates (ADCs) as the ultimate goal of this research program. Using a common payload, the assembly of these linker-drugs utilized different linkers and attachment points, providing opportunities to probe the optimal molecular design of the intended ADCs as targeted cancer therapies. In the course of ADC generation and in vitro evaluation, we identified two linker-drugs with a promising in vitro plasma stability profile and excellent targeted cytotoxicity and specificity. Conjugation of shishijimicin A enediyne payloads through their phenolic moiety represents a novel approach to enediyne ADC creation, while the pharmacological profiles of at least two of the generated ADCs compare well with the profiles of the corresponding clinically approved ADC Kadcyla.
- Nicolaou,Li, Ruofan,Chen, Qifeng,Lu, Zhaoyong,Pitsinos, Emmanuel N.,Schammel, Alexander,Lin, Baiwei,Gu, Christine,Sarvaiya, Hetal,Tchelepi, Robert,Valdiosera, Amanda,Clubb, Justin,Barbour, Nicole,Sisodiya, Vikram,Sandoval, Joseph,Lee, Christina,Aujay, Monette,Gavrilyuk, Julia
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supporting information
p. 12890 - 12899
(2020/09/15)
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- Heat stabilizer for PVC and synthesizing method of heat stabilizer
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The invention provides a novel metallic soap heat stabilizer. The novel metallic soap heat stabilizer structurally comprises maleimide groups, substituted amide groups, multi-ether groups and metal ions and can be used as the heat stabilizer in a PVC proc
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Paragraph 0025
(2019/01/06)
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- Synthesis and study of modified polyvinyl alcohol containing amino acid moieties as anticancer agent
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A series of new phthalimides compounds[3-7]a-i were synthesized from reaction of Malic anhydride, phthalic anhydride, nitro phthalic anhydride, 2-phenyl-4H-benzo[d][1,3]oxazin-4-one, 2-(4-nitrophenyl)-4H-benzo[d][1,3]oxazin-4-one with different amino acids as glycine, alanine, valine, leucine, isoleucine, serine, threonine, tyrosine and Phenyl alanine [1]a-i under fusion conditions. Compounds [3-7]a-i react with SOCl2 in the presence of benzene to produce compounds [8-12]a-i. Chemical modification of Poly(vinyl alcohol)were obtained by reaction of PVA with compounds [8-12]a-i using the dimethyl formamide to give compounds [13-17]a-i. The structure of the synthesized compounds was characterized by their analytical and spectral data as, IR spectra, 1H, 13C-NMR, Elemental analysis (CHN), UV-Vis Spectroscopy, Scanning electron microscopy (SEM), Antibacterial activity were screened via two kinds of bacteria. Also, anticancer activity were examined for most of the modified polyvinyl alcohol.
- Samir, Ali H.,Saeed, Ruwaidah S.,Matty, Fadhel S.
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p. 286 - 294
(2018/03/21)
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- Synthesis N - maleic imide-based arylalkylic and its succinyl eater of method
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The invention provides a method for synthesizing N-maleimidoalkyl acid and succinimido ester thereof, which comprises the following steps: (a) carrying out cyclization reaction on a compound disclosed as Formula (II) and phenyl 4-nitrotrifluoroacetate in an organic solvent in the presence of alkali to obtain N-maleimidoalkyl acid disclosed as Formula (III); and (b) reacting the N-maleimidoalkyl acid disclosed as Formula (III) and an acylation reagent in an organic solvent at reflux temperature to obtain an acyl chloride intermediate disclosed as (IV), reacting the acyl chloride intermediate disclosed as (IV) with N-hydroxy succinimide in an organic solvent in the presence of alkali to obtain the N-maleimidoalkyl acid succinimido ester disclosed as Formula (V). The method has the advantages of simple technique, high yield and high product purity, and is suitable for industrial production. The reaction route is disclosed in the specification.
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Paragraph 0059-0062
(2017/10/13)
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- Potent irreversible inhibitors of LasR quorum sensing in Pseudomonas aeruginosa
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Antagonism of quorum sensing represents a promising new antivirulence approach for the treatment of bacterial infection. The development of a novel series of non-natural irreversible antagonists of P. aeruginosa LasR is described. The lead compounds identified (25 and 28) display potent LasR antagonist activity and inhibit expression of the P. aeruginosa virulence factors pyocyanin and biofilm formation in PAO1 and PA14.
