- Keywords
- bioortogonální chemie,
- MeSH
- Alkynes chemistry MeSH
- Azides chemistry MeSH
- Chemical Phenomena MeSH
- Click Chemistry * methods MeSH
- Cycloaddition Reaction classification methods instrumentation MeSH
- Research MeSH
- Publication type
- Review MeSH
The oxidative photocyclization of aromatic Schiff bases was investigated as a potential method for synthesis of phenanthridine derivatives, biologically active compounds with medical applications. Although it is possible to prepare the desired phenanthridines using such an approach, the reaction has to be performed in the presence of acid and TEMPO to increase reaction rate and yield. The reaction kinetics was studied on a series of substituted imines covering the range from electron-withdrawing to electron-donating substituents. It was found that imines with electron-withdrawing substituents react one order of magnitude faster than imines bearing electron-donating groups. The 1H NMR monitoring of the reaction course showed that a significant part of the Z isomer in the reaction is transformed into E isomer which is more prone to photocyclization. The portion of the Z isomer transformed showed a linear correlation to the Hammett substituent constants. The reaction scope was expanded towards synthesis of larger aromatic systems, namely to the synthesis of strained aromatic systems, e.g., helicenes. In this respect, it was found that the scope of oxidative photocyclization of aromatic imines is limited to the formation of no more than five ortho-fused aromatic rings.
The target diosgenin-betulinic acid conjugates are reported to investigate their ability to enhance and modify the pharmacological effects of their components. The detailed synthetic procedure that includes copper(I)-catalyzed Huisgen 1,3-dipolar cycloaddition (click reaction), and palladium-catalyzed debenzylation by hydrogenolysis is described together with the results of cytotoxicity screening tests. Palladium-catalyzed debenzylation reaction of benzyl ester intermediates was the key step in this synthetic procedure due to the simultaneous presence of a 1,4-disubstituted 1,2,3-triazole ring in the molecule that was a competing coordination site for the palladium catalyst. High pressure (130 kPa) palladium-catalyzed procedure represented a successful synthetic step yielding the required products. The conjugate 7 showed selective cytotoxicity in human T-lymphoblastic leukemia (CEM) cancer cells (IC50 = 6.5 ± 1.1 µM), in contrast to the conjugate 8 showing no cytotoxicity, and diosgenin (1), an adaptogen, for which a potential to be active on central nervous system was calculated in silico. In addition, 5 showed medium multifarious cytotoxicity in human T-lymphoblastic leukemia (CEM), human cervical cancer (HeLa), and human colon cancer (HCT 116). Betulinic acid (2) and the intermediates 3 and 4 showed no cytotoxicity in the tested cancer cell lines. The experimental data obtained are supplemented by and compared with the in silico calculated physico-chemical and absorption, distribution, metabolism, and excretion (ADME) parameters of these compounds.
- MeSH
- Cycloaddition Reaction MeSH
- Diosgenin chemistry MeSH
- Hydrogenation MeSH
- Catalysis MeSH
- Humans MeSH
- Cell Line, Tumor MeSH
- Palladium chemistry MeSH
- Pentacyclic Triterpenes chemistry MeSH
- Antineoplastic Agents chemical synthesis chemistry pharmacology MeSH
- Drug Screening Assays, Antitumor MeSH
- Pressure MeSH
- Cell Survival drug effects MeSH
- Structure-Activity Relationship MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
To tailor cell-surface interactions, precise and controlled attachment of cell-adhesive motifs is required, while any background non-specific cell and protein adhesion has to be blocked effectively. Herein, a versatile and highly reproducible antifouling surface modification based on "clickable" groups and hierarchically structured diblock copolymer brushes for the controlled attachment of cells is reported. The polymer brush architecture combines an antifouling bottom block of poly(2-hydroxyethyl methacrylate) poly(HEMA) and an ultrathin azide-bearing top block, which can participate in well-established "click" reactions including the highly selective copper-catalyzed alkyne-azide cycloaddition (CuAAC) reaction under mild conditions. This straightforward approach allows the rapid conjugation of a cell-adhesive, alkyne-bearing cyclic RGD peptide motif, enabling subsequent specific attachment of NIH 3T3 fibroblasts, their extensive proliferation and confluent cell sheet formation after 48 h of incubation. The generally applicable strategy presented in this report can be employed for surface functionalization with diverse alkyne-bearing biological moieties via CuAAC or copper-free alkyne-azide cycloaddition protocols, making it a versatile functionalization approach and a promising tool for tissue engineering, biomaterial implant design, and other applications that require surfaces supporting highly specific cell attachment.
