25021-08-3Relevant articles and documents
Advanced aqueous-phase phosphoramidation reactions for effectively synthesizing peptide-oligonucleotide conjugates trafficked into a human cell line
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
, p. 2417 - 2433 (2012)
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.
Conjugation between maleimide-containing Pt(IV) prodrugs and furan or furan-containing drug delivery vectors via Diels-Alder cycloaddition
Gabano, Elisabetta,Perin, Elena,Bonzani, Diego,Ravera, Mauro
, p. 195 - 200 (2019)
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.
The stereodynamics of macrocyclic succinimide-thioethers
Lenz, Stefan,Horx, Philip,Geyer, Armin
, (2018)
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.
Incorporating 131I into a PAMAM (G5.0) dendrimer-conjugate: design of a theranostic nanosensor for medullary thyroid carcinoma
He,Wang,Su,Chen,Xie,Chen,Yu,Toledo,Abayaweera,Zhu,Bossmann
, p. 16181 - 16188 (2017)
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.
A simple network of synthetic replicators can perform the logical or operation
Allen, Victoria C.,Robertson, Craig C.,Turega, Simon M.,Philp, Douglas
, p. 1920 - 1923 (2010)
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
Structural and thermodynamic studies of simple aldose reductase-inhibitor complexes
Brownlee, June M.,Carlson, Erik,Milne, Amy C.,Pape, Erika,Harrison, David H.T.
, p. 424 - 444 (2006)
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.
Synthesis of functionalized copillar[4+1]arenes and rotaxane as heteromultivalent scaffolds
Chen, Wenzhang,Mohy Ei Dine, Tharwat,Vincent, Stéphane P.
supporting information, p. 492 - 495 (2021/01/25)
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.
Synthesis and Biological Evaluation of Shishijimicin A Type LinkerDrugs and Antibodya'Drug Conjugates
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
supporting information, p. 12890 - 12899 (2020/09/15)
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.
Heat stabilizer for PVC and synthesizing method of heat stabilizer
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Paragraph 0025, (2019/01/06)
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
Synthesis and study of modified polyvinyl alcohol containing amino acid moieties as anticancer agent
Samir, Ali H.,Saeed, Ruwaidah S.,Matty, Fadhel S.
, p. 286 - 294 (2018/03/21)
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.