- O'Brien, Kevin T.,Noto, Joseph G.,Nichols-O'Neill, Luke,Perez, Lark J.
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p. 162 - 167
(2015/03/04)
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- Elucidating the Origin of diastereoselectivity in a self-replicating system: Selfishness versus altruism
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We have investigated a diastereoselective self-replicating system based on a cycloaddition of a fulvene derivative and a maleimide using a two-pronged approach of combining NMR spectroscopy with computational modelling. Two diastereomers are formed with identical rates in the absence of replication. When replication is enabled, one diastereomer takes over the resources as a "selfish" autocatalyst, while exploiting the competitor as a weak "altruist", resulting in a diastereoselectivity of 16:1. We applied 1D and 2D NMR spectroscopic techniques supported by ab initio chemical shifts as well as ab initio molecular dynamics simulations to study the structure and dynamics of the underlying network. This powerful combination allowed us to decipher the energetic and structural rationale behind the observed behaviour, while static computational methods currently used in the field did not.
- Dieckmann, Arne,Beniken, Sabrina,Lorenz, Christian D.,Doltsinis, Nikos L.,Von Kiedrowski, Guenter
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supporting information; experimental part
p. 468 - 480
(2011/03/18)
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- Design, synthesis, inhibitory activity, and binding mode study of novel DNA methyltransferase 1 inhibitors
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To identify novel non-nucleoside DNA methyltransferase (DNMT) inhibitors, we designed and synthesized a series of maleimide derivatives. Among this series, compounds 5-8 were found to be more potent DNMT1 inhibitors than RG108, a DNMT1 inhibitor reported previously by Siedlecki et al. The binding mode analysis of compound 5 is also reported.
- Suzuki, Takayoshi,Tanaka, Rikako,Hamada, Shohei,Nakagawa, Hidehiko,Miyata, Naoki
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scheme or table
p. 1124 - 1127
(2010/06/15)
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- Synthesis and in vitro testing of new potent polyacridine-melittin gene delivery peptides
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The combination of a polyacridine peptide modified with a melittin fusogenic peptide results in a potent gene transfer agent. Polyacridine peptides of the general formula (Acr-X)n-Cys were prepared by solid-phase peptide synthesis, where Acr is
- Baumhover, Nicholas J.,Anderson, Kevin,Fernandez, Christian A.,Rice, Kevin G.
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experimental part
p. 74 - 83
(2010/11/04)
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- Synthesis and antimicrobial activity of some new N-acyl substituted phenothiazines
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A series of 2-substituted N-acylphenothiazines were synthesized by using imides, N-carboxymethyl imides and the structures of these newly synthesized compounds were confirmed by spectral and elemental analyses. All new compounds were tested for their antibacterial and antifungal activities. Some compounds showed promising antibacterial and antifungal activities.
- Bansode, Tanaji N.,Shelke, Jayant V.,Dongre, Vaijanath G.
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experimental part
p. 5094 - 5098
(2010/01/06)
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- Structure-reactivity relationships in a recognition mediated [3+2] dipolar cycloaddition reaction
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The [3+2] dipolar cycloaddition between an azide and maleimide can be accelerated by a factor of more than 100 simply by attaching complementary recognition sites to the reactive partners. This rate acceleration derives from the formation of a reactive bi
- Sinclair, Andrew J.,Del Amo, Vicente,Philp, Douglas
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supporting information; experimental part
p. 3308 - 3318
(2009/10/23)
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- Practical synthesis of maleimides and coumarin-linked probes for protein and antibody labelling via reduction of native disulfides
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The cellular tracking, detection and sensing of protein or antibody movement are important aspects to advance our understanding of biomolecular interactions and activity. Antibodies modified with fluorescent dyes are also valuable tools, especially in immunology research. We describe here a proof-of-principle study of a new water-soluble coumarin probe with a maleimide thiol-reacting unit to fluorescently tag biomolecules. Highlights include: (1) a convenient water-based preparation of N-substituted maleimides, (2) a one-pot preparation of activated maleimido-esters, and (3) a bio-conjugation protocol for the selenol-promoted reduction of native disulfide bonds and the 'site-specific' labelling of antibodies with no significant loss of activity.
