RESUMO
The precise control of mechanochemical activation within deep tissues via non-invasive ultrasound holds profound implications for advancing our understanding of fundamental biomedical sciences and revolutionizing disease treatments. However, a theory-guided mechanoresponsive materials system with well-defined ultrasound activation has yet to be explored. Here we present the concept of using porous hydrogen-bonded organic frameworks (HOFs) as toolkits for focused ultrasound programmably triggered drug activation to control specific cellular events in the deep brain, through on-demand scission of the supramolecular interactions. A theoretical model is developed to visualize the mechanochemical scission and ultrasound mechanics, providing valuable guidelines for the rational design of mechanoresponsive materials at the molecular level to achieve programmable and spatiotemporal activation control. To demonstrate the practicality of this approach, we encapsulate designer drug clozapine N-oxide (CNO) into the optimal HOF nanoparticles for FUS gated release to activate engineered G-protein-coupled receptors in the mice and rat ventral tegmental area (VTA), and hence achieved targeted neural circuits modulation even at depth 9 mm with a latency of seconds. This work demonstrates the capability of ultrasound to precisely control molecular interaction and develops ultrasound programmable HOFs to minimally invasive and spatiotemporally control cellular events, thereby facilitating the establishment of precise molecular therapeutic possibilities. We anticipate that this research could serve as a source of inspiration for precise and non-invasive molecular manipulation techniques, potentially applicable in programming molecular robots to achieve sophisticated control over cellular events in deep tissues.
RESUMO
A set of bioinspired carbamoyl CNP pincer complexes are reported that are relevant to [Fe]-hydrogenase (Hmd). The dicarbonyl species [(CNHNNHPR2)Fe(CO)2I] [R = Ph, 1; R = iPr, 2] undergoes ligand deprotonation, resulting in the dearomatized complexes of formulas [(CNHNN=PR2)Fe(CO)2] (5 and 6). The crystal structure and 1H{31P} NMR spectroscopy of the iodide-bound dearomatized species [Na(18-crown-6)][(CNHNN=PPh2)Fe(CO)2I] (7) showed that the deprotonated moiety was the phosphoramine N(H) linkage. Separately, the monocarbonyl complexes [(CNHNNHPR2)Fe(CO)(MeCN)2](BF4) (8 and 9) synthesized, as well as deprotonated and dearomatized in similar fashion. Reactivity studies revealed that the parent dicarbonyl complexes require more forceful conditions for H2 activation, compared with the monocarbonyl complexes. The ligand backbone was not found to participate in H2 activation and H2 â hydride transfer to an organic substrate was not observed in either case. Density functional theory calculations revealed that the higher reactivity of the monocarbonyl complex in H2 splitting could be attributed to its higher affinity for H2. This behavior is attributed to two key points related to the requisite dπ(Fe) â σ*(H2) back-bonding interaction in a conventional M-H2 Kubas interaction: (i) generally, the weaker π donor capacity of the dicarbonyls, and (ii) specifically, the detrimental effect of a strongly π acidic CO ligand (versus weakly π acidic MeCN ligand) trans to the H2 activation site. The higher reactivity of the monocarbonyl complex is also evidenced by the catalytic transfer hydrogenation by monocarbonyl 8, whereas dicarbonyl 1 was ineffective. Overall, the results suggest that Nature uses the dicarbonyl motif in [Fe]-hydrogenase to diminish the interaction between the Fe center and dihydrogen, thereby preventing premature H2 activation prior to substrate (H4MPT+) binding and any resulting nonspecific hydride transfer reactivity.
RESUMO
PCM-101 is a phosphine coordination material comprised of tris(p-carboxylato)triphenylphosphine and secondary pillaring groups coordinated to [M3 (OH)]5+ nodes (M=Co, Ni). PCM-101 has a unique topology in which R3 P: sites are arranged directly trans to one another, with a Pâ â â P separation distance dictated by the pillars. Post-synthetic coordination of soft metals to the P: sites proceeds at room temperature to provide X-ray quality crystals that permit full structural resolution. Addition of AuCl groups forces a large distortion of the parent framework. In contrast, CuBr undergoes insertion directly between the trans-P sites to form dimers that mimic solution-phase complexes, but that are geometrically strained due to steric pressure exerted by the MOF scaffold. The metalated materials are active in heterogeneous hydroaddition catalysis under mild conditions, yielding different major products compared to their molecular counterparts.
RESUMO
Determination of structure and folding of certain classes of proteins remains intractable by conventional structural characterization strategies and has spurred the development of alternative methodologies. Mass spectrometry-based approaches have a unique capacity to differentiate protein heterogeneity due to the ability to discriminate populations, whether minor or major, featuring modifications or complexation with non-covalent ligands on the basis of m/z. Cleavage of the peptide backbone can be further utilized to obtain residue-specific structural information. Here, hydrogen elimination monitoring (HEM) upon ultraviolet photodissociation (UVPD) of proteins transferred to the gas phase via nativespray ionization is introduced as an innovative approach to deduce backbone hydrogen bonding patterns. Using well-characterized peptides and a series of proteins, prediction of the engagement of the amide carbonyl oxygen of the protein backbone in hydrogen bonding using UVPD-HEM is demonstrated to show significant agreement with the hydrogen-bonding motifs derived from molecular dynamics simulations and X-ray crystal structures.
