Steric Features Research Articles

π‐Extended DPCB for Activation‐Free Homogeneous Gold Catalysis

AbstractThe catalytic properties of bis[chlorogold(I)] complexes that bear the 3,4‐bis(2,4,6‐tri‐tert‐butylphenyl)‐3,4‐diphosphinidenecyclobutene (DPCB) ligand could be improved by suitable extension of the π‐conjugation. If the 1‐naphthyl substituent was employed in the 1,2‐positions in the kinetically stabilized DPCB skeleton, high catalytic activity of the DPCB‐bis(chlorogold) complex was induced in the intermolecular alkoxycyclization of 1,6‐enyne without activation by a Ag cocatalyst. DFT calculations of the 1,2‐diaryl‐substituted DPCB derivatives indicated that both suitable energetic reduction of the LUMO level and steric characteristics of the ligand structure are important for the high catalytic activity. The optimized 1‐naphthyl‐substituted DPCB‐chlorogold(I) complex was further employed for catalytic intramolecular cyclizations to afford heterocyclic structures by the activation of terminal acetylene and allene moieties and the hydration of terminal acetylene under the mild conditions.

Fine-tuning the energy barrier for metal-mediated dinitrogen N≡N bond cleavage.

Experimental data support a mechanism for N≡N bond cleavage within a series of group 5 bimetallic dinitrogen complexes of general formula, {Cp*M[N((i)Pr)C(R)N((i)Pr)]}2(μ-N2) (Cp* = η(5)-C5Me5) (M = Nb, Ta), that proceeds in solution through an intramolecular "end-on-bridged" (μ-η(1):η(1)-N2) to "side-on-bridged" (μ-η(2):η(2)-N2) isomerization process to quantitatively provide the corresponding bimetallic bis(μ-nitrido) complexes, {Cp*M[N((i)Pr)C(R)N((i)Pr)](μ-N)}2. It is further demonstrated that subtle changes in the steric and electronic features of the distal R-substituent, where R = Me, Ph and NMe2, can serve to modulate the magnitude of the free energy barrier height for N≡N bond cleavage as assessed by kinetic studies and experimentally derived activation parameters. The origin of the contrasting kinetic stability of the first-row congener, {Cp*V[N((i)Pr)C(Me)N((i)Pr)]}2(μ-η(1):η(1)-N2) toward N≡N bond cleavage is rationalized in terms of a ground-state electronic structure that favors a significantly less-reduced μ-N2 fragment.

Ancillary Ligand Effects on Carbon Dioxide-Ethylene Coupling at Zerovalent Molybdenum

A series of zerovalent molybdenum complexes bearing triphosphine ligands, [Ar2PCH2CH2]2PPh, have been synthesized and evaluated for reductive functionalization of CO2 with ethylene. The ability to form dimeric triphosphine molybdenum(II) acrylate hydride species from CO2-ethylene coupling was found to be highly sensitive to steric encumbrance on the phosphine aryl substituents. Trapping of triphosphine molybdenum(II) acrylate hydride species using triphenylphosphine afforded isolable monomeric CO2 functionalization products with all ancillary ligands studied. Kinetic analysis of the acrylate formation reaction revealed a first-order dependence on molybdenum, but no influence from CO2 pressure or the triphenylphosphine trap. Systematic attenuation of steric and electronic features of the triphosphine ligands showed a strong CO2 functionalization rate influence for ligand size with [(3,5-tBu-C6H3)2PCH2CH2]2PPh coupling nearly four times slower than with [(3,5-Me-C6H3)2PCH2CH2]2PPh. A considerably milder electronic effect was observed with complexes bearing [(4-F-C6H4)2PCH2CH2]2PPh reducing CO2 at approximately half the rate as with [Ph2PCH2CH2]2PPh.

Understanding electrostatic and steric requirements related to hypertensive action of AT(1) antagonists using molecular modeling techniques.

AT1 receptor is an interesting biological target involved in several important diseases, such as blood hypertension and cardiovascular pathologies. In this study we investigated the main electrostatic and steric features of a series of AT1 antagonists related to hypertensive activity using structure and ligand-based strategies (docking and CoMFA). The generated 3D model had good internal and external consistency and was used to predict the potency of an external test set. The predicted values of pIC50 are in good agreement with the experimental results of biological activity, indicating that the 3D model can be used to predict the biological property of untested compounds. The electrostatic and steric CoMFA maps showed molecular recognition patterns, which were analyzed with structure-based molecular modeling studies (docking). The most and the least potent compounds docked into the AT1 binding site were subjected to molecular dynamics simulations with the aim to verify the stability and the flexibility of the ligand-receptor interactions. These results provided valuable insights on the electronic/structural requirements to design novel AT1 antagonists.

