Triazolophostins: a library of novel and potent agonists of IP3 receptors.

IP3 receptors are channels that mediate the release of Ca(2+) from the intracellular stores of cells stimulated by hormones or neurotransmitters. Adenophostin A (AdA) is the most potent agonist of IP3 receptors, with the β-anomeric adenine contributing to the increased potency. The potency of AdA and its stability towards the enzymes that degrade IP3 have aroused interest in AdA analogs for biological studies. The complex structure of AdA poses problems that have necessitated optimization of synthetic conditions for each analog. Such lengthy one-at-a-time syntheses limit access to AdA analogs. We have addressed this problem by synthesizing a library of triazole-based AdA analogs, triazolophostins, by employing click chemistry. An advanced intermediate having all the necessary phosphates and a β-azide at the anomeric position was reacted with various alkynes under Cu(i) catalysis to yield triazoles, which upon deprotection gave triazolophostins. All eleven triazolophostins synthesized are more potent than IP3 and some are equipotent with AdA in functional analyses of IP3 receptors. We show that a triazole ring can replace adenine without compromising the potency of AdA and provide facile routes to novel AdA analogs.A. M. V. thanks the University Grants Commission (UGC) India for a Senior Research Fellowship (SRF) during this work. K. M. S. thanks the Department of Science and Technology (DST) India for Swarnajayanti Fellowship, Ramanujan Fellowship and for financial support. C. W. T. and V. K. were supported by the Wellcome Trust, Biotechnology and Biological Sciences Research Council, and the German Academic Exchange Service (V. K.).This is the final published version. It first appeared at http://dx.doi.org/10.1039/C5OB00440

Synthesis of dimeric analogs of adenophostin A that potently evoke Ca2+ release through IP3 receptors.

Inositol 1,4,5-trisphosphate receptors (IP3Rs) are tetrameric intracellular channels through which many extracellular stimuli initiate the Ca2+ signals that regulate diverse cellular responses. There is considerable interest in developing novel ligands of IP3R. Adenophostin A (AdA) is a potent agonist of IP3R and since some dimeric analogs of IP3R ligands are more potent than the corresponding monomer; we considered whether dimeric AdA analogs might provide agonists with increased potency. We previously synthesized traizolophostin, in which a simple triazole replaced the adenine of AdA, and showed it to be equipotent to AdA. Here, we used click chemistry to synthesize four homodimeric analogs of triazolophostin, connected by oligoethylene glycol chains of different lengths. We evaluated the potency of these analogs to release Ca2+ through type 1 IP3R and established that the newly synthesized dimers are equipotent to AdA and triazolophostin.University Grants Commission India (Senior Research Fellowship), Department of Science and Technology India (Swarnajayanti Fellowship, Ramanujan Fellowship), Wellcome TrustThis is the author accepted manuscript. The final version is available from The Royal Society of Chemistry via http://dx.doi.org/10.1039/c6ra19413

Carbasugar Synthesis via Vinylogous Ketal: Total Syntheses of (+)-MK7607, (−)-MK7607, (−)-Gabosine A, (−)-Epoxydine B, (−)-Epoxydine C, <i>epi</i>-(+)-Gabosine E and <i>epi</i>-(+)-MK7607

Carbasugars, the carbocyclic analogues of sugars, constitute an important class of natural products with more than 140 members known and have attracted much attention due to their diverse biological activities like anticancer, antibacterial, herbicidal, and various enzyme inhibitory activities. As many carbohydrates are involved in various cellular signaling pathways, there is great interest in synthesis and biological exploration of carbasugars. Herein, we have developed a methodology to install an α,β-unsaturated aldehyde functionality on different inositols and derivatives by vinylogous elimination of the O-protecting group under mildly acidic condition. We have illustrated the versatility and utility of our methodology by the total syntheses of seven carbasugars viz. (−)-MK7607, (−)-gabosine A, (−)-epoxydine B, (−)-epoxydine C, (+)-MK7607, 1-<i>epi</i>-(+)-MK7607 and 1-<i>epi</i>-(+)-gabosine E

Strength from Weakness: Conformational Divergence between Solid and Solution States of Substituted Cyclitols Facilitated by CH···O Hydrogen Bonding

