C-Alkyl inositol phosphates for use in receptor-ligand engineering

The phosphatidylinositol phosphates (PIPns) and inositol phosphates (IPns) are intricately involved in cell signalling. They bind to a vast array of proteins, which results in a host of physiological responses. Therefore it is difficult to determine the precise downstream effects of an individual protein-phosphoinositide interaction. Perturbations of these networks occur in pathological conditions such as cancer and diabetes increasing the need to understand these systems. Receptor-Ligand Engineering (RLE) may provide the tools to map these interactions. Chemical modification of the small PIPn or IPn ligand and complementary mutation of binding site amino acids is used to create a unique protein-ligand binding pair. Once the modified protein is engineered into the cell line, the dose dependent effects of its stimulation with the complementary ligand can be studied in isolation from signal pathway cross-talk. Phosphatidylinositol 4,5-diphosphate [PtdIns(4,5)P2 / PIP2] and phosphatidylinositol 3,4,5- triphosphate [PtdIns(3,4,5)P3 / PIP3] analogues with C-alkyl groups replacing the axial inositol C-H protons would be suitable ligands for RLE. To date, no such analogues are known in the literature. The key challenges in preparation of such compounds are selective protection and deprotection of the myo-inositol hydroxyls, introduction of new inositol C-substituents with retention of myostereochemistry, and phosphorylation of an unnatural tertiary centre. 4-C-Alkyl IP3 and 4-C-alkyl IP4 analogues were chosen as targets to explore the chemical limitations of analogue synthesis. Orthoesters simultaneously tied up the 1-, 3- and 5-O differentiating between the remaining three hydroxyls in a rigid structure. Oxidation of the isolated 4-OH to the inos-4-ose and selective reintroduction of the myo-geometry by addition of dimethyl sulfoxonium methylide generated the key exo-methylene oxide intermediate. Lithium alkyl cyano cuprates were employed to open the exo-methylene oxide introducing primary, β-secondary, and β- tertiary alkyl and aryl protrusions. 4-C-Alkyl triols were prepared by regiocontrolled DIBAL-H reduction of the orthobenzoate to a benzyl ether, directed by the 4-C-alkyl protrusion. The corresponding 4-C-alkyl tetrols were obtained by acidic hydrolysis of the orthobenzoate and cleavage of the resultant benzoate ester. All polyols were then phosphorylated and globally deprotected to generate the final series of 4-C-alkyl IP3 and IP4 analogues. Some initial investigations were also performed to extend this methodology to prepare 4- and 5-C-alkyl derivatives from a common precursor

"The Violence of the Frame: Image, Animal, Interval in Lars von Trier's Nymphomaniac"

Building on the film philosophy of Gilles Deleuze and Jacques Rancière, this essay develops a queer naturalist account of film form centered on the ontogenetic dimensions of Lars von Trier’s film Nymphomaniac (2013)

The Life Aquatic: Liquid Poetics and the Discourse of Friendship inThe Faerie Queene

From Michel de Montaigne’s essay “Of Friendship” to Jacques Derrida’s rearticulation of the former in The Politics of Friendship, scholars both early modern and modern have sought ways to address the fluid co-mixture of bodies from which the discourse of friendship can and does emerge. More recently still, new materialist thinkers of ontology have begun to shift our attention to the ways both human and nonhuman bodies inter-animate in the making of political, interpersonal, and artistic life worlds. Together with these investigations, I argue that an aquacentric account of relation is necessary to think the subject of friendship in Spenser’s epic. Beginning with Spenser’s queer address to Ralegh in Book III of The Faerie Queene and continuing through Book IV, I argue that Spenser reimagines the discourse of friendship in terms of a liquid, transcorporeal poetics, one that not only takes to its logical extreme humoral descriptions of bodies as conduits for liquids and passions but also importantly reworks human-exceptionalist readings of ontology in Spenser’s epic

Dancing with Perdita: The Choreography of Lost Time in The Winter's Tale

Shakespeare scholarship has long been interested in the temporal dynamics of The Winter’s Tale, and has often turned to melancholic or traumatic time frames to explain the thematic persistence of lost time in Shakespeare’s romance. In this chapter, I argue that dance provides a key interpretive framework for understanding the play’s interest in bodily movements that exceed static oppositions between absence and presence, time lost and time regained. Drawing on recent theorizations of “crip time” and the posthuman, I read Perdita’s dance as a figuration of bodies, sexualities, and histories without proper figure; in so doing, this chapter sets out to choreograph lost time via the space between movements—where generativity and negativity dance