- MeSH
- Alkynes chemistry pharmacology MeSH
- Anti-Infective Agents chemical synthesis pharmacology MeSH
- Azides chemistry pharmacology MeSH
- Biocompatible Materials chemical synthesis pharmacology MeSH
- NIH 3T3 Cells MeSH
- Click Chemistry MeSH
- Cycloaddition Reaction MeSH
- Catalysis MeSH
- Mice MeSH
- Oligopeptides chemistry MeSH
- Polyhydroxyethyl Methacrylate chemistry MeSH
- Cell Proliferation drug effects MeSH
- Tissue Engineering MeSH
- Tissue Scaffolds * MeSH
- Animals MeSH
- Check Tag
- Mice MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
Modification of DNA with reactive groups and their post-synthetic transformations are useful for labelling, imaging, bioconjugations and cross-linking with other (bio)molecules. This review summarizes the recent progress in this field and covers transformations of oxo groups, cycloadditions, conjugate additions, alkylations, cross-couplings and other reactions. Examples of applications are given and the practicability and scope of the reactions are discussed.
Inverse-electron-demand Diels-Alder (iEDDA) cycloaddition between 1,2,4,5-tetrazines and strained dienophiles belongs among the most popular bioconjugation reactions. In addition to its fast kinetics, this cycloaddition can be tailored to produce fluorescent products from non-fluorescent starting materials. Here we show that even the reaction intermediates formed in iEDDA cycloaddition can lead to the formation of new types of fluorophores. The influence of various substituents on their photophysical properties and the generality of the approach with use of various trans-cyclooctene derivatives were studied. Model bioimaging experiments demonstrate the application potential of fluorogenic iEDDA cycloaddition.
- MeSH
- Cycloaddition Reaction MeSH
- Cyclooctanes chemistry MeSH
- Fluorescent Dyes chemical synthesis chemistry MeSH
- Microscopy, Fluorescence methods MeSH
- HeLa Cells MeSH
- Heterocyclic Compounds, 2-Ring chemical synthesis chemistry MeSH
- Heterocyclic Compounds, 1-Ring chemistry MeSH
- Microscopy, Confocal methods MeSH
- Humans MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
In this review, we summarize synthetic approaches to preparing single or fused oxazine and thiazine derivatives using solid-phase synthesis (SPS). The literature survey revealed that diverse compounds bearing variously functionalized 1,2-oxazine, 1,3-oxazine, or 1,4-oxazine scaffolds and the corresponding thiazines are accessible by SPS. The latest contributions involving the stereoselective polymer-supported syntheses of morpholines indicate that the field is continuing to expand.
- MeSH
- Cycloaddition Reaction MeSH
- Small Molecule Libraries chemistry MeSH
- Molecular Structure MeSH
- Morpholines chemistry MeSH
- Oxazines chemical synthesis MeSH
- Oxidation-Reduction MeSH
- Polymers chemistry MeSH
- Pyrazoles chemistry MeSH
- Stereoisomerism MeSH
- Solid-Phase Synthesis Techniques methods MeSH
- Thiazines chemical synthesis MeSH
- Publication type
- Journal Article MeSH
- Review MeSH
Human insulin-like growth factor 1 (IGF-1) is a 70 amino acid protein hormone, with key impact on growth, development, and lifespan. The physiological and clinical importance of IGF-1 prompted challenging chemical and biological trials toward the development of its analogs as molecular tools for the IGF-1 receptor (IGF1-R) studies and as new therapeutics. Here, we report a new method for the total chemical synthesis of IGF-1 analogs, which entails the solid-phase synthesis of two IGF-1 precursor chains that is followed by the CuI-catalyzed azide-alkyne cycloaddition ligation and by biomimetic formation of a native pattern of disulfides. The connection of the two IGF-1 precursor chains by the triazole-containing moieties, and variation of its neighboring sequences (Arg36 and Arg37), was tolerated in IGF-1R binding and its activation. These new synthetic IGF-1 analogs are unique examples of disulfide bonds' rich proteins with intra main-chain triazole links. The methodology reported here also presents a convenient synthetic platform for the design and production of new analogs of this important human hormone with non-standard protein modifications.