- Song, Hong Y.,Ngai, Mun H.,Song, Zhen Y.,MacAry, Paul A.,Hobley, Jonathan,Lear, Martin J.
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experimental part
p. 3400 - 3406
(2010/01/06)
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- Probing selectivity in recognition-mediated dynamic covalent processes
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Two simple recognition-mediated dynamic Diels-Alder systems are used to probe the role of kinetics and thermodynamics in determining the equilibrium position in exchanging libraries and the time taken to reach that equilibrium. The selectivity expressed by recognition-driven dynamic processes is demonstrated to be less than the free-energy difference between the components as a result of compensatory effects arising from the extent of conversion to products within the library.
- Bennes, Raphael M.,Philp, Douglas
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p. 3651 - 3654
(2007/10/03)
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- Probing structural effects on replication efficiency through comparative analyses of families of potential self-replicators
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A formidable synthetic apparatus for the creation of nanoscale molecular structures and supramolecular assemblies through molecular structures can potentially be created from systems that are capable of parallel automultiplication (self-replication). In order to achieve this goal, a detailed understanding of the relationship be tween molecular structure and replication efficiency is necessary. Diastereoisomeric templates that are capable of specific and simultaneous autocatalysis have been synthesised. A systematic experimental and theoretical evaluation of their behaviour and that of structurally-related systems reveals the key determinants that dictate the emergence of self-replicative function and defines the structural space within which this behaviour is observed.
- Kassianidis, Eleftherios,Pearson, Russell J.,Philp, Douglas
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p. 8798 - 8812
(2007/10/03)
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- Maleimidyl-containing material and production method thereof
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The invention provides a maleimidyl-containing material having a substituent group defined by the following structural formula (1) containing a maleimidyl group (maleimido group): wherein A denotes a spacer containing an amino acid or a peptide spacer P. Also, the invention provides a production method of the above-mentioned maleimidyl-containing material involving a step of reacting a material containing an amino acid or a peptide chain with a compound containing a maleimido group.
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Page/Page column 6
(2010/11/08)
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- Systems chemistry: Kinetic and computational analysis of a nearly exponential organic replicator
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Combining kinetic, structural, and computational studies on complex dynamic feedback systems may lead to the field of "systems chemistry". The approach is exemplified by the analysis of a simple organic self-replicating system that has the potential to ex
- Kindermann, Maik,Stahl, Insa,Reimold, Malte,Pankau, Wolf Matthias,Von Kiedrowski, Guenter
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p. 6750 - 6755
(2007/10/03)
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- Self-replication vs. reactive binary complexes - Manipulating recognition-mediated cycloadditions by simple structural modifications
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The rate of reaction and the selectivity of a Diels - Alder cycloaddition between a furan and a maleimide can be enhanced by the introduction of complementary recognition sites on the reactant species. Subtle manipulation of other structural elements allows the generation of the observed rate enhancements and selectivities through either self-replication or formation of a pre-reactivc binary complex.
- Pearson, Russell J.,Kassianidis, Eleftherios,Slawin, Alexandra M.Z.,Philp, Douglas
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p. 3434 - 3441
(2007/10/03)
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- Material for photo-alignment layer, photo-alignment layer and method of manufacturing the same
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The present invention provides a photo-alignment layer for a liquid crystal display device, which has good liquid crystal display device characteristics such as a good voltage holding ratio and also has good alignment stability and sufficient resistance t
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- Microwave-induced One-pot Synthesis of N-carboxyalkyl Maleimides and Phthalimides
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Maleic and phthalic anhydride condenses with amino acids and alkylamines under microwave irradiation to afford N-substituted maleimides and phthalimides in excellent yields.
- Borah, Harsha N.,Boruah, Romesh C.,Sandhu, Jagir S.
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p. 272 - 273
(2007/10/03)
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