CB[7]- and CB[8]-Based [2]-(Pseudo)rotaxanes with Triphenylphosphonium-Capped Threads: Serendipitous Discovery of a New High-Affinity Binding Motif

Financiado para publicación en acceso aberto: Universidade da Coruña/CISUG[Abstract] The synthesis of new triphenylphosphonium-capped cucurbit[7]uril (CB[7])- and cucurbit[8]uril (CB[8])-based [2]rotaxanes was achieved by a simultaneous threading-capping strategy. While the use of CB[7] produced the designed [2]rotaxane, attempts to obtain the CB[8] analogue were unsuccessful due to the unexpected strong interaction found between the host and the phosphonium caps leading to pseudo-heteroternary host–guest complexes. This unusual binding motif has been extensively studied experimentally, with results in good agreement with those obtained by dispersion-corrected DFT methods.This research was supported by the Agencia Estatal de Investigación (PID2019-105272GB-I00) and Xunta de Galicia (ED431C 2018/39). I.N. thanks the MECD (FPU program). The authors are indebted to Centro de Supercomputación de Galicia (CESGA) for providing the computer facilitiesXunta de Galicia; ED431C 2018/3

Reversible Control of DNA Binding with Cucurbit[8]uril-Induced Supramolecular 4,4′-Bipyridinium–Peptide Dimers

Financiado para publicación en acceso aberto: Universidade da Coruña/CISUGThe Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.bioconjchem.1c00063[Abstract] Many cellular processes in living organisms are regulated by complex regulatory networks, built from noncovalent interactions between relatively few proteins that perform their functions by switching between homo- and heterooligomeric assemblies or mono- and bivalent states. Herein, we demonstrate that the conjugation of a 4,4′-bipyridinium scaffold to the basic region of the GCN₄ bZip transcription factor can be exploited to control the dimerization of the conjugate by formation of a supramolecular complex with cucurbit[8]uril. Importantly, this supramolecular complex is able to specifically recognize its target dsDNA, and this binding can be reversibly switched by the application of external stimuli.We are thankful for the funding received from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (grant agreement No 851179), the Ministerio de Economía y Competitividad and Fondo Europeo de Desarrollo Regional (FEDER) (CTQ2016-75629-P), the Agencia Estatal de Investigación and FEDER (CTQ2017-89166-R and PID2019-105272GB-I00) and the Consellería de Educación, Universidade e Formación Profesional, Xunta de Galicia (ED431C 2018/39). P.N thanks the Ministerio de Ciencia, Innovación y Universidades for her PhD fellowship (FPU17/04357). E.P. thanks the UDC-Inditex InTalent Programme for her research contract and funding and the Xunta de Galicia for the Oportunius ProgrammeXunta de Galicia; ED431C 2018/39https://pubs.acs.org/doi/suppl/10.1021/acs.bioconjchem.1c00063/suppl_file/bc1c00063_si_001.pd

Stimuli-responsive metal-directed self-assembly of a ring-in-ring complex

[Abstract] Concentration, temperature and/or solvent polarity control the speciation on the metal-directed self-assembly of a ditopic pyridyl ligand L with cis-protected Pd(II) metal centers. This results into a controllable dynamic system, involving a [Pd2L2]6+ metallacycle and a [Pd4L4]12+ ring-in-ring complex.Ministerio de Economía y Competitividad; CTQ-201341097-PXunta de Galicia; EM2014/05

Self-Assembled Peptide–Inorganic Nanoparticle Superstructures: From Component Design to Applications