- MeSH
- Arginine chemistry MeSH
- NIH 3T3 Cells drug effects MeSH
- Click Chemistry MeSH
- Cycloaddition Reaction MeSH
- Disulfides chemistry MeSH
- Fibroblasts MeSH
- Phosphorylation MeSH
- Insulin-Like Growth Factor I analogs & derivatives chemical synthesis chemistry metabolism pharmacology MeSH
- Humans MeSH
- Copper chemistry MeSH
- Methionine chemistry MeSH
- Mice MeSH
- Drug Evaluation, Preclinical methods MeSH
- Protein Domains MeSH
- Proto-Oncogene Proteins c-akt metabolism MeSH
- Receptor, IGF Type 1 metabolism MeSH
- Solid-Phase Synthesis Techniques MeSH
- Triazoles chemistry MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Mice MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
In this work, we describe synthesis of conjugates of betulinic acid with substituted triazoles prepared via Huisgen 1,3-cycloaddition. All compounds contain free 28-COOH group. Allylic bromination of protected betulinic acid by NBS gave corresponding 30-bromoderivatives, their substitution with sodium azides produced 30-azidoderivatives and these azides were subjected to CuI catalysed Huisgen 1,3-cycloaddition to give the final conjugates. Reactions had moderate to high yields. All new compounds were tested for their in vitro cytotoxic activities on eight cancer and two non-cancer cell lines. The most active compounds were conjugates of 3β-O-acetylbetulinic acid and among them, conjugate with triazole substituted by benzaldehyde 9b was the best with IC50 of 3.3 μM and therapeutic index of 9.1. Five compounds in this study had IC50 below 10 μM and inhibited DNA and RNA synthesis and caused block in G0/G1 cell cycle phase which is highly similar to actinomycin D. It is unusual that here prepared 3β-O-acetates were more active than compounds with the free 3-OH group and this suggests that this set may have common mechanism of action that is different from the mechanism of action of previously known 3β-O-acetoxybetulinic acid derivatives. Benzaldehyde type conjugate 9b is the best candidate for further drug development.
- MeSH
- Benzaldehydes chemistry MeSH
- Cell Cycle drug effects MeSH
- Cycloaddition Reaction MeSH
- Humans MeSH
- Cell Line, Tumor MeSH
- Antineoplastic Agents chemistry pharmacology MeSH
- Triazoles chemistry MeSH
- Triterpenes chemistry MeSH
- Cell Survival drug effects MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
Derivatives of 3-methyl-3,6-dihydro-2H-1,2-oxazine-6-carboxylic acid prepared by regioselective hetero Diels-Alder reaction of arylnitroso compounds with sorbic acid were used for solid-phase synthesis of a library of derivatives that included modification of carboxylic group, dihydroxylation of double bond and cleavage of N-O bond. Derivatives of 2,3,4-trihydroxyhexanoic acid obtained from 3,6-dihydro-2H-1,2-oxazines after double bond dihydroxylation and N-O cleavage were used for simple and stereoselective formation of chiral lactones derived from 3,4-dihydroxydihydrofuran-2(3H)-one. The final compounds obtained as a mixture of stereoisomers were analyzed with use of chiral HPLC and SFC. HPLC analyses were not successful for all derivatives or required lengthy chromatography. On the other hand SFC afforded much shorter analyses and was effective for all studied derivatives. The method of synthesis and analysis is thus suitable for future study of stereoselective synthesis of lactones and other derivatives from single oxazine derivatives and application of high-throughput synthesis on solid-support and combinatorial chemistry.
- MeSH
- Cycloaddition Reaction MeSH
- Mass Spectrometry MeSH
- Lactones chemical synthesis chemistry MeSH
- Magnetic Resonance Spectroscopy MeSH
- Oxazines chemical synthesis chemistry MeSH
- Stereoisomerism MeSH
- Solid-Phase Synthesis Techniques MeSH
- Chromatography, High Pressure Liquid MeSH
- Publication type
- Journal Article MeSH
