Toward Optimal Ru(II) Photocages: Balancing Photochemistry, Stability, and Biocompatibility Through Fine Tuning of Steric, Electronic, and Physiochemical Features.
Ontology highlight
ABSTRACT:
SUBMITTER: Havrylyuk D
PROVIDER: S-EPMC8607748 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:Hybrid molecules combining photoactivated aryl acetylenes and a dicationic lysine moiety cause the most efficient double-strand (ds) DNA cleavage known to date for a small molecule. In order to test the connection between the alkylating ability and the DNA-damaging properties of these compounds, we investigated the photoreactivity of three isomeric aryl-tetrafluoropyridinyl (TFP) alkynes with amide substituents in different positions (o-, m-, and p-) toward a model ?-system. Reactions with 1,4-cyclohexadiene (1,4-CHD) were used to probe the alkylating properties of the triplet excited states in these three isomers whilst Stern-Volmer quenching experiments were used to investigate the kinetics of photoinduced electron transfer (PET). The three analogous isomeric lysine conjugates cleaved DNA with different efficiencies (34, 15, and 0% of ds DNA cleavage for p-, m-, and o-substituted lysine conjugates, respectively) consistent with the alkylating ability of the respective acetamides. The significant protecting effect of the hydroxyl radical and singlet oxygen scavengers to DNA cleavage was shown only with m-lysine conjugate. All three isomeric lysine conjugates inhibited human melanoma cell growth under photoactivation: The p-conjugate had the lowest CC(50) (50% cell cytotoxicity) value of 1.49 × 10(-7) M.
| S-EPMC3135214 | biostudies-literature
Project description:The nature of the electronic excited state of many symmetric multibranched donor-acceptor molecules varies from delocalized/multipolar to localized/dipolar depending on the environment. Solvent-driven localization breaks the symmetry and traps the exciton in one branch. Using a combination of ultrafast spectroscopies, we investigate how such excited-state symmetry breaking affects the photochemical reactivity of quadrupolar and octupolar A-(?-D)2,3 molecules with photoisomerizable A-?-D branches. Excited-state symmetry breaking is identified by monitoring several spectroscopic signatures of the multipolar delocalized exciton, including the S2???S1 electronic transition, whose energy reflects interbranch coupling. It occurs in all but nonpolar solvents. In polar media, it is rapidly followed by an alkyne-allene isomerization of the excited branch. In nonpolar solvents, slow and reversible isomerization corresponding to chemically-driven symmetry breaking, is observed. These findings reveal that the photoreactivity of large conjugated molecules can be tuned by controlling the localization of the excitation.
| S-EPMC7174366 | biostudies-literature
Project description:A series of Ru(ii) complexes bearing the tridentate 2,6-di(quinolin-2-yl)pyridine (dqpy) ligand were designed to undergo photoinduced ligand dissociation with red/near-IR light. The complexes [Ru(dqpy)(L)(CH3CN)]2+, where L = 2,2'-bipyridine (bpy, 1), 4,4'dimethyl-2,2'-bipyridine (Me2bpy, 2), and 1,10-phenanthroline (phen, 3). Complexes 1-3 exhibit red-shifted lowest energy metal-to-ligand charge transfer (MLCT) absorption maxima at ?600 nm, as compared to the corresponding tpy (2,2';6',2''-terpyridine) complexes with MLCT bands at ?565 nm which appear as shoulders to the MLCT bands at ?455 nm. This shift is attributed to the lower energy LUMO afforded by the dqpy ligand when compared to tpy, as evidenced by the shift of the first reduction wave to ?0.3 V more positive potentials in the former. In addition, the lowest MLCT maximum of [Ru(dqpy)(acac)(CH3CN)]+ (4; acac- = acetylacetonate) is observed at 770 nm, attributed to the additional increase in energy of the HOMO afforded by the presence of the ?-donating acac- ligand and supported by calculations. Complexes 1-3 undergo ligand substitution upon irradiation with red light, ? irr ? 610 nm, and the ligand substitution photochemistry of 4 is accessible with near-IR light, ? irr ? 715 nm and ? irr = 735 nm. Complexes 1-4 exhibit similar quantum yields of ligand exchange, ? L, with 450 and 600 nm irradiation, however, that of 4 is 2-3 times greater than those measured for 1-3. This enhancement is explained by the difference in ligand contributions to the HOMO. Density functional theory calculations predict partial dqpy ??* character in the MLCT states of 1-3 and a mixed Ru/acac- ? dqpy metal/ligand-to-ligand charge transfer (ML-LCT) state in 4. The photoreactivity of 1-4 with tissue-penetrating red and near-IR light, together with their exceptional dark stability (>48 h), makes the new Ru(ii)-dqpy platform ideal for the development of new complexes for photoinduced drug release and for other applications that require broad absorption from the ultraviolet and visible ranges into the near-IR, such as solar energy conversion.
