Stereochemical Features Research Articles

Dracomolphin A-E, new lignans from Dracocephalum moldavica

Eight new lignans, dracomolphin A-E (1–8), together with eight known lignans (9–16) were isolated from the aerial part of Dracocephalum moldavica. The structures of the isolated compounds were established based on NMR and HRESIMS data. Dracomolphin A (1–4) was elucidated as a lignan possessed a 5-membered ketal ring formed between C-8′ and C-3, C-4. The two stereogenic centers rendered dracomolphin A as a mixture of two diastereomeric pairs of enantiomers (1–4). All of the four isomers were separated successfully by using chiral HPLC and their stereochemical features were determined by CD spectra. Bioactivity screening revealed that compounds 1–4, 6, 7, 12, 15 and 16 were potential Nrf2 transcriptional activators. Dracomolphin E (8) reduced cell viability of lung cancer NCI-H292 cells associated with apoptosis.

Crystal Structure of Peptidyl-tRNA Hydrolase from <i>Acinetobacter baumannii</i> at 1.00 Å Resolution

The essential process of protein biosynthesis in the cell often gets stalled due to the premature abortion of the translation process and generates a byproduct of peptidyl-tRNA molecules. This defect is corrected by peptidyl-tRNA hydrolase (Pth) by hydrolyzing peptidyl-tRNA to yield tRNA and peptides. In order to understand the mechanism of catalytic action and detailed stereochemical features of the substrate binding site, the structure of Pth has been determined at 1.00 A resolution. The Pth enzyme from Acinetobacter baumannii (AbPth) was cloned, expressed, purified and crystallized. The structure was refined to Rcryst and Rfree values of 0.145 and 0.157 respectively. The electron densities were observed for many hydrogen atoms in the structure. In AbPth, the residues, Asn12, His22, Asn70, Asp95 and Asn116 are involved in the catalytic process. The structure determination revealed that His22 Nᵟ1 forms a hydrogen bond with Asp95 Oᵟ2 while His22 Ne2 is hydrogen bonded to Asn116 Nᵟ2. In this case, the side chain of Asn116 adopts a conformation with  value of 65°. Upon ligand binding, Asn116 adopts a different conformation with  value of -70⁰. In the present structure, the conformation of Tyr68 is observed in the disallowed region of Ramachandran’s plot with φ, ѱ values of 80⁰, 150⁰. However, it is observed that Tyr68 adopts both disallowed and allowed conformations in Pth enzymes indicating a structural flexibility. The structure determination also revealed multiple conformations of the side chains of a number of amino acid residues.

Insights into pH-dependent transformation of gibberellic acid in aqueous solution: Transformation pathway, mechanism and toxicity estimation

Gibberellic acid (GA3) is widely used in agriculture and maybe transfer with groundwater flow, which is an endocrine disruptor, but few studies have focused on the transformation pathway and toxicity assessment of GA3 and its products. Here, GA3 and its transformation products in aqueous solution were identified and quantified by liquid chromatography mass spectrometry hybrid ion trap time-of-flight (LCMS−IT−TOF) and high-performance liquid chromatography (HPLC), respectively. The results showed that the half-life of GA3 transformation in ultrapure water was 16.1–24.6 days at pH=2.0–8.0, with the lowest half-life occurring at pH=8.0 and highest half-life occurring at pH=3.3. Isomerized gibberellic acid (Iso-GA3) and gibberellenic acid (GEA) were the main transformation products with a little hydroxy gibberellic acid (OH-GA3). In North China groundwater, the mass balance of GA3 and its products was 76.2%, including Iso-GA3 (58%), GEA (7.9%), GA3 (7.3%) and OH-GA3 (3%) after reaching transformation equilibrium. Using Gaussian 09 for chemical computation, it was found that the transformation mechanism of GA3 was dependent upon the bond energy and the stereochemical feature of its molecular structure. GA3 always isomerized from the γ-lactone ring due to the lowest bond energy between the oxygen terminus of the γ-lactone ring and A ring. While GA3 and its transformation products all had developmental toxicity, the predicated LC50 (96 hr) and LD50 of the main products of GA3 were much lower than those of GA3, indicating GA3 would be transformed into higher toxicity derivatives in water environments, posing a significant health risk to humans and the environment.

Enantioconvergent Amination of Racemic Tertiary C-H Bonds.