[Abstract] Peptides have become excellent platforms for the design of peptide–nanoparticle hybrid superstructures, owing to their self-assembly and binding/recognition capabilities. Morover, peptide sequences can be encoded and modified to finely tune the structure of the hybrid systems and pursue functionalities that hold promise in an array of high-end applications. This feature article summarizes the different methodologies that have been developed to obtain self-assembled peptide–inorganic nanoparticle hybrid architectures, and discusses how the proper encoding of the peptide sequences can be used for tailoring the architecture and/or functionality of the final systems. We also describe the applications of these hybrid superstructures in different fields, with a brief look at future possibilities towards the development of new functional hybrid materials.We are thankful for the funding received from the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation programme (grant agreement no. 851179), the Ministerio de Economía y Competitividad and Fondo Europeo de Desarrollo Regional (FEDER) (CTQ2016-75629-P), the Agencia Estatal de Investigación and FEDER (CTQ2017-89166-R) and the Consellería de Educación, Universidade e Formación Profesional, Xunta de Galicia (ED431C 2018/39). E. P. thanks the UDC-Inditex InTalent Programme for her research contract and funding and the Xunta de Galicia for the Oportunius ProgrammeXunta de Galicia; ED431C 2018/3

Amino Acid–Viologen Hybrids: Synthesis, Cucurbituril Host–Guest Chemistry, and Implementation on the Production of Peptides

Financiado para publicación en acceso aberto: Universidade da Coruña/CISUG[Abstract] We present herein the development of a series of viologen–amino acid hybrids, obtained in good yields either by successive alkylations of 4,4′-bipyridine, or by Zincke reactions followed by a second alkylation step. The potential of the obtained amino acids has been exemplified, either as typical guests of the curcubituril family of hosts (particularly CB[7]/[8]) or as suitable building blocks for the solution/solid-phase synthesis of two model tripeptides with the viologen core inserted within their sequences.The authors are grateful for the funding received from the Agencia Estatal de Investigación and FEDER (PID2019-105272GB-I00 and CTQ2017-89166-R), the Consellería de Educación, Universidade e Formación Profesional, Xunta de Galicia (ED431C 2018/39 and 508/2020), and the European Research Council (Grant Agreement No. 851179). I.N. thanks the MECD (FPU program) for financial support. E.P. thanks the Agencia Estatal de Investigación for her Ramón y Cajal contract (RYC2019-027199-I). Funding for open access charge: Universidade da Coruña/CISUGXunta de Galicia; ED431C 2018/39Xunta de Galicia; ED431C 508/202

Controlled Binding of Organic Guests by Stimuli-Responsive Macrocycles

[Abstract] Synthetic supramolecular chemistry pursues not only the construction of new matter, but also control over its inherently dynamic behaviour. In this context, classic host–guest chemistry, based on the development of a myriad of macrocyclic receptors with fine-tuned affinities and selectivities, has enormously contributed to the discovery of new chemical function under self-assembly conditions. In turn, the use of molecular switches as control units within host–guest assemblies opened the door for the regulation of their dynamic interactional behaviour, which can be translated into controlled aggregation. In this review, we will focus on different strategies developed for the regulated binding of organic molecules by switchable macrocyclic hosts. As we will see, an appropriate design using stimuli-responsive versions of well-known organic receptors allows the molecular switches implemented within their structures to transform their regulated behaviour from the molecular to the supramolecular level.This research was supported by the Ministerio de Economía y Competitividad (MINECO FEDER, Grant CTQ2016-75629-P), Agencia Estatal de Investigación (AEI) and Fondo Europeo de Desarrollo Regional (FEDER) (CTQ2017-89166-R), and Xunta de Galicia (ED431C 2018/39). E. P. thanks the funding received from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (grant agreement No. 851179), the UDC-Inditex InTalent Programme for her research contract and funding and the Xunta de Galicia for the Oportunius Programme. I. N. thanks the MECD (FPU program) for financial supportXunta de Galicia; ED431C 2018/3

Vermellogens and the Development of CB[8]-Based Supramolecular Switches Using pH-Responsive and Non-Toxic Viologen Analogues

