Maximal superintegrability on N-dimensional curved spaces

A unified algebraic construction of the classical Smorodinsky-Winternitz systems on the ND sphere, Euclidean and hyperbolic spaces through the Lie groups SO(N+1), ISO(N), and SO(N,1) is presented. Firstly, general expressions for the Hamiltonian and its integrals of motion are given in a linear ambient space $R^{N+1}$, and secondly they are expressed in terms of two geodesic coordinate systems on the ND spaces themselves, with an explicit dependence on the curvature as a parameter. On the sphere, the potential is interpreted as a superposition of N+1 oscillators. Furthermore each Lie algebra generator provides an integral of motion and a set of 2N-1 functionally independent ones are explicitly given. In this way the maximal superintegrability of the ND Euclidean Smorodinsky-Winternitz system is shown for any value of the curvature.Comment: 8 pages, LaTe

Small Molecules as Dream Modulators: New Avenues for the Search of Drugs for Neurodegenerative Diseases

Trabajo presentado en el 9th drug Design and Medicinal Chemistry, celebrado en Berlín (Alemania) del 05 al 06 de mayo de 2015.Altered neuronal calcium homeostasis and early compensatory changes in transcriptional programs are common features of many neurodegenerative pathologies including Alzheimer¿s disease, Down syndrome and Huntington¿s disease. DREAM (Downstream Regulatory Element Antagonist Modulator), also known as calsenilin or KChIP-3 (potassium channel interacting protein-3), is a multifunctional calcium binding protein that controls the expression level and/or the activity of several proteins related to calcium homeostasis, neuronal excitability and neuronal survival. This protein is widely expressed in the brain and, depending on the cell type and physiological conditions, shows multiple subcellular localizations, in the nucleus, cytosol or cell membrane. The interest in DREAM is based on its key role in the regulation of intracellular calcium levels. As a calcium-dependent transcriptional repressor, DREAM is a master regulator of activity-dependent gene expression and controls genes important for calcium homeostasis such as the sodium/calcium exchanger-3 (NCX3), IP3R and L-type calcium channels. As an auxiliary protein in the plasma membrane, DREAM interacts with and regulates the gating of Kv4 potassium channels, L- and T-type voltage-dependent calcium channels and NMDA receptors. These findings suggest that DREAM could be a novel and versatile target for therapeutic intervention in neurodegeneration and that molecules able to bind to DREAM and block its physiological functions could be candidates for drugs to treat neurodegenerative diseases. Moreover, up to now, only two DREAM-binding molecules have been identified. In this communication we report the rational design and the synthesis of novel DREAM-binding molecules and their effects on the modulation of DREAM/protein interactions

Highly functionalized 2-oxopiperazine-based peptidomimetics: An approach to PAR1 antagonists

A series of pseudodipeptide-based chiral 1,3,4,5-tetrasubstituted-2- oxopiperazines has been designed and synthesized as potential PAR1 antagonists. These highly functionalized piperazines were synthesized from aromatic and basic amino acid derived Ψ[CH(CN)NH]pseudodipeptides through a four step pathway that involves reduction of the cyano group to build the 2-oxopiperazine ring, followed by selective functionalization at the N4-, N 1-positions, and at the exocyclic moiety at position C5. This regioselective functionalization required the fine tuning of reaction conditions. All new compounds were screened as inhibitors of human platelet aggregation induced by the PAR1 agonist SFLLRN and as cytotoxic agents in human cancer cell lines. Some of the compounds displayed moderate PAR1 antagonist activity, while, others were cytotoxic at μM concentration. No correlation was observed between both types of activities.Peer Reviewe

Conformationally restricted PACAP27 analogues incorporating type II/II′ IBTM β-Turn mimetics. Synthesis, NMR structure determination, and binding affinity

To probe the importance of a proposed β-turn within residues S9-R12 of PACAP for recognition by VIP/PACAP receptors, compounds 1 and 2, two conformationally restricted analogues of PACAP27 incorporating respectively (S)- or (R)-IBTM as type II or II′ β-turn dipeptide mimetic at the Y10-S11 position, were synthesized. According to 1H NMR conformational analyses in aqueous solution and 30% TFE, both PACAP27 and the [S-IBTM10,11]PACAP27 analogue 1 adopt similar ordered structures. PACAP27 shows an N-terminal disordered region (residues H1-F6) and an α-helical conformation within segment T7–L27. For residues S9–R12, our data seem more compatible with a segment of the α-helix than with the β-turn previously proposed for this fragment. In compound 1 the α-helix, also spanning T7–L27 residues, appears slightly distorted at the N-terminus relative to the native peptide. Although this distortion could lead to the marked decrease in binding affinity of this compound at the VIP/PACAP receptors, the lack of the Y10 side chain in analogues 1 and 2 could also significantly affect the binding of these compounds.Work at the Instituto de Quı́mica Médica and Universidad de Navarra was supported by CICYT (SAF 97 0030 and SAF 2000-0147), Fundación La Caixa (97/022) and Comunidad Autónoma de Madrid (08.5/0006/1998). Work at the Instituto de Estructura de la Materia was supported by DGICYT (PB98-0677) and the European Union (CEE B104-97-2086). Work at the Universidad de Barcelona was supported by Generalitat de Catalunya (CERBA). C.M.S. and M.M.-M. are recipients of a pre-doctoral and a post-doctoral fellowship, respectively, from the Comunidad Autónoma de Madrid, Spain. E.de O. is a post-doctoral fellow of Fundació Bosch i Gimpera, Universitat de Barcelona, Spain

