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In response to genotoxic stress, the tumor suppressor p53 acts as a transcription factor by regulating the expression of genes critical for cancer prevention. Mutations in the gene encoding p53 are associated with cancer development. PRIMA-1 and eprenetapopt (APR-246/PRIMA-1 MET ) are small molecules that are converted into the biologically active compound, methylene quinuclidinone (MQ), shown to reactivate mutant p53 by binding covalently to cysteine residues. Here, we investigate the structural basis of mutant p53 reactivation by MQ based on a series of high-resolution crystal structures of cancer-related and wild-type p53 core domains bound to MQ in their free state and in complexes with their DNA response elements. Our data demonstrate that MQ binds to several cysteine residues located at the surface of the core domain. The structures reveal a large diversity in MQ interaction modes that stabilize p53 and its complexes with DNA, leading to a common global effect that is pertinent to the restoration of non-functional p53 proteins. The tumor suppressor p53 is mutated in more than half of human cancers and the compound methylene quinuclidinone (MQ) was shown to reactivate p53 mutants by binding covalently to cysteine residues. Here, the authors present crystal structures of wild-type and cancer related p53 mutant core domains bound to MQ alone and in complex with their DNA response elements and observe that MQ is bound to several cysteine residues located at the surface of the core domain.

Cyclic organic molecules are common among natural products and pharmaceuticals 1 , 2 . In fact, the overwhelming majority of small-molecule pharmaceuticals contain at least one ring system, as they provide control over molecular shape, often increasing oral bioavailability while providing enhanced control over the activity, specificity and physical properties of drug candidates 3 – 5 . Consequently, new methods for the direct site and diastereoselective synthesis of functionalized carbocycles are highly desirable. In principle, molecular editing by C–H activation offers an ideal route to these compounds. However, the site-selective C–H functionalization of cycloalkanes remains challenging because of the strain encountered in transannular C–H palladation. Here we report that two classes of ligands—quinuclidine-pyridones ( L1 , L2 ) and sulfonamide-pyridones ( L3 )—enable transannular γ-methylene C–H arylation of small- to medium-sized cycloalkane carboxylic acids, with ring sizes ranging from cyclobutane to cyclooctane. Excellent γ-regioselectivity was observed in the presence of multiple β-C–H bonds. This advance marks a major step towards achieving molecular editing of saturated carbocycles: a class of scaffolds that are important in synthetic and medicinal chemistry 3 – 5 . The utility of this protocol is demonstrated by two-step formal syntheses of a series of patented biologically active small molecules, prior syntheses of which required up to 11 steps 6 . Quinuclidine-pyridone and sulfonamide-pyridone ligands enable transannular γ-methylene C–H arylation of cycloalkane carboxylic acids with a range of ring sizes, bringing us closer to molecular editing of saturated carbocycles.

Ionic flux mediates essential physiological and behavioral functions in defined cell populations. Cell type—specific activators of diverse ionic conductances are needed for probing these effects. We combined chemistry and protein engineering to enable the systematic creation of a toolbox of ligand-gated ion channels (LGICs) with orthogonal pharmacologic selectivity and divergent functional properties. The LGICs and their small-molecule effectors were able to activate a range of ionic conductances in genetically specified cell types. LGICs constructed for neuronal perturbation could be used to selectively manipulate neuron activity in mammalian brains in vivo. The diversity of ion channel tools accessible from this approach will be useful for examining the relationship between neuronal activity and animal behavior, as well as for cell biological and physiological applications requiring chemical control of ion conductance.

Quaternary ammonium compounds (QACs) are a biologically active group of chemicals with a wide range of different applications. Due to their strong antibacterial properties and broad spectrum of activity, they are commonly used as ingredients in antiseptics and disinfectants. In recent years, the spread of bacterial resistance to QACs, exacerbated by the spread of infectious diseases, has seriously threatened public health and endangered human lives. Recent trends in this field have suggested the development of a new generation of QACs, in parallel with the study of bacterial resistance mechanisms. In this work, we present a new series of quaternary 3-substituted quinuclidine compounds that exhibit potent activity across clinically relevant bacterial strains. Most of the derivatives had minimal inhibitory concentrations (MICs) in the low single-digit micromolar range. Notably, QA p Cl and QA p Br were selected for further investigation due to their strong antibacterial activity and low toxicity to human cells along with their minimal potential to induce bacterial resistance. These compounds were also able to inhibit the formation of bacterial biofilms more effectively than commercial standard, eradicating the bacterial population within just 15 min of treatment. The candidates employ a membranolytic mode of action, which, in combination with the generation of reactive oxygen species (ROS), destabilizes the bacterial membrane. This treatment results in a loss of cell volume and alterations in surface morphology, ultimately leading to bacterial cell death. The prominent antibacterial potential of quaternary 3-aminoquinuclidines, as exemplified by QA p Cl and QA p Br, paves the way for new trends in the development of novel generation of QACs.

Frustrated magnetic lattices offer the possibility of many exotic ground states that are of great fundamental importance. Of particular significance is the hunt for frustrated spin-1/2 networks as candidates for quantum spin liquids, which would have exciting and unusual magnetic properties at low temperatures. The few reported candidate materials have all been based on d 9 ions. Here, we report the ionothermal synthesis of [NH 4 ] 2 [C 7 H 14 N][V 7 O 6 F 18 ], an inorganic–organic hybrid solid that contains a S  = 1/2 kagome network of d 1 V 4+ ions. The compound exhibits a high degree of magnetic frustration, with significant antiferromagnetic interactions but no long-range magnetic order or spin-freezing above 2 K, and appears to be an excellent candidate for realizing a quantum spin liquid ground state in a spin-1/2 kagome network. Candidates for 'quantum spin liquid' materials are rare and often composed of two-dimensional kagome arrays of d 9 centres. Analogous systems based on d 1 metal ions may confer different properties, but there are no previously known examples. An inorganic–organic hybrid vanadium d 1 material has now been prepared that seems to be an excellent candidate for a spin-liquid ground state.