Racemization is considered to be an intrinsic stereochemical feature of free radical chemistry as can be seen in traditional radical halogenation reactions of optically active tertiary C-H bonds. If the facile process of radical racemization could be effectively combined with an ensuing step of bond formation in an enantioselective fashion, then it would give rise to deracemizative functionalization of racemic tertiary C-H bonds for stereoselective construction of chiral molecules bearing quaternary stereocenters. As a demonstration of this unique potential in radical chemistry, we herein report that metalloradical catalysis can be successfully applied to devise Co(II)-based catalytic system for enantioconvergent radical amination of racemic tertiary C(sp3)-H bonds. The key to the success of the radical process is the development of Co(II)-based metalloradical catalyst with fitting steric, electronic, and chiral environments of the D2-symmetric chiral amidoporphyrin as the supporting ligand. The existence of optimal reaction temperature is recognized as an important factor in the realization of the enantioconvergent radical process. Supported by an optimized chiral ligand, the Co(II)-based metalloradical system can effectively catalyze the enantioconvergent 1,6-amination of racemic tertiary C(sp3)-H bonds at the optimal temperature, affording chiral α-tertiary amines in excellent yields with high enantiocontrol of the newly created quaternary stereocenters. Systematic studies, including experiments utilizing optically active deuterium-labeled C-H substrates as a model system, shed light on the underlying mechanistic details of this new catalytic process for enantioconvergent radical C-H amination. The remarkable power to create quaternary stereocenters bearing multiple functionalities from ubiquitous C-H bonds, as showcased with stereoselective construction of bicyclic N-heterocycles, opens the door for future synthetic applications of this new radical technology.

Crystallographic structure of wild-type SARS-CoV-2 main protease acyl-enzyme intermediate with physiological C-terminal autoprocessing site

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the pathogen that causes the disease COVID-19, produces replicase polyproteins 1a and 1ab that contain, respectively, 11 or 16 nonstructural proteins (nsp). Nsp5 is the main protease (Mpro) responsible for cleavage at eleven positions along these polyproteins, including at its own N- and C-terminal boundaries, representing essential processing events for subsequent viral assembly and maturation. We have determined X-ray crystallographic structures of this cysteine protease in its wild-type free active site state at 1.8 Å resolution, in its acyl-enzyme intermediate state with the native C-terminal autocleavage sequence at 1.95 Å resolution and in its product bound state at 2.0 Å resolution by employing an active site mutation (C145A). We characterize the stereochemical features of the acyl-enzyme intermediate including critical hydrogen bonding distances underlying catalysis in the Cys/His dyad and oxyanion hole. We also identify a highly ordered water molecule in a position compatible for a role as the deacylating nucleophile in the catalytic mechanism and characterize the binding groove conformational changes and dimerization interface that occur upon formation of the acyl-enzyme. Collectively, these crystallographic snapshots provide valuable mechanistic and structural insights for future antiviral therapeutic development including revised molecular docking strategies based on Mpro inhibition.

Exploiting isohexide scaffolds for the preparation of chiral ionic liquids tweezers

New bis-quinolinium chiral ionic liquids (CILs) were synthesized in good yields starting from isomannide and isosorbide by a straightforward procedure that maintains the absolute stereostructure of the isohexide scaffolds. Thermal gravimetric analysis and differential scanning calorimetry, aimed at investigating the short thermal stability and the thermal behaviour of the synthesized ionic compounds are presented. The stereochemical features of both ionic derivatives and their neutral precursors were investigated by electronic circular dichroism (ECD) spectroscopy. ECD spectra of neutral compounds 5 and 6 and their N-methylated cations (5-Me+ and 6-Me+) were theoretically investigated by means of molecular modelling and excited-state calculations. A theoretical conformational analysis suggests the possible use of the isohexide derivatives as tweezers-type hosts in recognition processes toward different kinds of guests. Some of the ionic derivatives were successfully used in the NMR enantiorecognition of TFAE, discriminating the enantiomers through a tweezers-like mechanism.

New Insights into the Stereochemical Requirements of the Bombesin BB1 Receptor Antagonists Binding.

Members of the family of bombesinlike peptides exert a wide range of biological activities both at the central nervous system and in peripheral tissues through at least three G-Protein Coupled Receptors: BB1, BB2 and BB3. Despite the number of peptide ligands already described, only a few small molecule binders have been disclosed so far, hampering a deeper understanding of their pharmacology. In order to have a deeper understanding of the stereochemical features characterizing binding to the BB1 receptor, we performed the molecular modeling study consisting of the construction of a 3D model of the receptor by homology modeling followed by a docking study of the peptoids PD168368 and PD176252 onto it. Analysis of the complexes permitted us to propose prospective bound conformations of the compounds, consistent with the experimental information available. Subsequently, we defined a pharmacophore describing minimal stereochemical requirements for binding to the BB1 receptor that was used in silico screening. This exercise yielded a set of small molecules that were purchased and tested, showing affinity to the BB1 but not to the BB2 receptor. These molecules exhibit scaffolds of diverse chemical families that can be used as a starting point for the development of novel BB1 antagonists.

