Synthesis, Enantiomeric Resolution and Biological Evaluation of HIV Capsid Inhibition Activity for Racemic, (S)- and (R)-PF74.

PF74 is a capsid-targeting inhibitor of HIV replication that effectively perturbs the highly sensitive viral uncoating process. A lack of information regarding the optical purity (enantiomeric excess) of the single stereogenic centre of PF74 has resulted in ambiguity as to the potency of different samples of this compound. Herein is described the synthesis of enantiomerically enriched (S)- and (R)-PF74 and further enrichment of the samples (≥98%) using chiral HPLC resolution. The biological activities of each enantiomer were then evaluated, which determined (S)-PF74 (IC50 1.5 µM) to be significantly more active than (R)-PF74 (IC50 19 µM). Computational docking studies were then conducted to rationalise this large discrepancy in activity, which indicated different binding conformations for each enantiomer. The binding energy of the conformation adopted by the more active (S)-PF74 (ΔG = -73.8 kcal/mol) was calculated to be more favourable than the conformation adopted by the less active (R)-enantiomer (ΔG = -55.8 kcal/mol) in agreement with experimental observations.

Catalytic Isohypsic-Redox Sequences for the Rapid Generation of Csp3 -Containing Heterocycles.

Cross-coupling reactions catalyzed by transition metals are among the most influential in modern synthetic chemistry. The vast majority of transition-metal-catalyzed cross-couplings rely on a catalytic cycle involving alternating oxidation and reduction of the metal center and are generally limited to forging just one type of new bond per reaction (e.g., the biaryl linkage formed during a Suzuki cross-coupling). This work presents an Isohypsic-Redox Sequence (IRS) that uses one metal to effect two catalytic cycles, thereby generating multiple new types of bonds from a single catalyst source. We show that the IRS strategy is amenable to several widely used transformations including the Suzuki-Miyaura coupling, Buchwald-Hartwig amination, and Wacker oxidation. Furthermore, each of these reactions generates value-added heterocycles with significant sp3 -C (3-dimensional) content. Our results provide a general framework for generating complex products by using a single metal to fulfill multiple roles. By uniting different combinations of reactions in the isohypsic and redox phases of the process, this type of catalytic multiple bond-forming platform has the potential for wide applicability in the efficient synthesis of functional organic molecules.

Phonon-like Hydrogen-Bond Modes in Protic Ionic Liquids.

Gigahertz- to terahertz-frequency infrared and Raman spectra contain a wealth of information concerning the structure, intermolecular forces, and dynamics of ionic liquids. However, these spectra generally have a large number of contributions ranging from slow diffusional modes to underdamped librations and intramolecular vibrational modes. This makes it difficult to isolate effects such as the role of Coulombic and hydrogen-bonding interactions. We have applied far-infrared and ultrafast optical Kerr effect spectroscopies on carefully selected ions with a greater or lesser degree of symmetry in order to isolate spectral signals of interest. This has allowed us to demonstrate the presence of longitudinal and transverse optical phonon modes and a great similarity of alkylammonium-based protic ionic liquids to liquid water. The data show that such phonon modes will be present in all ionic liquids, requiring a reinterpretation of their spectra.

Identification and activity of inhibitors of the essential nematode-specific metalloprotease DPY-31.

Infection by parasitic nematodes is widespread in the developing world causing extensive morbidity and mortality. Furthermore, infection of animals is a global problem, with a substantial impact on food production. Here we identify small molecule inhibitors of a nematode-specific metalloprotease, DPY-31, using both known metalloprotease inhibitors and virtual screening. This strategy successfully identified several µM inhibitors of DPY-31 from both the human filarial nematode Brugia malayi, and the parasitic gastrointestinal nematode of sheep Teladorsagia circumcincta. Further studies using both free living and parasitic nematodes show that these inhibitors elicit the severe body morphology defect 'Dumpy' (Dpy; shorter and fatter), a predominantly non-viable phenotype consistent with mutants lacking the DPY-31 gene. Taken together, these results represent a start point in developing DPY-31 inhibition as a totally novel mechanism for treating infection by parasitic nematodes in humans and animals.

Targeted degradation of zDHHC-PATs decreases substrate S-palmitoylation.

