C-C Coupling in sterically demanding porphyrin environments.

Unlike their planar counterparts, classic synthetic protocols for C-C bond forming reactions on nonplanar porphyrins are underdeveloped. The development of C-C bond forming reactions on nonplanar porphyrins is critical in advancing this field of study for more complex porphyrin architectures, which could be used in supramolecular assemblies, catalysis, or sensing. In this work a library of arm-extended dodecasubstituted porphyrins was synthesized through the optimization of the classic Suzuki-Miyaura coupling of peripheral haloaryl substituents with a range of boronic acids.

Synthesis by diastereomeric resolution, biochemical evaluation and molecular modelling of chiral 3-hydroxyl b-lactam microtubule-targeting agents for the treatment of triple negative breast and chemoresistant colorectal cancers.

The synthesis and biochemical activity of a series of chiral trans 3-hydroxyl β-lactams targeting tubulin is described. Synthesis of the series of enantiopure β-lactams was achieved using chiral derivatising reagent N-Boc-l-proline. The absolute configuration was determined as 3S,4S for (+) enantiomer 4EN1 and 3R,4R for (-) enantiomer 4EN2.

Application of 2D EXSY and qNMR Spectroscopy for Diastereomeric Excess Determination Following Chiral Resolution of β-Lactams.

Trans-β-lactam isomers have garnered much attention as anti-cancer microtubule targeting agents. Currently available synthetic methods are available for the preparation of enantiopure β-lactams and favour isomeric cis/trans β-lactam mixtures. Indirect chiral resolution offers the opportunity for isolation of exclusively enantiopure trans-β-lactams.

Importance of molecular symmetry for enantiomeric excess recognition by NMR.

Recently prochiral solvating agents (-CSA) came under the spotlight for the detection of enantiopurity by NMR. Chemical shift non-equivalency in achiral hosts introduced by the presence of chiral guests yields observable resonance signal splitting (Δ) correlating to the enantiomeric excess (e.e.

Steric Repulsion Induced Conformational Switch in Supramolecular Structures.

Inspired by the rigidified architecture of 'picket-fence' systems, we propose a strategy utilizing strain to impose intramolecular tension in already peripherally overcrowded structures leading to selective atropisomeric conversion. Employing this approach, tuneable shape-persistent porphyrin conformations were acquired exhibiting distinctive supramolecular nanostructures based on the orientation of the peripheral groups. The intrinsic assemblies driven by non-covalent bonding interactions form supramolecular polymers while encapsulating small molecules in parallel channels or solvent-accessible voids.

Elucidating Atropisomerism in Nonplanar Porphyrins with Tunable Supramolecular Complexes.

Atropisomerism is a fundamental feature of substituted biaryls resulting from rotation around the biaryl axis. Different stereoisomers are formed due to restricted rotation about the single bond, a situation often found in substituted porphyrins. Previously NMR determination of porphyrin atropisomers proved difficult, if not almost impossible to accomplish, due to low resolution or unresolvable resonance signals that predominantly overlapped.

Short-Chained Anthracene Strapped Porphyrins and their Endoperoxides.

The syntheses of short-chained anthracene-strapped porphyrins and their Zn(II)complexes are reported. The key synthetic step is a [2+2] condensation between a dipyrromethane and an anthracene bisaldehyde, 2,2'-((anthracene-9,10-diylbis(methylene))bis(oxy))dibenzaldehyde. Following exposure to white light, self-sensitized singlet oxygen and the anthracene moieties underwent [4+2] cycloaddition reactions to yield the corresponding endoperoxides.

Design, Synthesis and Biochemical Evaluation of Novel Ethanoanthracenes and Related Compounds to Target Burkitt's Lymphoma.

Lymphomas (cancers of the lymphatic system) account for 12% of malignant diseases worldwide. Burkitt's lymphoma (BL) is a rare form of non-Hodgkin's lymphoma in which the cancer starts in the immune B-cells. We report the synthesis and preliminary studies on the antiproliferative activity of a library of 9,10-dihydro-9,10-ethanoanthracene based compounds structurally related to the antidepressant drug maprotiline against BL cell lines MUTU-1 and DG-75.

Light-harvesting, 3rd generation Ru/Co MOF with a large, tubular channel aperture.

A photoactive, hetero-metallic CoII/RuII-based metal-organic framework (MOF) with a large channel aperture, ca. 21 Å, is reported. The photophysical properties of the MOF are derived from the RuII nodes giving rise to emission centred at ca.

The effect of the linker size in C-symmetrical chiral ligands on the self-assembly formation of luminescent triple-stranded di-metallic Eu(iii) helicates in solution.