Synthesis and stereochemical features of tartratostannates with complex 1,10-phenanthroline cations of Fe(II), Co(II), Ni(II), Cu(II), Zn(II)

Five heterometallic mixed-ligand cation-anionic complexes perspective for creation of new effective non-toxic drugs [Fe(phen)3]2[Sn2(µ-Tart)2(H2Tart)2]·2H2O (I), [Co(phen)3]2[Sn2(µ-Tart)2(H2Tart)2]·8H2O (II), [Ni(phen)3]2[Sn2(µ-Tart)2(H2Tart)2]·2H2O (III), [Cu(phen)3]2[Sn2(µ-Tart)2(H2Tart)2]·2H2O (IV), [Zn(phen)3]2[Sn2(µ-Tart)2(H2Tart)2]·6H2O (V) with two types of ligands: ditopic polydentate tartaric acid (Tart) and cyclic bidentate 1,10-phenanthroline (phen), p-(Sn) and d-metals (Fe, Co, Ni, Cu, Zn) in their composition were synthesized. The studied complexes I–V are isostructural and contain complex anion [Sn2(µ-Tart)2(H2Tart)2]4-, polyhedrons of two Sn atoms are octahedrons, that are formed by dimeric Sn2(Tart4-)2 fragment and bidentate coordination of two terminal H2Tart2-. All cations in I-V have similar structures [Me(phen)3]2+ with Me = Fe, Co, Ni, Cu, Zn. The present study compares electronic analogues Sn (IV) and Ge (IV) and reveals structural features of the novel tartratostannates and previously obtained tartratogermanates with the same compositional units.

Computational modelling and docking insight of bacterial peptide as ideal anti-tubercular and anticancer agents

The present investigation was assessed to predict the anti-tubercular and anticancer attributes of bacterial peptide SMANF2 using in silico docking tool. Initially, the structure of peptide SMANF2 was modelled and its stereo-chemical, physiochemical, and functional parameters were determined using various computational tools. Further, in silico molecular docking between peptide and targeted proteins of Mycobacterium tuberculosis and cancer cells (lung cancer – A540 cell line; colon cancer – HT-29 cell line) were predicted using Hex 8.0.0 docking software. Results predicted good stereo-chemical, physiochemical, and functional features of peptide SMANF2. The peptide exhibited the highest negative energy value (E-value) of -747.99 kJ/mol with LysA, followed by -735.43, -631.07, -549.28, and -285.06 kJ/mol with ribonucleotide reductase, alanine racemase, DNA gyrase, and isocitrate lyase, respectively of M. tuberculosis. Among targeted proteins of A540 cell line, peptide SMANF2 revealed the highest docking score of -539.12 kJ/mol with Bcl-2. On the other hand, the peptide showed highest negative E-value of -422.70 kJ/mol with Bcl-xL among targeted HT-29 cell line. In a nutshell, this in silico study predicted the anti-tubercular and anticancer traits of peptide SMANF2 that can be used as auspicious therapeutic agent in future.

Gating mechanism of elongating \u03b2-ketoacyl-ACP synthases

Carbon-carbon bond forming reactions are essential transformations in natural product biosynthesis. During de novo fatty acid and polyketide biosynthesis, β-ketoacyl-acyl carrier protein (ACP) synthases (KS), catalyze this process via a decarboxylative Claisen-like condensation reaction. KSs must recognize multiple chemically distinct ACPs and choreograph a ping-pong mechanism, often in an iterative fashion. Here, we report crystal structures of substrate mimetic bearing ACPs in complex with the elongating KSs from Escherichia coli, FabF and FabB, in order to better understand the stereochemical features governing substrate discrimination by KSs. Complemented by molecular dynamics (MD) simulations and mutagenesis studies, these structures reveal conformational states accessed during KS catalysis. These data taken together support a gating mechanism that regulates acyl-ACP binding and substrate delivery to the KS active site. Two active site loops undergo large conformational excursions during this dynamic gating mechanism and are likely evolutionarily conserved features in elongating KSs.