Reversible S-palmitoylation of protein cysteines, catalysed by a family of integral membrane zDHHC-motif containing palmitoyl acyl transferases (zDHHC-PATs), controls the localisation, activity, and interactions of numerous integral and peripheral membrane proteins. There are compelling reasons to want to inhibit the activity of individual zDHHC-PATs in both the laboratory and the clinic, but the specificity of existing tools is poor. Given the extensive conservation of the zDHHC-PAT active site, development of isoform-specific competitive inhibitors is highly challenging. We therefore hypothesised that proteolysis-targeting chimaeras (PROTACs) may offer greater specificity to target this class of enzymes. In proof-of-principle experiments we engineered cell lines expressing tetracycline-inducible Halo-tagged zDHHC5 or zDHHC20, and evaluated the impact of Halo-PROTACs on zDHHC-PAT expression and substrate palmitoylation. In HEK-derived FT-293 cells, Halo-zDHHC5 degradation significantly decreased palmitoylation of its substrate phospholemman, and Halo-zDHHC20 degradation significantly diminished palmitoylation of its substrate IFITM3, but not of the SARS-CoV-2 spike protein. In contrast, in a second kidney derived cell line, Vero E6, Halo-zDHHC20 degradation did not alter palmitoylation of either IFITM3 or SARS-CoV-2 spike. We conclude from these experiments that PROTAC-mediated targeting of zDHHC-PATs to decrease substrate palmitoylation is feasible. However, given the well-established degeneracy in the zDHHC-PAT family, in some settings the activity of non-targeted zDHHC-PATs may substitute and preserve substrate palmitoylation.

Total synthesis of (+)-sieboldine a: evolution of a pinacol-terminated cyclization strategy.

This article describes synthetic studies that culminated in the first total synthesis of the Lycopodium alkaloid sieboldine A. During this study, a number of pinacol-terminated cationic cyclizations were examined to form the cis-hydrindanone core of sieboldine A. Of these, a mild Au(I)-promoted 1,6-enyne cyclization that was terminated by a semipinacol rearrangement proved to be most efficient. Fashioning the unprecedented N-hydroxyazacyclononane ring embedded within the bicyclo[5.2.1]decane-N,O-acetal moiety of sieboldine A was a formidable challenge. Ultimately, the enantioselective total synthesis of (+)-sieboldine A was completed by forming this ring in good yield by cyclization of a protected-hydroxylamine thioglycoside precursor.

Supramolecular Click Chemistry for Surface Modification of Quantum Dots Mediated by Cucurbit[7]uril.

Cucurbiturils (CBs), barrel-shaped macrocyclic molecules, are capable of self-assembling at the surface of nanomaterials in their native state, via their carbonyl-ringed portals. However, the symmetrical two-portal structure typically leads to aggregated nanomaterials. We demonstrate that fluorescent quantum dot (QD) aggregates linked with CBs can be broken-up, retaining CBs adsorbed at their surface, via inclusion of guests in the CB cavity. Simultaneously, the QD surface is modified by a functional tail on the guest, thus the high affinity host-guest binding (logKa > 9) enables a non-covalent, click-like modification of the nanoparticles in aqueous solution. We achieved excellent modification efficiency in several functional QD conjugates as protein labels. Inclusion of weaker-binding guests (logKa = 4-6) enables subsequent displacement with stronger binders, realising modular switchable surface chemistries. Our general "hook-and-eye" approach to host-guest chemistry at nanomaterial interfaces will lead to divergent routes for nano-architectures with rich functionalities for theranostics and photonics in aqueous systems.

Piperazic acid-containing natural products: isolation, biological relevance and total synthesis.

Since their first discovery in 1959, natural products containing the piperazic acid motif have been isolated from a variety of sources and exhibit diverse biological activity profiles. This review provides information about their isolation and biological activities, and presents an overview of recent total syntheses of these molecules.

Total synthesis of chloptosin: a dimeric cyclohexapeptide.

Here we describe in full our investigations into the synthesis of the dimeric cyclohexapeptide chloptosin in 17 linear steps. Particularly, this work features an organocatalytic tandem process for the synthesis of the embedded piperazic acids, in which a differentially protected azodicarboxylate is used together with pyrrolidinyl tetrazole as the catalyst. The central biaryl bond is being formed by Stille coupling of two sterically demanding ortho-chloropyrroloindole fragments. The inherent flexibility of the synthetic strategy proved beneficial as the route could be adjusted smoothly during the progression of the synthesis programme.

The use of nanovibration to discover specific and potent bioactive metabolites that stimulate osteogenic differentiation in mesenchymal stem cells.

