Discovery and optimization of narrow spectrum inhibitors of Tousled like kinase 2 (TLK2) using quantitative structure activity relationships.

The oxindole scaffold has been the center of several kinase drug discovery programs, some of which have led to approved medicines. A series of two oxindole matched pairs from the literature were identified where TLK2 was potently inhibited as an off-target kinase. The oxindole has long been considered a promiscuous kinase inhibitor template, but across these four specific literature oxindoles TLK2 activity was consistent, while the kinome profile was radically different ranging from narrow to broad spectrum kinome coverage. We synthesized a large series of analogues, utilizing quantitative structure-activity relationship (QSAR) analysis, water mapping of the kinase ATP binding sites, kinome profiling, and small-molecule x-ray structural analysis to optimize TLK2 inhibition and kinome selectivity. This resulted in the identification of several narrow spectrum, sub-family selective, chemical tool compounds including 128 (UNC-CA2-103) that could enable elucidation of TLK2 biology.

Facial Selectivity in Mechanical Bond Formation: Axially Chiral Enantiomers and Geometric Isomers from a Simple Prochiral Macrocycle.

In 1971, Schill recognized that a prochiral macrocycle encircling an oriented axle led to geometric isomerism in rotaxanes. More recently, we identified an overlooked chiral stereogenic unit in rotaxanes that arises when a prochiral macrocycle encircles a prochiral axle. Here, we show that both stereogenic units can be accessed using equivalent strategies, with a single weak stereodifferentiating interaction sufficient for moderate to excellent stereoselectivity. Using this understanding, we demonstrated the first direct enantioselective (70% ee) synthesis of a mechanically axially chiral rotaxane.

A redox switch allows binding of Fe(II) and Fe(III) ions in the cyanobacterial iron-binding protein FutA from Prochlorococcus.

The marine cyanobacterium Prochlorococcus is a main contributor to global photosynthesis, whilst being limited by iron availability. Cyanobacterial genomes generally encode two different types of FutA iron-binding proteins: periplasmic FutA2 ABC transporter subunits bind Fe(III), while cytosolic FutA1 binds Fe(II). Owing to their small size and their economized genome Prochlorococcus ecotypes typically possess a single futA gene. How the encoded FutA protein might bind different Fe oxidation states was previously unknown. Here, we use structural biology techniques at room temperature to probe the dynamic behavior of FutA. Neutron diffraction confirmed four negatively charged tyrosinates, that together with a neutral water molecule coordinate iron in trigonal bipyramidal geometry. Positioning of the positively charged Arg103 side chain in the second coordination shell yields an overall charge-neutral Fe(III) binding state in structures determined by neutron diffraction and serial femtosecond crystallography. Conventional rotation X-ray crystallography using a home source revealed X-ray-induced photoreduction of the iron center with observation of the Fe(II) binding state; here, an additional positioning of the Arg203 side chain in the second coordination shell maintained an overall charge neutral Fe(II) binding site. Dose series using serial synchrotron crystallography and an XFEL X-ray pump-probe approach capture the transition between Fe(III) and Fe(II) states, revealing how Arg203 operates as a switch to accommodate the different iron oxidation states. This switching ability of the Prochlorococcus FutA protein may reflect ecological adaptation by genome streamlining and loss of specialized FutA proteins.

A Platform Approach to Cleavable Macrocycles for the Controlled Disassembly of Mechanically Caged Molecules.

Inspired by interlocked oligonucleotides, peptides and knotted proteins, synthetic systems where a macrocycle cages a bioactive species that is "switched on" by breaking the mechanical bond have been reported. However, to date, each example uses a bespoke chemical design. Here we present a platform approach to mechanically caged structures wherein a single macrocycle precursor is diversified at a late stage to include a range of trigger units that control ring opening in response to enzymatic, chemical, or photochemical stimuli. We also demonstrate that our approach is applicable to other classes of macrocycles suitable for rotaxane and catenane formation.