Trypanosomatid parasites are the causative agents of many neglected tropical diseases and there is currently considerable interest in targeting endogenous sterol biosynthesis in these organisms as a route to the development of novel anti-infective drugs. Here, we report the first x-ray crystallographic structures of the enzyme squalene synthase (SQS) from a trypanosomatid parasite, Trypanosoma cruzi, the causative agent of Chagas disease. We obtained five structures of T. cruzi SQS and eight structures of human SQS with four classes of inhibitors: the substrate-analog S-thiolo-farnesyl diphosphate, the quinuclidines E5700 and ER119884, several lipophilic bisphosphonates, and the thiocyanate WC-9, with the structures of the two very potent quinuclidines suggesting strategies for selective inhibitor development. We also show that the lipophilic bisphosphonates have low nM activity against T. cruzi and inhibit endogenous sterol biosynthesis and that E5700 acts synergistically with the azole drug, posaconazole. The determination of the structures of trypanosomatid and human SQS enzymes with a diverse set of inhibitors active in cells provides insights into SQS inhibition, of interest in the context of the development of drugs against Chagas disease.

The selective binding of six (S)-quinuclidine-triazoles and their (R)-enantiomers to nicotinic acetylcholine receptor (nAChR) subtypes α3β4 and α7, respectively, were analyzed by in silico docking to provide the insight into the molecular basis for the observed stereospecific subtype discrimination. Homology modeling followed by molecular docking and molecular dynamics (MD) simulations revealed that unique amino acid residues in the complementary subunits of the nAChR subtypes are involved in subtype-specific selectivity profiles. In the complementary β4-subunit of the α3β4 nAChR binding pocket, non-conserved AspB173 through a salt bridge was found to be the key determinant for the α3β4 selectivity of the quinuclidine-triazole chemotype, explaining the 47–327-fold affinity of the (S)-enantiomers as compared to their (R)-enantiomer counterparts. Regarding the α7 nAChR subtype, the amino acids promoting a however significantly lower preference for the (R)-enantiomers were the conserved TyrA93, TrpA149 and TrpB55 residues. The non-conserved amino acid residue in the complementary subunit of nAChR subtypes appeared to play a significant role for the nAChR subtype-selective binding, particularly at the heteropentameric subtype, whereas the conserved amino acid residues in both principal and complementary subunits are essential for ligand potency and efficacy.

Alzheimer’s disease (AD) poses a significant public health issue. Despite the fact that today there are several methods of maintenance therapy, one of the most widely used methods is designed to correct the deficiency of acetylcholine. In the search for new potential inhibitors of cholinesterase enzymes, eight new derivatives of 3-oxo- or 2,3-indolo-triterpenic acid conjugated with amino-quinuclidine bicyclic cores were designed and synthesized. Then, the obtained compounds were screened in Ellman’s assays for their ability to inhibit acetylcholinesterase enzyme, and for each of the active compounds, the type of inhibition was determined. The obtained results demonstrate the dependence of the activity on the triterpenoid structure and the type of substituents. The best activity for ursolic acid derivatives was observed for the 3-oxoamide 8, with an IC50 value of 0.43 µM, acting as a mixed-type inhibitor. In turn, for the oleanane type, the amide with an indole unit in the A ring 11 exhibited the best activity with an IC50 value of 0.47 µM (while the ursane-type analog was weakly active) and led to an uncompetitive type of inhibition. Thus, 3-amidoquinuclidine-triterpenoids conjugates could be considered novel inhibitors of acetylcholinesterase with a different mechanism of action.

Angiogenesis is the growth of new capillaries from existing blood vessels that supply oxygen and nutrients and provide gateways for immune surveillance. Abnormal vessel growth in term of excessive angiogenesis is a hallmark of cancer, inflammatory and eye diseases. VEGFR-2 (vascular endothelial growth factor receptor 2) dominating the process of angiogenesis has led to approval of therapeutic inhibitors and is becoming a promising target for anti-angiogenic drugs. Notwithstanding these successes, the clinical use of current VEGFR-2 blockers is more challenging than anticipated. Taking axitinib as a reference drug, in our study we found three potent VEGFR-2 inhibitors (ZINC08254217, ZINC08254138, and ZINC03838680) from natural derivatives. Each of the three inhibitors acquired a better grid score than axitinib (−62.11) when docked to VEGFR-2. Molecular dynamics simulations demonstrated that ZINC08254217– and ZINC08254138–VEGFR-2 complexes were more stable than axitinib. Similar to bind free energy for axitinib (−54.68 kcal/mol), such for ZINC03838680, ZINC08254217, and ZINC08254138 was −49.37, −43.32, and −32.73 kcal/mol respectively. These results suggested these three compounds could be candidate drugs against angiogenesis, with comparable VEGFR-2 binding affinity of axitinib. Hence findings in our study are able to provide valuable information on discovery of effective anti-angiogenesis therapy.

Preliminary results concerning the first asymmetric synthesis of highly functionalized 1-benzamido-1,4-dihydropyridine derivatives via the reaction of hydrazones with alkylidenemalononitriles in the presence of β-isocupreidine catalyst are reported. The moderate, but promising, enantioselectivity observed (40–54% ee), opens the door to a new area of research for the asymmetric construction of new chiral 1,4-dihydropyridine derivatives, whose enantioselective catalytic preparation are still very limited. Moreover, the use of hydrazones for the enantioselective construction of chiral 1,4-dihydropyridines has been overlooked in the literature so far. Therefore, our research represents a pivotal example in this field which remains still unexplored.