| S-EPMC6115629 | biostudies-literature
Project description:The nanoscale interpenetrating network of active layer plays a key role in determining the exciton dissociation and charge transport in all small-molecule nonfullerene solar cells (AS-NFSCs). However, fabricating interpenetrating networks in all small-molecule blends remains a critical hurdle due to the uncontrolled crystallization behavior of small molecules. In this study, we proposed that the balanced crystal size between the donor and the acceptor is an essential prerequisite to construct optimal interpenetrating networks. We also provided a solvent additive strategy to reduce the gap of crystal size between the donor and the acceptor in S-TR:ITIC all small-molecule blend system through manipulating the solution state and film-forming kinetics. As a result, the crystal size of S-TR decreased and the crystal size of ITIC increased, leading to nanoscale interpenetrating networks. This optimized morphology improved the exciton dissociation efficiency and suppressed the bimolecular recombination, achieving almost double power conversion efficiency compared to the reference device. This work demonstrates that manipulation of the balanced crystal size of donor and acceptor may be a key to further boost the efficiency of AS-NFSCs.
| S-EPMC6644795 | biostudies-literature
Project description:Cell proliferation and differentiation is a complex process involving many cellular mechanisms. One of the best-studied phenomena in cell differentiation is erythrocyte development during hematopoiesis in vertebrates. In recent years, a new class of small, endogenous, non-coding RNAs called microRNAs (miRNAs) emerged as important regulators of gene expression at the post-transcriptional level. Thousands of miRNAs have been identified in various organisms, including protozoa, fungi, bacteria and viruses, proving that the regulatory miRNA pathway is conserved in evolution. There are many examples of miRNA-mediated regulation of gene expression in the processes of cell proliferation, differentiation and apoptosis, and in cancer genesis. Many of the collected data clearly show the dependence of the proteome of a cell on the qualitative and quantitative composition of endogenous miRNAs. Numerous specific miRNAs are present in the hematopoietic erythroid line. This review attempts to summarize the state of knowledge on the role of miRNAs in the regulation of different stages of erythropoiesis. Original experimental data and results obtained with bioinformatics tools were combined to elucidate the currently known regulatory network of miRNAs that guide the process of differentiation of red blood cells.
| S-EPMC6276011 | biostudies-literature
Project description:Redirecting CD8 T cell immunity with self/tumor-specific affinity-matured T cell receptors (TCRs) is a promising approach for clinical adoptive T cell therapy, with the aim to improve treatment efficacy. Despite numerous functional-based studies, little is known about the characteristics of TCR signaling (i.e., intensity, duration, and amplification) and the regulatory mechanisms underlying optimal therapeutic T cell responses. Using a panel of human SUP-T1 and primary CD8 T cells engineered with incremental affinity TCRs against the cancer-testis antigen NY-ESO-1, we found that upon activation, T cells with optimal-affinity TCRs generated intense and sustained proximal (CD3?, LCK) signals associated with distal (ERK1/2) amplification-gain and increased function. In contrast, in T cells with very high affinity TCRs, signal initiation was rapid and strong yet only transient, resulting in poor MAPK activation and low proliferation potential even at high antigen stimulation dose. Under resting conditions, the levels of surface TCR/CD3?, CD8?, and CD28 expression and of CD3? phosphorylation were significantly reduced in those hyporesponsive cells, suggesting the presence of TCR affinity-related activation thresholds. We also show that SHP phosphatases were involved along the TCR affinity gradient, but displayed spatially distinct regulatory roles. While PTPN6/SHP-1 phosphatase activity controlled TCR signaling initiation and subsequent amplification by counteracting CD3? and ERK1/2 phosphorylation, PTPN11/SHP-2 augmented MAPK activation without affecting proximal TCR signaling. Together, our findings indicate that optimal TCR signaling can be finely tuned by TCR affinity-dependent SHP-1 and SHP-2 activity, and this may readily be determined at the TCR/CD3 complex level. We propose that these TCR affinity-associated regulations represent potential protective mechanisms preventing high affinity TCR-mediated autoimmune diseases.