Chirality: a key parameter in chemical probes.

Many small molecule bioactive and marketed drugs are chiral. They are often synthesised from commercially available chiral building blocks. However, chirality is sometimes incorrectly assigned by manufacturers with consequences for the end user ranging from: experimental irreproducibility, wasted time on synthesising the wrong product and reanalysis, to the added cost of purchasing the precursor and resynthesis of the correct stereoisomer. Further on, this could lead to loss of reputation, loss of funding, to safety and ethical concerns due to potential in vivo administration of the wrong form of a drug. It is our firm belief that more stringent control of chirality be provided by the supplier and, if needed, requested by the end user, to minimise the potential issues mentioned above. Certification of chirality would bring much needed confidence in chemical structure assignment and could be provided by a variety of techniques, from polarimetry, chiral HPLC, using known chiral standards, vibrational circular dichroism, and x-ray crystallography. A few case studies of our brushes with wrong chirality assignment are shown as well as some examples of what we believe to be good practice.

Machine Learning-Guided Development of Trialkylphosphine Ni(I) Dimers and Applications in Site-Selective Catalysis.

Owing to the unknown correlation of a metal's ligand and its resulting preferred speciation in terms of oxidation state, geometry, and nuclearity, a rational design of multinuclear catalysts remains challenging. With the goal to accelerate the identification of suitable ligands that form trialkylphosphine-derived dihalogen-bridged Ni(I) dimers, we herein employed an assumption-based machine learning approach. The workflow offers guidance in ligand space for a desired speciation without (or only minimal) prior experimental data points. We experimentally verified the predictions and synthesized numerous novel Ni(I) dimers as well as explored their potential in catalysis. We demonstrate C-I selective arylations of polyhalogenated arenes bearing competing C-Br and C-Cl sites in under 5 min at room temperature using 0.2 mol % of the newly developed dimer, [Ni(I)(µ-Br)PAd2(n-Bu)]2, which is so far unmet with alternative dinuclear or mononuclear Ni or Pd catalysts.

Synthesis and Structural Characterization of Copper Complexes Containing "R-Substituted" Bis-7-Azaindolyl Borate Ligands.

The coordination chemistry of scorpionate ligands based on borates containing the 7-azaindole heterocycle is relatively unexplored. Thus, there is a requirement to further understand their coordination chemistry. This article outlines the synthesis and characterization of a family of complexes containing anionic flexible scorpionate ligands of the type [(R)(bis-7-azaindolyl)borohydride]- ([RBai]-), where R = Me, Ph or naphthyl. The three ligands were coordinated to a series of copper(I) complexes containing a phosphine co-ligand to form the complexes, [Cu(MeBai)(PPh3)] (1), [Cu(PhBai)(PPh3)] (2), [Cu(NaphthBai)(PPh3)] (3), [Cu(MeBai)(PCy3)] (4), [Cu(PhBai)(PCy3)] (5) and [Cu(NaphthBai)(PCy3)] (6). Additional copper(II) complexes, namely, [Cu(MeBai)2] (7) and [Cu(PhBai)2] (8), were obtained during attempts to obtain single crystals from complexes 4 and 2, respectively. Complexes 7 and 8 were also prepared independently from CuCl2 and two equivalents of the corresponding Li[RBai] salt alongside an additional complex, namely, [Cu(NaphthBai)2] (9). The copper(I) and copper(II) complexes were characterized using spectroscopic and analytical methods. Furthermore, a crystal structure was obtained for eight of the nine complexes. In all cases, the boron-based ligand was found to bind to the metal centers via a κ3-N,N,H coordination mode.

A catenane that is topologically achiral despite being composed of oriented rings.