Rational Design of Allosteric and Selective Inhibitors of the Molecular Chaperone TRAP1

TRAP1 is the mitochondrial paralog of the heat shock protein 90 (HSP90) chaperone family. Its activity as an energy metabolism regulator has important implications in cancer, neurodegeneration, and ischemia. Selective inhibitors of TRAP1 could inform on its mechanisms of action and set the stage for targeted drug development, but their identification was hampered by the similarity among active sites in HSP90 homologs. We use a dynamics-based approach to identify a TRAP1 allosteric pocket distal to its active site that can host drug-like molecules, and we select small molecules with optimal stereochemical features to target the pocket. These leads inhibit TRAP1, but not HSP90, ATPase activity and revert TRAP1-dependent downregulation of succinate dehydrogenase activity in cancer cells and in zebrafish larvae. TRAP1 inhibitors are not toxic per se, but they abolish tumorigenic growth of neoplastic cells. Our results indicate that exploiting conformational dynamics can expand the chemical space of chaperone antagonists to TRAP1-specific inhibitors with wide therapeutic opportunities.

Thiourea Derivative of 2-[(1R)-1-Aminoethyl]phenol: A Flexible Pocket-like Chiral Solvating Agent (CSA) for the Enantiodifferentiation of Amino Acid Derivatives by NMR Spectroscopy.

Thiourea derivatives of 2-[(1R)-1-aminoethyl]phenol, (1S,2R)-1-amino-2,3-dihydro-1H-inden-2-ol, (1R,2R)-(1S,2R)-1-amino-2,3-dihydro-1H-inden-2-ol, and (R)-1-phenylethanamine have been compared as chiral solvating agents (CSAs) for the enantiodiscrimination of derivatized amino acids using nuclear magnetic resonance (NMR) spectroscopy. Thiourea derivative, prepared by reacting 2-[(1R)-1-aminoethyl]phenol with benzoyl isothiocyanate, constitutes an effective CSA for the enantiodiscrimination of N-3,5-dinitrobenzoyl (DNB) derivatives of amino acids with free or derivatized carboxyl functions. A base additive 1,4-diazabicyclo[2.2.2]octane(DABCO)/N,N-dimethylpyridin-4-amine (DMAP)/NBu4OH) is required both to solubilize amino acid derivatives with free carboxyl groups in CDCl3 and to mediate their interaction with the chiral auxiliary to attain efficient differentiation of the NMR signals of enantiomeric substrates. For ternary systems CSA/substrate/DABCO, the chiral discrimination mechanism has been ascertained through the NMR determination of complexation stoichiometry, association constants, and stereochemical features of the diastereomeric solvates.

Стереохимические особенности кристаллизации восьмичленных 1,5-диазагетероциклов с хиральными аминоинданольными фрагментами при атомах азота

Рассмотрена в сравнении кристаллическая структура двух гидрохлоридов восьмичленных 1,5-диазагетероциклов с хиральными аминоинданольными фрагментами одинаковой конфигурации при атомах азота. Несмотря на химическую и стереохимическую идентичность половин молекул диазагетероциклов, в кристаллах эти соединения реализуются не в частном положении на оси второго порядка, а в общем положении. В качестве причин асимметризации молекул в кристалле рассмотрены следующие: конформация восьмичленного гетероцикла, избирательное протонирование одного из двух атомов азота, расположение противоиона и сольватной молекулы в ячейке, неэквивалентная система водородных связей.

Stereochemical Features of the Crystallization of Eight-Membered 1,5-Diazaheterocycles with Chiral Aminoindanole Fragments at Nitrogen Atoms

The work juxtaposes crystal structures of two hydrochlorides of eight-membered 1,5-diazaheterocycles with chiral aminoindanole fragments located at the nitrogen atoms and having similar configurations. In spite of chemical and stereochemical identity of a half of diazaheterocycle molecules, in crystals these compound are realized in the general position rather than the special position on the twofold axis of rotation. The following reasons are considered to be responsible for the asymmetrization of the molecules in the crystal: conformation of the eight-membered heterocycle, selective protonation of only one of two nitrogen atoms, positions of the counter-ion and the solvent molecule within the unit cell, and a nonequivalent system of hydrogen bonds.

Synthesis and stereoisomerism of [n]cyclo-2,9-phenanthrenylene congeners possessing alternating E/Z- and R/S-biaryl linkages.