Single-molecule conductance of a chemically modified, {\pi}-extended tetrathiafulvalene and its charge-transfer complex with F4TCNQ

We describe the synthesis and single molecule electrical transport properties of a molecular wire containing a ${\pi}$-extended tetrathiafulvalene (exTTF) group and its charge-transfer complex with F4TCNQ. We form single molecule junctions using the in-situ break junction technique using a home-built scanning tunneling microscope with a range of conductance between 10 G$_{0}$ down to 10$^{-7}$ G$_{0}$. Within this range we do not observe a clear conductance signature of the neutral parent molecule, suggesting either that its conductance is too low or that it does not form stable junctions. Conversely, we do find a clear conductance signature in the experiments carried out on the charge-transfer complex. Due to the fact we expected this species to have a higher conductance than the neutral molecule, we believe this supports the idea that the conductance of the neutral molecule is very low, below our measurement sensitivity. This is further supported by our theoretical calculations. To the best of our knowledge, these are the first reported single molecule conductance measurements on a molecular charge-transfer species

Synthesis, conformational analysis, and cytotoxicity of conformationally constrained aplidine and tamandarin A analogues incorporating a spirolactam β-turn mimetic

With the aim of studying the contribution of the β II turn conformation at the side chain of didemnins to the bioactive conformation responsible for their antitumoral activity, conformationally restricted analogues of aplidine and tamandarin A, where the side chain dipeptide Pro8-N-Me-d-Leu7 is replaced with the spirolactam β II turn mimetic (5R)-7-[(1R)-1-carbonyl-3-methylbutyl]-6-oxo-1,7-diazaspiro[4.4]nonane, were prepared. Additionally, restricted analogues, where the aplidine (pyruvyl9) or tamandarin A [(S)-Lac9] acyl groups are replaced with the isobutyryl, Boc, and 2-methylacryloyl groups, were also prepared. These structural modifications were detrimental to cytotoxic activity, leading to a decrease of 1−2 orders of magnitude with respect to that exhibited by aplidine and tamandarin A. The conformational analysis of one of these spirolactam aplidine analogues, by NMR and molecular modeling methods, showed that the conformational restriction caused by the spirolactam does not produce significant changes in the overall conformation of aplidine, apart from preferentially stabilizing the trans rotamer at the pyruvyl9−spirolactam amide bond, whereas in aplidine both cis and trans rotamers at the pyruvyl9−Pro8 amide bond are more or less equally stabilized. These results seem to indicate a preference for the cis form at that amide bond in the bioactive conformation of aplidine. The significant influence of this cis/trans isomerism upon the cytotoxicity suggests a possible participation of a peptidylprolyl cis/trans isomerase in the mechanism of action of aplidine.This work was supported by CICYT (Grant SAF2000-0147), MCYT-FEDER (Grant BIO2002-2301), Generalitat de Catalunya (Group Consolidat 1999SGR0042 and Centre de Referència en Biotecnologia), and Pharma Mar, S.A

Tumor xenograft modeling identifies an association between TCF4 loss and breast cancer chemoresistance

Understanding the mechanisms of cancer therapeutic resistance is fundamental to improving cancer care. There is clear benefit from chemotherapy in different breast cancer settings; however, knowledge of the mutations and genes that mediate resistance is incomplete. In this study, by modeling chemoresistance in patientderived xenografts (PDXs), we show that adaptation to therapy is genetically complex and identify that loss of transcription factor 4 (TCF4; also known as ITF2) is associated with this process. A triple-negative BRCA1-mutaied PDX was used to study the genetics of chemoresistance. The PDX was treated in parallel with four chemotherapies for five iterative cycles. Exome sequencing identified few genes with de novo or enriched mutations in common among the different therapies, whereas many common depleted mutations/ genes were observed. Analysis of somatic mutations from The Cancer Genome Atlas (TCGA) supported the prognostic relevance of the identified genes. A mutation in TCF4 was found de novo in all treatments, and analysis of drug sensitivity profiles across cancer cell lines supported the link to chemoresistance. Loss of TCF4 conferred chemoresistance in breast cancer cell models, possibly by altering cell cycle regulation. Targeted sequencing in chemoresistant tumors identified an intronic variant of TCF4 that may represent an expression quantitative trait locus associated with relapse outcome in TCGA. Immunohistochemical studies suggest a common loss of nuclear TCF4 expression post-chemotherapy. Together, these results from tumor xenograft modeling depict a link between altered TCF4 expression and breast cancer chemoresistance