Chiral lanthanide-based supramolecular structures have gained significant importance in view of their application in imaging, sensing and other functional purposes. We have designed chiral C2-symmetrical ligands (L) based on the use of two 2,6-pyridine-dicarboxylic-amide moieties (pda), that differ from one another by the nature of the diamine spacer groups (from 1,3-phenylenedimethanamine (1(S,S), 2(R,R)) and benzene-1,3-diamine (3(S,S), 4(R,R)) to much bulkier 4,4'-(cyclohexane-1,1-diyl)bis(2,6-dimethylaniline) (5(S,S), 6(R,R))) between these two pda units. The self-assembly between L and Eu(iii) ions were investigated in CH3CN solution at low concentration whereby the changes in the absorbance, fluorescence and Eu(iii)-centred emission spectra allowed us to model the binding equilibria occurring in the solution to the presence of [Eu:L2], [Eu2:L2], [Eu2:L3] assemblies and reveal their high binding constant values.

Fixing the Conformation of Calix[4]arenes: When Are Three Carbons Not Enough?

Calix[4]arenes are unique macrocycles that through judicious functionalisation at the lower rim can be either fixed in one of four conformations or remain conformationally flexible. Introduction of propynyl or propenyl groups unexpectedly provides a new possibility; a unidirectional conformational switch, with the 1,3-alternate and 1,2-alternate conformers switching to the partial cone conformation, whilst the cone conformation is unchanged, under standard experimental conditions. Using H NMR kinetic studies, rates of switching have been shown to be dependent on the starting conformation, upper-rim substituent, where reduction in bulk enables faster switching, solvent and temperature with 1,2-alternate conformations switching fastest.

A folded [2 × 2] metallo-supramolecular grid from a bis-tridentate (1,2,3-triazol-4-yl)-picolinamide (tzpa) ligand.

A flexible ditopic ligand 1 containing two N,N,O-tridentate (1,2,3-triazol-4-yl)-picolinamide chelating pockets is reported and the formation of multimetallic architectures is explored in the solid and the solution phase. The self-assembled Zn complex [Zn(1)](ClO) exhibited a folded [2 × 2] square grid supramolecular architecture that selectively assembled in MeCN solution as shown using various spectroscopic techniques. The closely related Fe complex shows equivalent behaviour in the solid state, while a discrete dinuclear species [Cu(NO)1]·5MeCN was the sole product observed in the solid state from the reaction between 1 and Cu under similar conditions.

Identification of pyrolysis products of the new psychoactive substance 2-amino-1-(4-bromo-2,5-dimethoxyphenyl)ethanone hydrochloride (bk-2C-B) and its iodo analogue bk-2C-I.

2-Amino-1-(4-bromo-2,5-dimethoxyphenyl)ethanone hydrochloride (bk-2C-B) has recently emerged as a new psychoactive substance (NPS). It is most commonly consumed orally, although there are indications that it might also be ingested by inhalation or 'smoking'. Information about the stability of bk-2C-B when exposed to heat is unavailable and the potential for pyrolytic degradation and formation of unknown substances available for inhalation prompted an investigation using a simulated 'meth pipe' scenario.

Lanthanide directed self-assembly of highly luminescent supramolecular "peptide" bundles from α-amino acid functionalized 2,6-bis(1,2,3-triazol-4-yl)pyridine (btp) ligands.

Ligands containing the [2,6-bis(1,2,3-triazol-4-yl)pyridine] (btp) motif have recently shown promise in coordination chemistry. The motif is synthesized via the Cu(I)-catalyzed "click" reaction and can be conveniently functionalized when compared to other terdentate chelating motifs. Ligand 1 was synthesized and shown to sensitize Eu(III) and Tb(III) excited states effectively.

The syntheses, characterization and in vitro metabolism of nitracaine, methoxypiperamide and mephtetramine.

Three legal highs; nitracaine (3-(diethylamino)-2,2-dimethylpropyl 4-nitrobenzoate), methoxypiperamide (MEOP, (4-methoxyphenyl)(4-methylpiperazin-1-yl)methanone) and mephtetramine (MTTA, 2-((methylamino)methyl)-3,4-dihydronaphthalen-1(2H)-one) appeared in 2013 as new psychoactive substances (NPS) on Internet websites selling 'research chemicals'. These compounds were synthesized and analyzed via our synthesize, analyze, and metabolize (SAM) protocol. Nitracaine was synthesized by the transesterification of methyl 4-nitrobenzoate with 3-(diethylamino)-2,2-dimethylpropan-1-ol.

Characterization of the pyrolysis products of methiopropamine.

1-(Thien-2-yl)-2-methylaminopropane (methiopropamine, MPA), appeared as a 'legal high' in late 2010. It is structurally similar to methamphetamine, with a thiophene ring replacing the benzene moiety. Methiopropamine reportedly retains the pharmacological properties of amphetamine stimulants, but it does not fall under existing drug laws in the USA and Ireland.

Synthesis, spectroscopic and biological studies of a fluorescent Pt(II) (terpy) based 1,8-naphthalimide conjugate as a DNA targeting agent.

The bi-functional complex [Pt(II)(terpy)(py-naphth)](NO3)2(), incorporating both 2,2':6',2''-terpyridine and 4-N,N'-dimethylamino-1,8-naphthalimide moieties, displays a high binding affinity for DNA as well as displaying cytotoxicity towards and inducing apoptosis in malignant cell lines.