Centmitor-1, a novel acridinyl-acetohydrazide, possesses similar molecular interaction field and antimitotic cellular phenotype as rigosertib, on 01910.Na.

Mitosis is an attractive target for the development of new anticancer drugs. In a search for novel mitotic inhibitors, we virtually screened for low molecular weight compounds that would possess similar steric and electrostatic features, but different chemical structure than rigosertib (ON 01910.Na), a putative inhibitor of phosphoinositide 3-kinase (PI3K) and polo-like kinase 1 (Plk1) pathways. Highest scoring hit compounds were tested in cell-based assays for their ability to induce mitotic arrest. We identified a novel acridinyl-acetohydrazide, here named as Centmitor-1 (Cent-1), that possesses highly similar molecular interaction field as rigosertib. In cells, Cent-1 phenocopied the cellular effects of rigosertib and caused mitotic arrest characterized by chromosome alignment defects, multipolar spindles, centrosome fragmentation, and activated spindle assembly checkpoint. We compared the effects of Cent-1 and rigosertib on microtubules and found that both compounds modulated microtubule plus-ends and reduced microtubule dynamics. Also, mitotic spindle forces were affected by the compounds as tension across sister kinetochores was reduced in mitotic cells. Our results showed that both Cent-1 and rigosertib target processes that occur during mitosis as they had immediate antimitotic effects when added to cells during mitosis. Analysis of Plk1 activity in cells using a Förster resonance energy transfer (FRET)-based assay indicated that neither compound affected the activity of the kinase. Taken together, these findings suggest that Cent-1 and rigosertib elicit their antimitotic effects by targeting mitotic processes without impairment of Plk1 kinase activity.

Microporous Carbon and Mesoporous Silica by Use of Twin Polymerization: An Integrated Experimental and Theoretical Approach to Precursor Reactivity

AbstractSpirocyclic silicon alkoxides were synthesized by reaction of Si(OMe)4 with derivatives of salicylic alcohol and studied by in situ differential scanning calorimetry with regard to twin polymerization (TP). Both, thermally induced and proton‐assisted TP gave nanostructured hybrid materials composed of a phenolic resin and silica. Carbonization and subsequent treatment with HF(aq) resulted in microporous carbon, whereas oxidation in air provided mesoporous silica. DFT calculations were performed to obtain a more detailed insight into the first reaction steps of proton‐assisted TP and to support the hypothesis of a reactivity scale based on steric and electronic features of the silicon‐containing precursors (twin monomers). The calculated reaction barriers for the initial reaction steps of proton‐assisted TP are qualitatively in accordance with the Hammett constants of the substituents at the salicylate moiety. This result offers a simple method to predict the reactivity for twin monomers.

Evaluation and SAR analysis of the cytotoxicity of tanshinones in colon cancer cells

AimThis study was designed to evaluate the anti-cancer actions of tanshinone I and tanshinone IIA, and six derivatives of tanshinone IIA on normal and cancerous colon cells. Structure activity relationship (SAR) analysis was conducted to delineate the significance of the structural modifications of tanshinones for improved anti-cancer action. MethodTanshinone derivatives were designed and synthesized according to the literature. The cytotoxicity of different compounds on colon cancer cells was determined by the MTT assay. Apoptotic activity of the tanshinones was measured by flow cytometry (FCM). ResultsTanshinone I and tanshinone IIA both exhibited significant cytotoxicity on colon cancer cells. They are more effective in p53+/+ colon cancer cell line. It was also noted that the anti-cancer activity of tanshinone I was more potent and selective. Two of the derivatives of tanshinone IIA (N1 and N2) also exhibited cytotoxicity on colon cancer cells. ConclusionThe anti-colon cancer activity of tanshinone I was more potent and selective than tanshinone IIA, and is p53 dependent. The derivatives obtained by structural modifications of tanshinone IIA exhibited lower cytotoxicity on both normal and colon cancer cells. From steric and electronic characteristics point of view, it was concluded that structural modifications of ring A and furan or dihydrofuran ring D on the basic structure of tanshinones influences the activity. An increase of the delocalization of the A and B rings could enhance the cytotoxicity of such compounds, while a non-planar and small sized D ring region would provide improved anti-cancer activity.