We have investigated the conformational preferences of a series of cyclitol derivatives, namely mono- and diesters of 1,2:5,6-di-<i>O</i>-isopropylidene-<i>myo</i>-inositol and 1,2:5,6-di-<i>O</i>-cyclohexylidene-<i>myo</i>-inositol, in both solid and solution states. The solid-state conformations were determined by single-crystal X-ray analysis. The solution-state conformations were determined by using NMR. The experimental ³<i>J</i>_HH values were applied in the Haasnoot–Altona equation to calculate the dihedral angle (ϕ) between the respective vicinal protons. By fixing the dihedral angle between different sets of vicinal protons, the molecules were energy-minimized by MM2 method to visualize their conformation in solution. As the solvent polarities can influence the conformational preference, we have determined the conformations of these molecules in various solvents of different polarities such as benzene-<i>d</i>₆, chloroform-<i>d</i>, acetonitrile-<i>d</i>₃, acetone-<i>d</i>₆, methanol-<i>d</i>₄, and DMSO-<i>d</i>₆. All of the compounds adopted boat conformations in solution irrespective of the solvents, acyl groups, or alkylidene protecting groups. This conformation places H6 and O3 of the cyclitol ring in proximity, such that an intramolecular CH···O hydrogen bond between them stabilizes this otherwise unstable conformation. However, in the solid state, several intermolecular CH···O hydrogen bonds force these molecules to adopt the chair conformation. This study uncovers the role of weak noncovalent interactions in influencing the molecular conformations differentially in different states

Topochemical Azide–Alkyne Cycloaddition Reaction in Gels: Size-Tunable Synthesis of Triazole-Linked Polypeptides

Though topochemical reactions are attractive, the difficulty associated with crystallization such as low yield, unsuitability for large-scale synthesis, etc. warranted the exploitation of other self-assembled media for topochemical reactions. We synthesized a dipeptide gelator decorated with azide and alkyne at its termini, N₃-Ala-Val-NHCH₂-CCH, which is designed to self-assemble through intermolecular hydrogen bonds to β-sheets thereby placing the azide and alkyne motifs in proximity. As anticipated, this peptide forms gels in organic solvents and water via hydrogen-bonded β-sheet assembly as evidenced from IR spectroscopy and PXRD profiling. The microscopic fibers present in organogel and hydrogel have different morphology as was evident from scanning electron microscopy (SEM) imaging of their xerogels, XG_h (xerogel made from hydrogel) and XG_o (xerogel made from organogel). Heating of xerogels at 80 °C resulted in the topochemical azide–alkyne cycloaddition (TAAC) polymerization to 1,4-triazole-linked oligopeptides. Under identical conditions, XG_o produced larger oligopeptides, and XG_h produced smaller peptides, as evidenced from MALDI-TOF spectrometry. We have also shown that degree of TAAC polymerization can be controlled by changing gel fiber thickness, which in turn can be controlled by concentration. SEM studies suggested the morphological intactness of the fibers even after the reaction, and their PXRD profiles revealed that both XG_h and XG_o undergo fiber-to-fiber oligomerization without losing their crystallinity. In contrast to crystals, the xerogels undergo TAAC polymerization in two distinct stages as shown by DSC analyses. Interestingly, XG_h and XG_o undergo spontaneous TAAC polymerization at room temperature; the latter shows faster kinetics. This is not only the first demonstration of the use of xerogels for thermally induced topochemical polymerization but also the first report on a spontaneous topochemical reaction in xerogels

A Spontaneous Single-Crystal-to-Single-Crystal Polymorphic Transition Involving Major Packing Changes

4,6-<i>O</i>-Benzylidene-α-d-galactosyl azide crystallizes into two morphologically distinct polymorphs depending on the solvent. While the α form appeared as thick rods and crystallized in <i>P</i>2₁ space group (monoclinic) with a single molecule in the asymmetric unit, the β form appeared as thin fibers and crystallized in <i>P</i>1 space group (triclinic) with six molecules in the asymmetric unit. Both the polymorphs appeared to melt at the same temperature. Differential scanning calorimetry analysis revealed that polymorph α irreversibly undergoes endothermic transition to polymorph β much before its melting point, which accounts for their apparently same melting points. Variable temperature powder X-ray diffraction (PXRD) experiments provided additional proof for the polymorphic transition. Single-crystal XRD analyses revealed that α to β transition occurs in a single-crystal-to-single-crystal (SCSC) fashion not only under thermal activation but also spontaneously at room temperature. The SCSC nature of this transition is surprising in light of the large structural differences between these polymorphs. Polarized light microscopy experiments not only proved the SCSC nature of the transition but also suggested nucleation and growth mechanism for the transition