Bioactive metabolites have wide-ranging biological activities and are a potential source of future research and therapeutic tools. Here, we use nanovibrational stimulation to induce osteogenic differentiation of mesenchymal stem cells, in the absence of off-target, nonosteogenic differentiation. We show that this differentiation method, which does not rely on the addition of exogenous growth factors to culture media, provides an artifact-free approach to identifying bioactive metabolites that specifically and potently induce osteogenesis. We first identify a highly specific metabolite, cholesterol sulfate, an endogenous steroid. Next, a screen of other small molecules with a similar steroid scaffold identified fludrocortisone acetate with both specific and highly potent osteogenic-inducing activity. Further, we implicate cytoskeletal contractility as a measure of osteogenic potency and cell stiffness as a measure of specificity. These findings demonstrate that physical principles can be used to identify bioactive metabolites and then enable optimization of metabolite potency can be optimized by examining structure-function relationships.

Total synthesis of (+)-sieboldine A.

The first total synthesis of (+)-sieboldine A was completed in 20 steps from readily available (3aS,6aR)-3,3a,4,6a-tetrahydro-2H-cyclopenta[b]furan-2-one (5). Key steps are as follows: (a) a pinacol-terminated 1,6-enyne cyclization reaction to form the cis-hydrindanone core (11 --> 12), (b) formation of the spiro tetrahydrofuran ring by stereoselective DMDO oxidation of tricyclic dihydropyran intermediate 15, and (c) formation of the unprecedented N-hydroxyazacyclononane ring by cyclization of a thioglycoside precursor (18 --> 19).

MIDA boronate allylation - synthesis of ibuprofen.

MIDA boronates are among the most useful reagents for the Suzuki-Miyaura reaction. This chemistry typically generates new bonds between two aromatic rings, thereby restricting access to important areas of chemical space. Here we demonstrate the coupling of MIDA boronates to allylic electrophiles, including a new synthesis of the well-known COX inhibitor ibuprofen.

Synthesis of 3,3-Disubstituted Heterocycles by Pd-Catalyzed Arylallylation of Unactivated Alkenes.

Finding new methods of carbon-carbon bond formation is a key goal in expanding current methodology for heterocycle formation. Because of their inherently nonplanar shape, new methods of forming sp3-rich scaffolds are of particular importance. Although there are methods for combining heterocyclization and formation of new sp3-sp3 carbon-carbon bonds, these form the carbon-heteroatom bond rather than a carbon-carbon bond of the heterocycle. Here, we show a new alkene arylallylation reaction that generates a heterocycle with concomitant formation of two new carbon-carbon bonds. Furthermore, we demonstrate that this process occurs through an isohypsic (redox neutral) mechanism. Overall, this carboallylation reaction gives a new route to the synthesis of 3,3-disubstituted heterocycles.

Characterisation of oil and aluminium complex on replica and historical 19th c. Turkey red textiles by non-destructive diffuse reflectance FTIR spectroscopy.

This work investigates historical and replica Turkey red textiles with diffuse reflectance infrared (DRIFT) spectroscopy to study the coordination complex between cellulose, fatty acids, and the aluminium ions that form the basis of the colour lake. Turkey red was produced in Scotland for around 150 years, and is held in many museum and archive collections. The textile was renowned for its brilliant red hue, and for its fastness to light, washing, rubbing, and bleaching. This was attributed to its unusual preparatory process, the chemistry of which was never fully understood, that involved imbuing cotton with a solution of aqueous fatty acids and then aluminium in the following step. Here we show, for the first time, a characterisation of the Turkey red complex on replica and historical textiles. The development of techniques for non-destructive and in situ analysis of historical textiles is valuable for improving understanding of their chemistry, hopefully contributing to better conservation and display practices. The results show the fatty acids condense onto the cellulose polymer via hydrogen bonding between the CO and OH of the respective compounds, then the aluminium forms a bridging complex with the fatty acid carboxyl. This contributes to an improved understanding of Turkey red textiles, and shows the useful application of handheld diffuse FTIR instruments for heritage textile research.

Conversion of the enantiomers of spiro[4.4]nonane-1,6-diol into both epimeric carbaspironucleosides having natural C1' absolute configuration.

[reaction: see text] The enantiomers of spiro[4.4]nonane-1,6-diol have been transformed by different reaction pathways into the two possible carbaspironucleoside epimers with natural C1' absolute stereochemistry.