The synthesis and cyclostereoisomerism of [n]cyclo-2,9-phenanthrenylenes ([n]CPhen2,9, n = 4, 6 and 8), possessing hybrid E/Z- and R/S-biaryl linkages, were elaborated. The dimer of a phenanthrene derivative was used as a starting material and underwent Ni-mediated Yamamoto-type coupling to afford [6]CPhen2,9 as a major cyclic product, as well as [4]CPhen2,9 and [8]CPhen2,9 as minor products. The stereoisomers of [n]CPhen2,9 were isolated and characterized, and the number of stereoisomers indicated that E/Z linkages did not provide any experimentally separable isomers, whereas the chirality in [n]CPhen2,9 originated from the intrinsic axial chirality at constrained R/S linkages. Theoretical calculations predicted that the 2,2'-linkages in [n]CPhen2,9 adopted a fixed Z- or E-configuration, which suggested a novel type of dynamics of atropisomerism in contrast to the reported rigid or flexible behavior. This study enriches our understanding of the stereochemical features of E/Z linkages in aromatic macrocycles.

Neurokinin-1 Receptor Antagonists as Anticancer Drugs

Background::Human tumor cells lines and tumor samples overexpress the neurokinin-1 receptor (NK-1R). Substance P (SP), after binding to NK-1Rs, induces tumor cell proliferation, an antiapoptotic effect and promotes angiogenesis and the migration of cancer cells for invasion and metastasis.Methods: :In contrast, NK-1R antagonists block the previous pathophysiological actions mediated by SP. These antagonists promote the death of tumor cells by apoptosis. Peptide and non-peptide NK-1R antagonists have been reported.Results: :Peptide NK-1R antagonists show chemical modifications of the SP molecule (L-amino acids being replaced by D-amino acids), whereas non-peptide NK-1R antagonists include numerous compounds with different chemical compositions while showing similar stereochemical features (affinity for the NK- 1R). Currently, there are more than 300 NK-1R antagonists.Conclusion::In combination therapy with classic cytostatics, NK-1R antagonists have additive or synergic effects and minimize the side-effects of cytostatics. The effect of NK-1R antagonists as broad-spectrum anticancer drugs is reviewed and the use of these antagonists for the treatment of cancer is suggested.

Progress towards the Total Syntheses of Lycopodium Alkaloid, Lycopladine A

AbstractSeveral alkaloids derived from discrete Lycopodium species can treat Alzheimer's disease and increase the efficiency of learning and memory in animals. Thus, Lycopodium alkaloids bearing amazingly unique hetero‐polycyclic ring scaffolds persuaded scientists to look upon its biogenetic and biosynthetic pathways and to design its ambitious total syntheses. Recently, a C16N type Lycopodium alkaloid, (+)‐lycopladine A; isolated from the club moss Lycopodium complanatum, showed selective but modest cytotoxicity towards murine lymphoma L1210 cells (IC50 7 μg/mL). Owing to its dense array of stereochemical features, as well as intriguing biological activity, lycopladine A has been an important synthetic target for last 12 years. An overview of the synthetic studies of lycopladine A is presented, covering literature from 2006 until March 2019.

Interaction of S,N-Derivatives of Alkylhydrazines with Carbon Sorbents

S,N-derivatives of alkylhydrazines, including 1,1-dimethylhydrazine, have been synthesized for the quantitative analysis of trace impurities of hydrazines in environmental objects. The molecular-statistical method has been used to calculate the thermodynamic characteristics of their adsorption on graphitic thermal carbon black. The dependences of the thermodynamic functions of S,N-derivatives of alkylhydrazines on their molecular mass and stereochemical features of hydrocarbon radicals have been found. The results have been compared with experimental data obtained by liquid chromatography when studying the interaction of S,N-derivatives of 1,1-dimethylhydrazine with Hypercarb graphitic carbon sorbent.

First total synthesis of (±)-floribundane B: An approach based on Johnson-Claisen rearrangement of a Morita-Baylis-Hillman adduct

The first total synthesis of (±)-floribundane B is reported. Johnson-Claisen rearrangement of a Morita-Baylis-Hillman adduct assembled all of the stereochemical features of this secoiridoid. The formal synthesis of (±)-oleocanthal and the synthesis of a chemical constituent of olive press juice is also reported.

Diastereodivergent Enantioselective [8 + 2] Annulation of Tropones and Enals Catalyzed by N-Heterocyclic Carbenes.

N-Heterocyclic carbene catalysts are used for the first time to mediate asymmetric [8 + 2] cycloadditions of enals with tropones. The kinetic [8 + 2] cis-cycloadducts can be epimerized to their trans analogues by simply using increased amounts of base and longer reaction times. Substituted tropones are also tolerated, and the cycloaddition products can be derivatized by hydrogenation or methanolysis. The main stereochemical features of the process have been rationalized by microkinetic modeling based on the results of DFT calculations.