Catenanes-molecules comprising two interlocking rings held together like links in a chain-are topologically non-trivial: a catenane is a topological isomer of its separated rings, but the rings cannot be disconnected without bond scission. Catenanes can exist as topological enantiomers if both rings have directionality conferred by a defined atom sequence, but this has led to the assumption that the stereochemistry of chiral catenanes composed of oriented rings is inherently topological in nature. Here we show that this assumption is incorrect by synthesizing an example that contains the same fundamental stereogenic unit but whose stereochemistry is Euclidean. One ring in this chiral catenane is oriented by the geometry of an exocyclic double rather than determined by atom sequence within the ring. Isomerization of the exocyclic double bond results in racemization of the catenane, confirming that the stereochemistry is not topological in nature. Thus, we can unite the stereochemistry of catenanes with that of their topologically trivial cousins, the rotaxanes, enabling a more unified approach to their discussion.

Hydroxypyridine/Pyridone Interconversions within Ruthenium Complexes and Their Application in the Catalytic Hydrogenation of CO2.

Reaction of a new ligand 6-DiPPon (6-diisopropylphosphino-2-pyridone) with 0.5 equiv of [RuCl2(p-cymene)]2 resulted in the formation of a mixture of [RuCl2(p-cymene)(κ1-P-6-DiPPon)]2 (1) and [RuCl(p-cymene)(κ2-P,N-6-DiPPin)]Cl ([2]Cl) (where 6-DiPPin = 6-diisopropylphosphino-2-hydroxypyridine). The ratio between the two products can be controlled by the nature of the solvent. The similar reaction between 6-DiPPon and [RuCl2(p-cymene)]2 in the presence of AgOTf and Na[BArF24] (where BArF24 = [{3,5-(CF3)2C6H3}4B]-) resulted in the formation of the complexes [RuCl(p-cymene)(κ2-P,N-6-DiPPin)]OTf, ([2]OTf) and [RuCl(p-cymene)(κ2-P,N-6-DiPPin)]BArF24 ([2]BArF24), respectively. Reactions between complex [2]Cl, [2]OTf, or [2]BArF24 and a base (either DBU or NaOMe) resulted in the deprotonation of the hydroxyl functional group to form a novel neutral orange-colored dearomatized complex, 3. The identity of complex 3 was confirmed as [RuCl(p-cymene)(κ2-P,N-6-DiPPon*)], where 6-DiPPon* is the anionic species (6-diisopropylphosphino-2-oxo-pyridinide), which contains the deprotonated moiety. The new 6-DiPPon ligand and its corresponding air stable half-sandwich derivative ruthenium complexes 1, [2]OTf, [2]BArF24, and 3 were all isolated in good yields and fully characterized by spectroscopic and analytical methods. The interconversions between the neutral and anionic forms of the ligands 6-DiPPon, 6-DiPPin, and 6-DiPPon* offer the potential for novel secondary sphere interactions and proton shuttling reactivity. The consequences for this have been explored in the activation of H2 and the subsequent catalytic hydrogenations of CO2 into formate salts in the presence of a base.

Fluorine-based Zn salan complexes.

We synthesised and characterised the racemic and chiral versions of two Zn salan fluorine-based complexes from commercially available materials. The complexes are susceptible to absorbing H2O from the atmosphere. In solution (DMSO-H2O) and at the millimolar level, experimental and theoretical studies identify that these complexes exist in a dimeric-monomeric equilibrium. We also investigated their ability to sense amines via19F NMR. In CDCl3 or d6-DMSO, strongly coordinating molecules (H2O or DMSO) are the limiting factor in using these easy-to-make complexes as chemosensory platforms since their exchange with analytes requires an extreme excess of the latter.

Chiral Co3Y Propeller-Shaped Chemosensory Platforms Based on 19F-NMR.