Pharmacophore and 3D QSAR Study of TGFβ Inhibitors

In the present study, 3D-QSAR analysis was performed on a set of 37 TGF-β inhibitors utilizing pharmacophore based alignment to uncover the essential structural and steric features of these newly discovered b-annulated 1,4- dihydropyridine (1,4-DHP) molecules to get better antagonism of the TGF-β receptor. The best 3D-QSAR model identified with PLS factor 4 that had the highest values of external predictability parameters exhibited Q2 (0.8972), and R2 (0.9826) and displayed high values of F (281.9) and low SD (0.0785). This selected model was validated statistically by determining Pearson-r (0.9718) for test set molecules. Contours thus obtained from different properties generated using our QSAR model explained the variation in the activity of dataset with respect to different attachments in the core structure. This would help to make suitable structural modifications in 1, 4-DHP molecules so as to make a better complementary fit to the active site of TGF-β receptor, which in turn would improve the potency of newly designed molecules.

Conformation of polydispersed chains grafted on nanoparticles

The conformations of polydispersed polymer chains grafted on nanoparticles (NPs) are investigated by coarse-grained molecular dynamics simulations. Combined with the geometric and steric features, we find that most results can be understood by analysing the excluded volume interaction condition of the accommodated chains. By controlling suitable NP size and grafting density, as well as designing a suitable route for preparing the grafted chains with controllable polydispersity and length, it is possible to obtain polymer chains with various conformations, which may be greatly helpful for improving the dispersion of the grafted NPs in the polymer matrix. These results shed light on improved designs of grafted NPs and a better control of dispersion in polymer matrices for promoting the performance of polymer nanocomposite materials.

ChemInform Abstract: Copper‐Catalyzed Asymmetric Hydrogenation of Aryl and Heteroaryl Ketones.

High throughput screening enabled the development of a Cu-based catalyst system for the asymmetric hydrogenation of prochiral aryl and heteroaryl ketones that operates at H2 pressures as low as 5 bar. A ligand combination of (R,S)-N-Me-3,5-xylyl-BoPhoz and tris(3,5-xylyl)phosphine provided benzylic alcohols in good yields and enantioselectivities. The electronic and steric characteristics of the ancillary triarylphosphine were important in determining both reactivity and selectivity.

Probing the Steric and Electronic Characteristics of a New Bis-Pyrrolide Pincer Ligand

A new pincer ligand is synthesized to be dianionic, with the potential to be redox active. It has pyrrrole rings attached to both ortho sites of a pyridine, as the linking element. This H2L can be doubly deprotonated and then used to replace two chloride ligands in MCl2(NCPh)2, to form LM(NCPh) for M = Pd, Pt. The acid form H2L reacts with ZnEt2 with elimination of only 1 mol of ethane to yield (HL)ZnEt, a three-coordinate species with one pendant pyrrole NH functionality. This molecule binds the Lewis base p-dimethylaminopyridine (DMAP) to give first a simple 1:1 adduct that eliminates ethane on heating to form four-coordinate LZn(DMAP), which has an unusual structure due to the strong preference of the pincer ligand to bind in a mer (planar) geometry. A molecule with two HL(-) ligands each bonded in a bidentate manner to FeCl2 is synthesized and shown to contain four-coordinate iron with a flattened-tetrahedral structure. The electrochemistry of LM(NCPh) and (L)Zn(DMAP) shows three oxidation processes, which is interpreted to involve at least two oxidations of the pyrrolide arms.

Molecular modelling and quantitative structure-activity relationship studies of anatoxin-a and epibatidine derivatives with affinity to rodent nAChR receptors

AbstractAnatoxin-a and epibatidine are natural toxins with a high affinity to nicotinic acetylcholine receptors (nAChR). Nicotinic ligands have the potential to become novel therapeutic agents for various cognitive disorders such as Alzheimer’s and Parkinson’s diseases. The determination of the physicochemical and biological properties of anatoxin-a and epibatidine derivatives is important because these might lead to the development of new cholinergic therapeutic agents. To study these features, the toxins and a set of their derivatives were subjected to a molecular modelling study and QSAR analysis. The structural analyses indicated that the geometric and steric features are important determinants of the compound’s activities. The descriptors selected for the QSAR model also highlighted the roles of the geometric and steric features, together with the importance of electronic features.