Identification of (2-aminopropyl)indole positional isomers in forensic samples.

In 2012, 5-(2-aminopropyl)indole (5-API, 5-IT) was reported by Norwegian authorities to the European Monitoring Centre for Drugs and Drug Addiction (EMCDDA) via the Early Warning System (EWS). The 3- isomer, 3-(2-aminopropyl)indole (3-API, AMT, alpha-methyltryptamine), has been available on the recreational drugs market for a somewhat longer time, having first been reported to the EMCDDA by Finnish authorities in 2001. Both isomers are available from online vendors of 'legal highs'.

The analysis of amphetamine-like cathinone derivatives using positive electrospray ionization with in-source collision-induced dissociation.

Rationale: Amphetamine-like cathinone derivatives have become popular as recreational drugs over the past several years but their identification for forensic purposes is made difficult as they undergo extensive fragmentation under commonly used electron ionization (EI) conditions to afford ambiguous mass spectra. To overcome this, the feasibility of using positive electrospray ionization (ESI) with in-source collision-induced dissociation (CID) to produce distinguishable product ion mass spectra was examined.

Methods: A set of six homologous cathinone derivatives was analyzed using an LTQ/Orbitrap™ high-resolution mass spectrometer to establish if there are any commonalities or uniqueness in their mass spectra.

Electrostatic interactions play an essential role in the binding of oleic acid with α-lactalbumin in the HAMLET-like complex: a study using charge-specific chemical modifications.

Human α-lactalbumin made lethal to tumor cells (HAMLET) and its analogs are partially unfolded protein-oleic acid (OA) complexes that exhibit selective tumoricidal activity normally absent in the native protein itself. To understand the nature of the interaction between protein and OA moieties, charge-specific chemical modifications of lysine side chains involving citraconylation, acetylation, and guanidination were employed and the biophysical and biological properties were probed. Upon converting the original positively-charged lysine residues to negatively-charged citraconyl or neutral acetyl groups, the binding of OA to protein was eliminated, as were any cytotoxic activities towards osteosarcoma cells.

Photochemical [2 + 2] cycloaddition reactions of 6-alkenyl-3-phenylcyclohex-2-en-1-ones: using biradical conformation control to account for exceptions to the "rule of five".

A series of 6-alkenyl-3-phenylcyclohex-2-enones has been synthesised and the structures of the products obtained from them on irradiation have been determined. The 6-propenyl compounds afforded a tricyclic 'parallel' [2 + 2] cycloaddition product and a bicyclic enone resulting from hydrogen abstraction in the biradical intermediate. The 6-butenyl and 6-pentenyl analogues gave 'crossed' cycloaddition products only.

Preparation and characterisation of novel chlorothiazide potassium solid-state salt forms: Intermolecular self assembly suprastructures.

Chlorothiazide (CTZ) is a poorly soluble diuretic agent. The aim of the present work was to produce and characterise a potassium salt form of chlorothiazide which has the potential advantages of improved aqueous solubility and potassium supplementation. A number of novel potassium salt forms of CTZ (CTZK) were prepared: CTZK monohydrate (form I), CTZK dihydrate (form II), anhydrous CTZK (form III), CTZK monohydrate hemiethanolate (form IV) and a desolvate of CTZK monohydrate hemiethanolate (form V).

Preparation and solid state characterisation of chlorothiazide sodium intermolecular self-assembly suprastructure.

Chlorothiazide (CTZ), unlike other thiazide diuretics, can form salts. An injectable formulation containing the sodium salt is available; however neither the physicochemical characteristics of the salt nor its solid state form have been previously reported. This work reports on the crystal structure of chlorothiazide sodium.

Synthesis and in vitro toxicity of 4-MTA, its characteristic clandestine synthesis byproducts and related sulfur substituted alpha-alkylthioamphetamines.

4-Methylthioamphetamine (4-MTA) is recognised as a 3,4-methylenedioxymethamphetamine (MDMA)-like drug of abuse. Such amphetamine-type drugs often contain byproducts of uncontrolled, illegal clandestine synthetic processes. We report the isolation and structural identification of a number of novel pyridines, dihydropyridone and N,N-di(1-aryl-2-propyl) amines as route-specific byproducts associated with clandestine synthesis of 4-MTA and related amphetamines.

alpha-Lactalbumin, engineered to be nonnative and inactive, kills tumor cells when in complex with oleic acid: a new biological function resulting from partial unfolding.

HAMLET (human alpha-lactalbumin made lethal to tumor cells) is a tumoricidal complex consisting of partially unfolded protein and fatty acid and was first identified in casein fractions of human breast milk. The complex can be produced from its pure components through a modified chromatographic procedure where preapplied oleic acid binds with partially unfolded alpha-lactalbumin on the stationary phase in situ. Because native alpha-lactalbumin itself cannot trigger cell death, HAMLET's remarkable tumor-selective cytotoxicity has been strongly correlated with the conformational change of the protein upon forming the complex, but whether a recovery to the native state subsequently occurs upon entering the tumor cell is yet unclear.