Two propeller-shaped chiral CoIII3YIII complexes built from fluorinated ligands are synthesized and characterized by single-crystal X-ray diffraction (SXRD), IR, UV-vis, circular dichroism (CD), elemental analysis, thermogravimetric analysis (TGA), electron spray ionization mass spectroscopy (ESI-MS), and NMR (1H, 13C, and 19F). This work explores the sensing and discrimination abilities of these complexes, thus providing an innovative sensing method using a 19F NMR chemosensory system and opening new directions in 3d/4f chemistry. Control experiments and theoretical studies shed light on the sensing mechanism, while the scope and limitations of this method are discussed and presented.

FeIII in the high-spin state in dimethylammonium bis[3-ethoxysalicylaldehyde thiosemicarbazonato(2-)-κ3O2,N1,S]ferrate(III).

The synthesis and crystal structure (100 K) of the title compound, [(CH3)2NH2][Fe(C10H11O2N3S)2], are reported. The asymmetric unit consists of an octahedral [FeIII(L)2]- fragment, where L2- is 3-ethoxysalicylaldehyde thiosemicarbazonate(2-), and a dimethylammonium cation. Each L2- ligand binds with the thiolate S, the imine N and the phenolate O atoms as donors, resulting in an FeIIIS2N2O2 chromophore. The ligands are orientated in two perpendicular planes, with the O and S atoms in cis positions, and mutually trans N atoms. The FeIII ion is in the high-spin state at 100 K. The variable-temperature magnetic susceptibility measurements (5-320 K) are consistent with the presence of a high-spin FeIII ion with D = 0.83 (1) cm-1 and g = 2.

Discovery and Optimization of Narrow Spectrum Inhibitors of Tousled Like Kinase 2 (TLK2) Using Quantitative Structure Activity Relationships.

The oxindole scaffold has been the center of several kinase drug discovery programs, some of which have led to approved medicines. A series of two oxindole matched pairs from the literature were identified where TLK2 was a potent off-target kinase. The oxindole has long been considered a promiscuous inhibitor template, but across these 4 specific literature oxindoles TLK2 activity was consistent, while the kinome profile was radically different from narrow to broad spectrum coverage. We synthesized a large series of analogues and through quantitative structure-activity relationship (QSAR) analysis, water mapping of the kinase ATP binding sites, small-molecule x-ray structural analysis and kinome profiling, narrow spectrum, sub-family selective, chemical tool compounds were identified to enable elucidation of TLK2 biology.

Synthesis and 83Kr NMR spectroscopy of Kr@C60.

Synthesis of Kr@C60 is achieved by quantitative high-pressure encapsulation of the noble gas into an open-fullerene, and subsequent cage closure. Krypton is the largest noble gas entrapped in C60 using 'molecular surgery' and Kr@C60 is prepared with >99.4% incorporation of the endohedral atom, in ca. 4% yield from C60. Encapsulation in C60 causes a shift of the 83Kr resonance by -39.5 ppm with respect to free 83Kr in solution. The 83Kr spin-lattice relaxation time T1 is approximately 36 times longer for Kr encapsulated in C60 than for free Kr in solution. This is the first characterisation of a stable Kr compound by 83Kr NMR.

Scale-up and optimization of the synthesis of dual CBP/BRD4 inhibitor ISOX-DUAL.

ISOX-DUAL is a dual inhibitor of CBP/p300 (IC50 = 0.65 µM) and BRD4 (IC50 = 1.5 µM) bromodomains, and a useful chemical probe for epigenetic research. Aspects of the published synthetic route to this compound and its analogues are small-scale, poor-yielding or simply unamenable to scale-up without optimization. Herein we describe the development of a refined synthesis that circumvents the challenges of the original report, with notable improvements to several of the key synthetic transformations. Moreover, a general Suzuki Miyaura protocol for the late stage installation of alternative dimethyl-isoxazole acetyl-lysine (KAc) binding motifs is presented.

Solvent-Free Synthesis of Core-Functionalised Naphthalene Diimides by Using a Vibratory Ball Mill: Suzuki, Sonogashira and Buchwald-Hartwig Reactions.