ChemInform Abstract: Stereocontrolled Synthesis of 1,3‐Diamino‐2‐ols by Aminohydroxylation of Bicyclic Methylene‐Aziridines.

Nitrogen-containing stereotriads, which are defined as compounds with three adjacent stereodefined carbon atoms, are common structural motifs in several biologically relevant compounds. The 1,3-diamino-2-ol motif in particular is an important pharmacophore for which there are limited stereoselective synthetic approaches. In this communication, we describe the aminohydroxylation of a series of bicyclic methylene-aziridines obtained from the aziridination of a series of homoallenic carbamates. The unusual electronic and steric features of these useful heterocyclic scaffolds render the Os-catalyzed aminohydroxylation of the exocyclic alkene highly regio- and stereoselective. Rearrangement of the proposed N,O-aminal intermediate to a 1,3-diamino-2-one is followed by reduction with NaBH4 to deliver the desired 1,3-diamino-2-ols in good yields with high diastereomeric ratios.

Copper-Catalyzed Asymmetric Hydrogenation of Aryl and Heteroaryl Ketones

High throughput screening enabled the development of a Cu-based catalyst system for the asymmetric hydrogenation of prochiral aryl and heteroaryl ketones that operates at H2 pressures as low as 5 bar. A ligand combination of (R,S)-N-Me-3,5-xylyl-BoPhoz and tris(3,5-xylyl)phosphine provided benzylic alcohols in good yields and enantioselectivities. The electronic and steric characteristics of the ancillary triarylphosphine were important in determining both reactivity and selectivity.

Unsupervised selection of informative descriptors in QSAR study of anti-HIV activities of HEPT derivatives

With the increasing ease of measuring and calculating multiple descriptors per molecule in quantitative structure–activity relationship, the importance of variable selection for data reduction and improving interpretability is gaining importance. While variable selection has been extensively studied in the context of supervised learning, in this paper, an unsupervised learning method is proposed for variable selection and its performance is assessed using a typical QSAR data set. Whereas there is no real dependent variable in the proposed variable selection algorithm, applied variable selection is unsupervised indeed. Besides, scores that are the linear combination of the data variables are set as dependent variables (artificial dependent variables). It includes 107 derivatives of HEPT molecule, characterized by 160 descriptors encoding the steric, hydrophobic, electronic and structural features of HEPT derivatives. The aims of this procedure are generating a subset of descriptors from a data set with the relevant variables, eliminating redundancy, and reducing multicollinearity. The core of this methodology is based on jack-knife resampling method. In this paper, using jack-knife led to selection of 48 out of 160 initial descriptors, so that the data information was preserved. Lastly, using influence effect on prediction resulted in eight descriptors as representative of the 160 descriptors. Constructed model with final 8 descriptors has Q2IN=0.67, R2=0.74, Q2EXT=0.85. It represents adequacy of our strategy for preserving data structure.

Simulating movement of tRNA through the ribosome during hybrid-state formation

Biomolecular simulations provide a means for exploring the relationship between flexibility, energetics, structure, and function. With the availability of atomic models from X-ray crystallography and cryoelectron microscopy (cryo-EM), and rapid increases in computing capacity, it is now possible to apply molecular dynamics (MD) simulations to large biomolecular machines, and systematically partition the factors that contribute to function. A large biomolecular complex for which atomic models are available is the ribosome. In the cell, the ribosome reads messenger RNA (mRNA) in order to synthesize proteins. During this essential process, the ribosome undergoes a wide range of conformational rearrangements. One of the most poorly understood transitions is translocation: the process by which transfer RNA (tRNA) molecules move between binding sites inside of the ribosome. The first step of translocation is the adoption of a "hybrid" configuration by the tRNAs, which is accompanied by large-scale rotations in the ribosomal subunits. To illuminate the relationship between these rearrangements, we apply MD simulations using a multi-basin structure-based (SMOG) model, together with targeted molecular dynamics protocols. From 120 simulated transitions, we demonstrate the viability of a particular route during P/E hybrid-state formation, where there is asynchronous movement along rotation and tRNA coordinates. These simulations not only suggest an ordering of events, but they highlight atomic interactions that may influence the kinetics of hybrid-state formation. From these simulations, we also identify steric features (H74 and surrounding residues) encountered during the hybrid transition, and observe that flexibility of the single-stranded 3'-CCA tail is essential for it to reach the endpoint. Together, these simulations provide a set of structural and energetic signatures that suggest strategies for modulating the physical-chemical properties of protein synthesis by the ribosome.