| S-EPMC5694758 | biostudies-literature
Project description:To create a dataset of PSMs that does not exhibit tryptic bias, we selected PSMs with a uniform distribution of amino acids at the C-terminal peptide positions from two datasets: MassIVE-KB [Wang2018] and PROSPECT [Shouman2022]. The MassIVE-KB dataset contains 30 million PSMs and consists entirely of data generated using trypsin; hence, only a small proportion of the MassIVE-KB peptides do not end in K or R, corresponding to those that appear at the C-terminus of the corresponding protein. The PROSPECT dataset is a collection of 61 million PSMs generated from synthetic peptides. To avoid overrepresentation of some peptides in this dataset, we randomly selected at most 100 PSMs per unique peptide, similar to the processing that was done during the creation of the MassIVE-KB dataset. This pre-selection step reduced the size of the PROSPECT dataset to 12.6 million PSMs. Finally, to create a non-enzymatic dataset containing 1 million peptides, we selected 50,000 PSMs for each canonical amino acid. These PSMs were selected at random from MassIVE-KB, then supplemented as necessary from PROSPECT to obtain the desired count (see Yilmaz et al. [Yilmaz2023] Supplementary Table S1). This dataset contained PSMs from 247,859 unique peptides, which were randomly split into training, validation and test sets in the ratio 80/10/10. FTP directory contains the mgf files corresponding to train, validation and test splits.
[Wang2018] M. Wang, J. Wang, J. Carver, B. Pullman, S. Won Cha, N. Bandeira, "Assembling the Community-Scale Discoverable Human Proteome", Cell Systems, Volume 7, Issue 4, 2018.
[Shouman2022] O. Shouman, W. Gabriel, V. Giurcoiu, V. Sternlicht, M. Wilhelm, "PROSPECT: Labeled Tandem Mass Spectrometry Dataset for Machine Learning in Proteomics", NeurIPS Datasets and Benchmarks, 2022
[Yilmaz2023] M. Yilmaz*, W. Fondrie*, W. Bittremieux, R. Nelson, V. Ananth, S. Oh, and W. Noble,"Sequence-to-sequence translation from mass spectra to peptides with a transformer model", bioRxiv, 2023
2024-02-05 | MSV000094014 | MassIVE
Project description:?-Diketiminates are widely used supporting ligands for building a range of metal complexes with different oxidation states, structures, and reactivities. This Perspective summarizes the steric and electronic influences of ligand substituents on these complexes, with an eye toward informing the design of new complexes with optimized properties. The backbone and N-aryl substituents can give significant steric effects on structure, reactivity and selectivity of reactions. The electron density on the metal can be tuned by installation of electron withdrawing or donating groups on the ?-diketiminate ligand as well. Examples are shown from throughout the transition metal series to demonstrate different types of effects attributable to systematic variation of ?-diketiminate ligands.
| S-EPMC4581995 | biostudies-literature
Project description:Fine-tuning quantitative traits for continuous subtle phenotypes is highly advantageous. We engineer the highly conserved upstream open reading frame (uORF) of FvebZIPs1.1 in strawberry (Fragaria vesca), using base editor A3A-PBE. Seven novel alleles are generated. Sugar content of the homozygous T1 mutant lines is 33.9-83.6% higher than that of the wild-type. We also recover a series of transgene-free mutants with 35 novel genotypes containing a continuum of sugar content. All the novel genotypes could be immediately fixed in subsequent generations by asexual reproduction. Genome editing coupled with asexual reproduction offers tremendous opportunities for quantitative trait improvement.
| S-EPMC7470447 | biostudies-literature
Project description:Reverse turns are solvent-exposed motifs in proteins that are crucial in nucleating ?-sheets and drive the protein folding. The solvent-exposed nature makes reverse turns more amenable to chemical modifications than ?-helices or ?-sheets towards modulating the stability of re-engineered proteins. Here, we utilize van der Waals repulsive forces in tuning the steric restraint at the reverse turn. The steric restraint induced upon N-methylation of the i+1-i+2 amide bond at the reverse turn results in well-folded and stable ?-sheets in aqueous solution at room temperature. The developed superactive turn inducing motif is tolerant to a wide variety of functional groups present on coded amino acids making the designed turn fully compatible with bioactive loops in proteins. We demonstrate that the steric restraint and the functional groups at the reverse turn act in synergy to modulate the folding of re-engineered ?-sheets. Introduction of the turn motifs onto a three-stranded ?-sheet protein, Pin 1 WW domain, resulted in various analogs showing a cooperative two-state transition with thermal stability (TM) ranging from 62 °C to 82 °C. Despite modulating the stability of Pin 1 variants by ?2.8 kcal mol-1 (??Gf), the native fold in all the protein variants was found to be unperturbed. This structural stability is brought about by conformational preorganization at the engineered reverse turn that results in strong intramolecular hydrogen bonds along the three dimensional structure of the protein. Thus, this simple loop engineering strategy via two amino acid substitution provides us a "toolkit" to modulate the stability of ?-sheet containing peptides and proteins in aqueous solution that will greatly expand the scope of de novo protein and foldamer design.
| S-EPMC5969505 | biostudies-literature