Solvent-free synthesis by using a vibratory ball mill (VBM) offers the chance to access new chemical reactivity, whilst reducing solvent waste and minimising reaction times. Herein, we report the core functionalisation of N,N'-bis(2-ethylhexyl)-2,6-dibromo-1,4,5,8-naphthalenetetracarboxylic acid (Br2 -NDI) by using Suzuki, Sonogashira and Buchwald-Hartwig coupling reactions. The products of these reactions are important building blocks in many areas of organic electronics including organic light-emitting diodes (OLEDs), organic field-effect transistors (OFETs) and organic photovoltaic cells (OPVCs). The reactions proceed in as little as 1 h, use commercially available palladium sources (frequently Pd(OAc)2 ) and are tolerant to air and atmospheric moisture. Furthermore, the real-world potential of this green VBM protocol is demonstrated by the double Suzuki coupling of a monobromo(NDI) residue to a bis(thiophene) pinacol ester. The resulting dimeric NDI species has been demonstrated to behave as an electron acceptor in functioning OPVCs.

Reversible P-P bond cleavage at an iridium(III) metal centre.

Treatment of a κ1-P-monodentate bicyclic diphosphane iridium(III) complex with a labile gold(I) precursor afforded an unusual IrIII/AuI complex in which the P-P single bond has been cleaved. This reaction was cleanly reversed upon addition of tertiary phosphine. Carbon-carbon bond activation, across neighbouring P2C2N rings of the coordinated bicyclic diphosphane, occurred upon thermolysis of the IrIII/AuI complex.

Expanding the Repertoire of Low-Molecular-Weight Pentafluorosulfanyl-Substituted Scaffolds.

The pentafluorosulfanyl (-SF5 ) functional group is of increasing interest as a bioisostere in medicinal chemistry. A library of SF5 -containing compounds, including amide, isoxazole, and oxindole derivatives, was synthesised using a range of solution-based and solventless methods, including microwave and ball-mill techniques. The library was tested against targets including human dihydroorotate dehydrogenase (HDHODH). A subsequent focused approach led to synthesis of analogues of the clinically used disease modifying anti-rheumatic drugs (DMARDs), Teriflunomide and Leflunomide, considered for potential COVID-19 use, where SF5 bioisostere deployment led to improved inhibition of HDHODH compared with the parent drugs. The results demonstrate the utility of the SF5 group in medicinal chemistry.

FeIII in a high-spin state in bis(5-bromosalicylaldehyde 4-ethylthiosemicarbazonato-κ3O,N1,S)ferrate(III) nitrate monohydrate, the first example of such a cationic FeIII complex unit.

The synthesis and crystal structure (100 K) of the title compound, [Fe(C10H11BrN3OS)2]NO3·H2O, is reported. The asymmetric unit consists of an octahedral [FeIII(HL)2]+ cation, where HL- is H-5-Br-thsa-Et or 5-bromosalicylaldehyde 4-ethylthiosemicarbazonate(1-) {systematic name: 4-bromo-2-[(4-ethylthiosemicarbazidoidene)methyl]phenolate}, a nitrate anion and a noncoordinated water molecule. Each HL- ligand binds via the thione S, the imine N and the phenolate O atom, resulting in an FeIIIS2N2O2 chromophore. The ligands are orientated in two perpendicular planes, with the O and S atoms in cis and the N atoms in trans positions. This [Fe(HL)2](anion)·H2O compound contains the first known cationic FeIII entity containing two salicylaldehyde thiosemicarbazone derivatives. The FeIII ion is in the high-spin state at 100 K. In addition, a comparative IR spectroscopic study of the free ligand and the ferric complex is presented, demonstrating that such an analysis provides a quick identification of the degree of deprotonation and the coordination mode of the ligand in this class of metal compounds. The variable-temperature magnetic susceptibility measurements (5-320 K) are consistent with the presence of a high-spin FeIII ion with a zero-field splitting D = 0.439 (1) cm-1.