Conformationally Armed 3,6-Tethered Glycosyl Donors: Synthesis, Conformation, Reactivity, and Selectivity

The reactivity and selectivity of 3,6-tethered glycosyl donors have been studied using acceptors with different steric and electronic characteristics. Eight (four anomeric pairs) 3,6-bridged-glycosyl donors were synthesized in high yields from their common parent sugars. The glycosylation properties were tested using at least three different acceptors and several promoter systems. Thiophenyl 2,4-di-O-benzyl-3,6-O-(di-tert-butylsilylene)-α-D-glucopyranoside gave α/β mixtures with standard NIS/TfOH mediated activation, whereas the corresponding fluoride was found to be highly β-selective, when using SnCl2/AgB(C6F5)4 as the promoter system. Mannosyl donors were highly α-selective despite the altered conformation. Galactosylations using NIS/TfOH were generally α-selective, but more β-selective using the galactosyl fluoride and depending on the acceptor used. Thiophenyl 2-azido-2-deoxy-4-O-benzyl-3,6-O-(di-tert-butylsilylene)-α-D-glucopyranoside was found to be α-selective. The reactivity of the donors was investigated using competition experiments, and some but not all were found to be highly reactive. Generally it was found that the α-thioglycosides were significantly more reactive than the β; this difference in reactivity was not found for 3,6-anhydro-, armed-(benzylated), or the classic super armed (silylated) donors. A mechanism supporting the unusual observations has been suggested.

Crystal Structure of a Human Prion Protein Fragment Reveals a Motif for Oligomer Formation

The structural transition of the prion protein from α-helical- to β-sheet-rich underlies its conversion into infectious and disease-associated isoforms. Here we describe the crystal structure of a fragment from human prion protein consisting of the disulfide-bond-linked portions of helices 2 and 3. Instead of forming a pair-of-sheets steric zipper structure characteristic of amyloid fibers, this fragment crystallized into a β-sheet-rich assembly of hexameric oligomers. This study reveals a never before observed structural motif for ordered protein aggregates and suggests a possible mechanism for self-propagation of misfolded conformations by such nonamyloid oligomers.

Stereocontrolled Synthesis of 1,3‐Diamino‐2‐ols by Aminohydroxylation of Bicyclic Methylene‐Aziridines

AbstractNitrogen‐containing stereotriads, which are defined as compounds with three adjacent stereodefined carbon atoms, are common structural motifs in several biologically relevant compounds. The 1,3‐diamino‐2‐ol motif in particular is an important pharmacophore for which there are limited stereoselective synthetic approaches. In this communication, we describe the aminohydroxylation of a series of bicyclic methylene‐aziridines obtained from the aziridination of a series of homoallenic carbamates. The unusual electronic and steric features of these useful heterocyclic scaffolds render the Os‐catalyzed aminohydroxylation of the exocyclic alkene highly regio‐ and stereoselective. Rearrangement of the proposed N,O‐aminal intermediate to a 1,3‐diamino‐2‐one is followed by reduction with NaBH4 to deliver the desired 1,3‐diamino‐2‐ols in good yields with high diastereomeric ratios.

High Specificity in Response of the Sodium-Dependent Multivitamin Transporter to Derivatives of Pantothenic Acid

Essential nutrients are attractive targets for the transport of biologically active agents across cell membranes, since many are substrates for active cellular importation pathways. The sodium-dependent multivitamin transporter (SMVT) is among the best characterized of these, and biotin derivatives have been its most popular targets. We have surveyed 45 derivatives of pantothenic acid, another substrate of SMVT, long known as a competitive inhibitor of biotin transport. Variations of the β-alanyl fragment of pantothenate were uniformly rejected by the transporter, including derivatives with very similar steric and acidic characteristics to the natural substrate. The secondary hydroxyl of the 2,2-dimethyl-1,3-propanediol (pantoyl) fragment was the only position at which potential linkers could be attached while retaining activity as an inhibitor of biotin uptake and a substrate for sodium-dependent transport. However, triazole conjugates to several drug-like cargo motifs were not accepted as substrates by human SMVT in cell culture. Two compounds were observed which did not inhibit biotin uptake but were themselves transported in a sodium-dependent fashion, suggesting more complex behavior than expected. These studies represent the most extensive examination to date of pantothenate as an anchor for SMVT-mediated drug delivery, showing that this route requires further investigation before being judged promising.