The Synergistic Effect of N2 and N7 Modifications on the Inhibitory Efficacy of mRNA Cap Analogues.

In the fight against cancer, researchers have turned their attention to the eukaryotic initiation factor eIF4E, a protein whose increased level is strongly correlated with the development and progression of various types of cancer. Among the numerous strategies devised to tackle eIF4E overexpression, the use of 5' end mRNA cap analogues has emerged as a promising approach. Here, we present new candidates as potent m7GMP analogues for inhibiting translation and interfacing with eIF4E. By employing an appropriate strategy, we synthesized doubly modified mono- and dinucleotide cap analogues, introducing simultaneous substituents at both the N7 and N2 positions of the guanine ring. This approach was identified as an effective and promising combination. Our findings reveal that these dual modifications increase the potency of the dinucleotide analogue, marking a significant advancement in the development of cancer therapeutics targeting the eIF4E pathway.

The effect of urea moiety in amino acid binding by ß-cyclodextrin derivatives: A 1000-fold increase in efficacy comparing to native ß-cyclodextrin.

Water soluble amphiphilic anion receptors based on urea-substituted ß-cyclodextrin were synthesized via a copper(I) mediated azide-alkyne coupling reaction. The synthetic route was designed to minimize the number of operations of cyclodextrins. Stable products were obtained in 90% yield. They were successfully tested as amino acid receptors, showing excellent affinity constants (103-104M-1) in a highly competitive environment (pH 8 phosphate-buffered water solution). Isothermal titration calorimetry indicated that complex formation strongly depends on the hydrophobic nature of the guest and that the urea moiety of the receptor is necessary to efficiently bind amino acids.

Long-chain-linked ß-cyclodextrin dimers: Synthesis and relationship between reactivity and inclusion complex formation.

We synthesized ditopic compounds bearing two ß-cyclodextrin moieties linked by long aryl-alkyl linkers. The process of linker inclusion into ß-cyclodextrin cavity was observed during Sharpless click-chemistry conjugation. The target cyclodextrin dimers exhibit self-complexation via a glucose unit inversion phenomenon that is significantly weaker as compared with earlier reported analogs. It was confirmed that both cavities of such cyclodextrin dimers are available for interaction with larger guest molecules.

Cyclodextrin derivatives conjugated with aromatic moieties as pH-responsive drug carriers for anthracycline.

The modification of cyclodextrins (CDs) with side chains containing aromatic groups was found to lead to an increase of the stability of the complex with the anticancer drug doxorubicin (Dox). The formation constants evaluated by voltammetry were several orders of magnitude larger than that of the unmodified ß-CD ligand. For the CDs with aromatic moieties connected by linkers containing a triazole group, the formation constants of the complexes at pH 5.5 and 7.4 were very different. At lower pH, binding was much weaker as a result of protonation of the triazole moiety in the linker. The drug was then released from the complex. Molecular modeling of the Dox-ß-CD system revealed different possible interactions between Dox and ß-CD. The observed pH dependence of the complex formation constant can be exploited for drug delivery to the targeted cells. The toxicities of the synthesized complexes and each of the complex components were tested by the MTT assay on two cell lines, the human lung carcinoma and human cervical cancer cell lines.

Study of near-symmetric cyclodextrins by compressed sensing 2D NMR.

The compressed sensing NMR (CS-NMR) is an approach to processing of nonuniformly sampled NMR data. Its idea is to introduce minimal l(p) -norm (0 < p ≤ 1) constraint to a penalty function used in a reconstruction algorithm. Here, we demonstrate that 2D CS-NMR spectra allow the full spectral assignment of near-symmetric ß-cyclodextrin derivatives (mono-modified at the C6 position). The application of CS-NMR ensures experimental time saving and the resolution improvement, necessary because of very low chemical shift dispersion. In the overnight experimental time, the set of properly resolved 2D NMR spectra required for the unambiguous assignment of mono(6-deoxy-6-(1-1,2,3-triazo-4-yl)-1-propane-3-O-(phenyl)) ß-cyclodextrin was obtained. The highly resolved HSQC spectrum was reconstructed from 5.12% of the data. Moreover, reconstructed 2D HSQC-TOCSY spectrum yielded information about the correlations within one sugar unit, and 2D HSQC-NOESY technique allowed the sequential assignment of the glucosidic units.

Intermolecular interactions between doxorubicin and ß-cyclodextrin 4-methoxyphenol conjugates.

Newly synthesized derivatives of ß-cyclodextrin, mono(6-deoxy-6-(1-1,2,3-triazo-4-yl)-1-propane-3-O-(4-methoxyphenyl))ß-cyclodextrin (1) and mono(6-deoxy-6thio(1-propane-3-O-(4-methoxyphenyl))) ß-cyclodextrin (2) were designed to be receptors of the anticancer drug doxorubicin, which could potentially decrease the adverse effects of the drug during treatment. In both aqueous and aqueous dimethyl sulfoxide (DMSO) solutions, doxorubicin forms an inclusion complex with the new cyclodextrin derivatives with formation constants of K(s) = 2.3 × 10(4) and K(s) = 3.2 × 10(5) M(-1) for cyclodextrins 1 and 2, respectively. The stabilities of the complexes are 2-3 orders of magnitude greater than those with native ß-cyclodextrin, and the flexibility of the linker of the side group of the cyclodextrins contributes to this stability. In a hydrogen-bond-accepting solvent, such as pure DMSO, an association that includes hydrogen bonding and chloride ions is favored over the binding of doxorubicin in the cavity of the cyclodextrin derivative. This contrasts with an aqueous medium in which a strong inclusion complex is formed. Cyclic voltammetry, UV-vis, (1)H NMR, and molecular modeling studies of solutions in DMSO and of solutions in water/DMSO demonstrated that the two different modes of intermolecular interaction between doxorubicin and the cyclodextrin derivative depended on the solvent system being utilized.

Probing secondary carbohydrate-protein interactions with highly dense cyclodextrin-centered heteroglycoclusters: the heterocluster effect.

Comparison of the lectin-binding properties for highly dense beta-cyclodextrin-centered homo- and heteroglycoclusters with defined architecture provides evidence for the existence of strong synergic effects (heterocluster effect) on carbohydrate-protein recognition events.

Beta-cyclodextrin-based ferrocene-imprinted gold electrodes.

A new stepwise self-assembly procedure is described for the preparation of functional cyclodextrin-modified electrodes. The approach is based on the formation of alkanethiol/lipoylamide-beta-cyclodextrin monolayers with the thiol component responsible for blocking of the electrode surface and lipoylamide-beta-cyclodextrin molecules-for controlled opening of the access of the electroactive probe to the electrode. Functionalization of the electrode is achieved by means of a new cyclodextrin derivative-mono(6-deoxy-6-lipoylamide)-per-2,3,6-O-acetyl-beta-cyclodextrin-prepared in the peracetyl form and deacetylated directly on the electrode surface following the cyclodextrin self-assembly. The progress of deacetylation was monitored by the MALDI MS technique. Deacetylation caused opening of the active sites toward solution probes. The response toward ferrocene was found to be highly improved when ferrocene was added to the solution following self-assembly of cyclodextrin but prior to the thiol self-assembly step (imprinting method). The proposed synthesis and sequential monolayer formation scheme lead to well-organized and stable modified electrode surfaces with improved sensitivity toward solution species compared to other procedures of electrode modification with the cyclodextrin derivatives.