Nanoparticle-Based Molecular Imaging in Living Subjects
Martin G. Pomper, Juri G. Gelovani, Benjamin Tsui, Kathleen Gabrielson, Richard Wahl, S. Sam Gambhir, Jeff Bulte, Raymond Gibson, William C. Eckelman in Molecular Imaging in Oncology, 2008
In the first instance, multimodality imaging is achieved by linking both magnetic resonance imaging (MRI) and optically active molecules to dendrimers (39). G-6 PAMAM dendrimers (5.5 nm in hydrodynamic radius) were selected as carrier nanoparticles. Thiourea linkages were formed to covalently bind DTPA chelators to reactive functional groups on the dendrimer surface in non-saturating quantities. Remaining surface amines were then bound via amide bonds to Cy5.5 dye. Understanding of steric hindrance and (non)saturating conditions are critical parameters to such chemistries. This is because reactions can unintentionally either saturate or be far from saturation sans careful calculations and consideration of the size, shape, and hydrophobicity of the molecules involved, as well as solvents and other factors. Alternatively, titrations can be performed to obtain desired saturations. It is particularly important for saturation conditions to be carefully considered in this manner when surface functional groups are all identical. Conversely, if different surface functional groups are presented, chemistries can be designed to be specific to each type of functional group. For the G-6 PAMAM magnetooptical dendrimer, after Cy5.5 is appended, the chemistry is completed by adding an MR-active metal complex based on gadolinium (Gd(III)) to the dendrimer solution for direct chelation to DTPA.
Silicones in Cosmetics
E. Desmond Goddard, James V. Gruber in Principles of Polymer Science and Technology in Cosmetics and Personal Care, 1999
Alkoxysilanes are prepared by addition reactions of alcohols with organochlorosilanes, by reaction of organometallic reagents with lower alkoxysilanes, or by hydrosilylation using Grignard compounds as catalysts. Organic substitution of chlorosilanes becomes increasingly difficult with increasing size of the organic groups because of steric hindrance effects. The effect of steric hindrance becomes even more difficult with increasing organic substitution, i.e., diorgano, triorgano, and so forth. These reactions are frequently carried out at high temperatures for long periods with a large excess of the Grignard compound, and often with cobalt chloride as a cocatalyst (36-39). Like organic esters, the Si—O—R bond is subject to hydrolytic cleavage; however, its sensitivity to hydrolysis is considerably lower than that of the Si—X bond. The susceptibility to hydrolysis decreases with increasing number of carbon atoms in the substituent chain, and aryloxy groups are less easily split off than lower alkoxy groups, with phenylaryloxysilanes being most resistant because of the size and electronegativity of the phenyl groups .
Molecular Recognition and Chemical Modification of Biopolymers — Two Main Components of Affinity Modification
Dmitri G. Knorre, Valentin V. Vlassov in Affinity Modification of Biopolymers, 1989
Indeed, the effect of a complex formation on the reactivity of functional groups in a biopolymer is not always only by direct steric hindrance. In some cases, a complex formation can induce conformational changes of biopolymers followed by a decrease or enhancement of reactivity of some residues located outside the interaction area. The former case is hardly distinguishable from the steric hindrance effect, while the latter case is especially informative suggesting appreciable changes in the biopolymer structure. Thus, at pH 7 in the absence of nucleotides, only one of the two essential sulfhydryl (SH) groups of myosin reacts with N-ethylmaleimide while another group is practically inaccessible to the reagent. The addition of MgADP to the protein drastically increases the reactivity of the second SH group most likely due to a conformational change of myosin.56
Targeting the tumor microenvironment in cholangiocarcinoma: implications for therapy
Published in Expert Opinion on Therapeutic Targets, 2021
Corentin Louis, Julien Edeline, Cédric Coulouarn
Changes in the composition and the structure of ECM within TME can also negatively impact the response to therapies [45]. Indeed, both the density and the stiffness of the stroma can create an impenetrable barrier, concealing tumor cells from therapeutic agents. Steric hindrance also leads to an impaired supply in nutrients, oxygen, and metabolites resulting in an increased hypoxia and metabolic stress, which could lead to the activation of anti-apoptotic and drug resistance pathways. In addition, modification of the ECM components have been reported to be involved in the response of tumor cells to radiotherapy [46]. Accordingly, addressing the TME in early drug discovery has been recommended as a strategy to overcome drug resistance and identify novel targets for cancer therapy [45].
Inhibition of α-, β- and γ-carbonic anhydrases from the pathogenic bacterium Vibrio cholerae with aromatic sulphonamides and clinically licenced drugs – a joint docking/molecular dynamics study
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2021
Alessandro Bonardi, Alessio Nocentini, Sameh Mohamed Osman, Fatmah Ali Alasmary, Tahani Mazyad Almutairi, Dalal Saied Abdullah, Paola Gratteri, Claudiu T. Supuran
Similarly to 15, compound 18 forms a water bridged H-bond with G102 C=O by the p-carboxy function (Figure 3(D)); however, the presence of the charged group COO- nearby the lipophilic area of the active site might be the cause of the weakening of the binding interaction up to a KI value of 515 nM. In the case of 16 (KI = 304 nM), and 17 (KI = 3530 nM), the chain elongation is effective only for n = 1 (16), while in the alkylamine analogues 3 and 4 (with KI > 10000 nM) the presence of some ligand strains, allowed by the docking algorithm, together with the proximity of the charged amine group to the lipophilic part of VchCAβ active site, is responsible for the decreasing in the inhibition profile. Steric hindrance effects prevent the complementarity of the compounds 10 and 11 with the target although the second sulphonamide group in 11 directly binds with the hydroxyl side chain group of Y83 through an H-bond interaction. Modelling the flexible positioning of 13 and 14 (KI = 82.3 nM) within pointed out the detrimental effect of the N4-methylation of the thiadiazole ring, as it disables the water-bridged H-bond stabilisation observed with 13 (Figure S7A). Further, N-acetylation of 13 and 14 to give derivatives AAZ (Figure S7B) and MZA (Figure S7C) produces steric strains within the VchCAβ active site that cause a drop of inhibitory efficacy. Similarly, it was observed for EZA (Figure S7D).
Enhanced detection of ATTR amyloid using a nanofibril-based assay
Published in Amyloid, 2021
M. Mahafuzur Rahman, Benjamin Schmuck, Henrik Hansson, Torleif Härd, Gunilla T. Westermark, Mats Sandgren
Steric hindrance prevents the antibody from simultaneous binding to all epitopes on a polyvalent antigen, where binding epitopes are closely spaced on the surface [31]. Thus, the addition of excess antibody in an immunolabeling experiment does not improve the reactivity. For immunolabeling experiments, lower antibody concentration is often preferred. However, lower antibody concentration may generate very weak signals, especially when targeting small antigen deposits (aggregates). Therefore, linking an additional antibody to the antigen, by any means, could offer a valuable tool in immunolabeling experiments. With the use of Ab-bNF, we succeeded in introducing 10-times more primary antibody to amyloid deposits on tissue sections, which resulted in very strong signals, indicating that our concept nicely tackles the steric hindrance issue. Moreover, our enhanced method demonstrated the potential to amplify fluorescence signals from minute amyloid deposits in tissue.
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