[Abstract] We present herein the “vermellogens”, a new class of pH-responsive viologen analogues, which replace the direct linking between para-substituted pyridinium moieties within those by a hydrazone functional group. A series of such compounds have been efficiently synthesized in aqueous media by hydrazone exchange reactions, displaying a marked pH-responsivity. Furthermore, the parent N,N′-dimethylated “vermellogen”: the “red thread”, an analogue of the herbicide paraquat and used herein as a representative model of the series, showed anion-recognition abilities, non-reversible electrochemical behavior, and non-toxicity of the modified bis-pyridinium core. The host–guest chemistry for the “red thread” with the CB[7,8] macrocyclic receptors has been extensively studied experimentally and by dispersion corrected density functional theory methods, showing a parallel behavior to that previously described for the herbicide but, crucially, swapping the well-known redox reactive capabilities of the viologen-based inclusion complexes by acid–base supramolecular responsiveness.This work is supported by Grants PID2019-105272GB-I00 and CTQ2017-89166-R funded by MCIN/AEI/10.13039/501100011033 and the Consellería de Educación, Universidade e Formación Profesional, Xunta de Galicia (ED431C 2018/39 and 508/2020). A.B.-G., I.N., and R.S. thank, respectively, Xunta de Galicia (ED481B-2021-099), the MECD (FPU program), and Erasmus+ program for financial support. We are very grateful for helpful discussions with Professors Hao Li (Zhejiang University), Patrice Woisel (Université de Lille) and José Luis Barriada (Universidade da Coruña). We also acknowledge the use of RIAIDT-USC analytical facilities, and CESGA (Xunta de Galicia) for computational time.Xunta de Galicia; ED431C 2018/39Xunta de Galicia; ED431C 508/2020Xunta de Galicia; ED481B-2021-09

Subcellular duplex DNA and G‐quadruplex interaction profiling of a hexagonal PtII metallacycle

[Abstract] Metal‐driven self‐assembly afforded a multitude of fascinating supramolecular coordination complexes (SCCs) with applications as catalysts, host–guest, and stimuli‐responsive systems. However, the interest in the biological applications of SCCs is only starting to emerge and thorough characterization of their behavior in biological milieus is still lacking. Herein, we report on the synthesis and detailed in‐cell tracking of a Pt2L2 metallacycle. We show that our hexagonal supramolecule accumulates in cancer cell nuclei, exerting a distinctive blue fluorescence staining of chromatin resistant to UV photobleaching selectively in nucleolar G4‐rich regions. SCC co‐localizes with epitopes of the quadruplex‐specific antibody BG4 and replaces other well‐known G4 stabilizers. Moreover, the photophysical changes accompanying the metallacycle binding to G4s in solution (fluorescence quenching, absorption enhancement) also take place intracellularly, allowing its subcellular interaction tracking.Ministerio de Economía, Industria y Competitividad; CTQ2016-75629-

Age-Dependence of Flow Homeostasis in the Left Ventricle

Background: Intracardiac flow homeostasis requires avoiding blood stasis and platelet activation during its transit through the cardiac chambers. However, the foundations of intraventricular blood washout and its exposure to shear stresses have been poorly addressed. We aimed to characterize and quantify these features in a wide population of healthy subjects and assess the relationships of these indices with age.Methods: We used color-Doppler echocardiography and custom post-processing methods to study 149 healthy volunteers from 26 days to 80 years old. From the intraventricular flow-velocity fields we obtained personalized maps of (1) the residence time of blood in the LV, and (2) the shear index, a metric accounting for the strongest occurrence of shear stresses inside the chamber. From these maps we derived quantitative indices of the overall intraventricular blood washout and shear exposure. We addressed the age-dependence of these indices and analyzed their relationship with age-related changes in filling-flow.Results: The entire intraventricular blood pool was replaced before 8 cycles. Average residence time of blood inside the LV was <3 cycles in all subjects and followed an inverse U-shape relationship with age, increasing from median (IQR) of 1.0 (0.7 to 1.2) cycles in the 1st year of life to 1.8 (1.4–2.2) cycles in young adults (17–30 years old), becoming shorter again thereafter. Shear index showed no relation with age and was bounded around 20 dyn·s/cm2. Regions with the longest residence time and highest shear index were identified near the apex. Differences in the degree of apical penetration of the filling waves and the duration of the late-filling phase explained the age-dependence of residence time (Radj2 = 0.48, p < 0.001).Conclusions: In average, blood spends 1 to 3 beats inside the LV with very low shear stress rates. The apical region is the most prone to blood stasis, particularly in mid-aged adults. The washout of blood in the normal LV is age-dependent due to physiological changes in the degree of apical penetration of the filling waves