CD‐sensitive Zn‐porphyrin tweezer host‐guest complexes,part 2: Cis‐ and trans‐3‐hydroxy‐4‐aryl/alkyl‐β‐lactams. A case study

This article describes an application of the host‐guest chiral recognition approach called tweezer methodology for the determination of the absolute configuration of 3‐hydroxy‐β‐lactams. These substrates represent challenging cases due to their chemical reactivity, the presence of multiple stereogenic centers and several functional groups which offer various possibilities of binding to the Zn‐porphyrin host. OPLS‐2005, the force field used in this work to predict the interporphyrin twist, modeled correctly the host‐guest complexation mechanism and revealed conformational details of the bound substrates. The computational study also suggested that in cases where an increase in the magnitude of the stereodifferentiation and an intense experimental CD are observed, the bound conformation of the conjugates are hydrogen bonded. The present investigation provides evidence that when the tweezer method is assisted by the OPLS‐2005 based computational approach, it can be successfully applied to the configurational and conformational elucidation of multi‐functional compounds with multiple stereogenic centers. Chirality, 2010. © 2009 Wiley‐Liss, Inc.     

Bulky melamine-based Zn-porphyrin tweezer as a CD probe of molecular chirality

The transfer of chirality from a guest molecule to an achiral host is the subject of significant interest especially when, upon chiral induction, the chiroptical response of the host/guest complex can effectively report the absolute configuration (AC) of the guest. For more than a decade, dimeric metalloporphyrin hosts (tweezers) have been successfully applied as chirality probes for determination of the AC for a wide variety of chiral synthetic compounds and natural products. The objective of this study is to investigate the utility of a new class of melamine-bridged Zn-porphyrin tweezers as sensitive AC reporters. A combined approach based on an experimental CD analysis and a theoretical prediction of the prevailing interporphyrin helicity demonstrates that these tweezers display favorable properties for chiral recognition. Herein, we discuss the application of the melamine-bridged tweezer to the chiral recognition of a diverse set of chiral guests, such as 1,2-diamines, α-amino-esters and amides, secondary alcohols, and 1,2-amino-alcohols. The bulky periphery and the presence of a rigid porphyrin linkage lead, in some cases, to a more enhanced CD sensitivity than that reported earlier with other tweezers.     

Chiral recognition of cyclic alpha-hydroxyketones by CD-sensitive zinc tetraphenylporphyrin tweezer

A combined chemical/chiroptical microscale protocol for the determination of absolute configurations of cyclic alpha-hydroxyketones is described. The hydroxyl group in cyclic alpha-hydroxyketones is converted into (3-aminopropylamino)acetate (NH2CH2CH2CH2NHCH2COOR), or more generally, according to a newly developed protocol, into (3-hydroxypropylamino)acetate group (HOCH2CH2CH2NHCH2COOR). The resultant conjugated compound forms a 1:1 host-guest complex with a dimeric zinc porphyrin tweezer, which exhibits exciton-coupled bisignate CD spectrum centered around the 420-nm porphyrin Soret band due to induced helicity between the two porphyrins in the complex. The absolute configurations of the alpha-stereogenic center is then determined by comparison of the sign of the observed CD exciton couplet of the complex with that of the preferred porphyrin twist predicted by the Merck Molecular Force Field (MMFFs) method.     

Enantioselective complexation of 1‐phenylethanol with chiral compounds bearing urea moiety

A detailed study of diastereomeric complexes of chiral ureido‐1,1′‐binaphthalene derivatives with chiral 1‐phenylethanol showed that a derivative bearing only one urea unit makes five times more stable complex with (S)‐enantiomer than with (R)‐enantiomer of the alcohol. This phenomenon could be used in chiral discrimination processes. The influence of individual parts of the structure on the complexation properties is shown. The probable structure of diastereomeric complexes based on experimental results and computational methods is proposed.     

Enantioseparation of Four Organophosphonate Derivatives on N‐(3,5‐Dinitrobenzoyl)‐ l‐leucine–n‐Propylamide Stationary Phase by Molecular Modeling

Four groups of organophosphonate derivatives enantiomers were separated on N‐(3,5‐dinitrobenzoyl)‐S‐leucine chiral stationary phase. The three‐dimensional structures of the complexes between the single enantiotopic chiral compounds and chiral stationary phase have been studied using molecular model and molecular dynamics simulation. Detailed results regarding the conformation, auto‐docking, and thermodynamic estimation are presented. The elution order of the enantiomer could be determined from the energy. The predicted chiral discrimination was obtained by computational results. Chirality 25:101–106, 2013. © 2012 Wiley Periodicals, Inc.     

HPLC‐ECD and TDDFT‐ECD study of hexahydropyrrolo[1,2‐a]quinoline derivatives

Synthesis of racemic hexahydropyrrolo[1,2‐a]quinoline derivatives ( 1 ‐ 8 ) was performed by utilizing the Knoevenagel‐[1,5]‐hydride shift‐cyclization domino reaction. Separation of the enantiomers of the chiral products ( 1 ‐ 8 ) was carried out by chiral high‐performance liquid chromatography, and online high‐performance liquid chromatography‐electronic circular dichroism (ECD) spectra were recorded to elucidate the absolute configuration by comparing the experimental and time‐dependent density functional theory‐ECD spectra obtained at various theoretical levels. For 1 of the products, the time‐dependent density functional theory‐ECD calculations allowed determining both the relative and the absolute configuration by distinguishing the 4 stereoisomers. One of the compounds with spiro 1,3‐cyclohexanedione moiety ( 7 ) possessed moderate acetylcholinesterase inhibitory activity, while 3 showed neuroprotective activity in oxygen‐glucose deprivation‐induced neurotoxicity in human neuroblastoma SH‐SY5Y cells.     

NMR chiral discrimination of chalcogen containing secondary alcohols

Here, we report the general strategies by which NMR spectroscopy can be used to determine the enantiopurity and absolute configuration of chalcogen containing secondary alcohols, including the evaluation of the use of chiral solvating and chiral derivatizing agents. The BINOL/DMAP ternary complex demonstrated a simple and fast protocol for determining enantiopurity. The drug Naproxen afforded a stable, nonhygroscopic, and readily available chiral derivatizing agent (CDA) for NMR chiral discrimination of chalcogen containing secondary alcohols. The chiral recognition by CDA and chiral solvating agent (CSA) was assessed using ¹H, ⁷⁷Se‐{1H}, and ¹²⁵Te‐{1H} NMR spectroscopy. A simple model for the assignment of the absolute configuration from NMR data is presented.     

A computational approach for studying antibody–antigen interactions without prior structural information: the anti‐testosterone binding antibody as a case study

Given the increasing exploitation of antibodies in different contexts such as molecular diagnostics and therapeutics, it would be beneficial to unravel the atomistic level properties of antibody‐antigen complexes with the help of computational modeling. Thus, here we have studied the feasibility of computational tools to gather atomic scale information regarding the antibody‐antigen complexes solely starting from an amino acid sequence. First, we constructed a homology model for the anti‐testosterone binding antibody based on the knowledge based classification of complementary determining regions (CDRs) and implicit solvent molecular dynamics simulations. To further examine whether the generated homology model is suitable for studying antibody‐antigen interactions, docking calculations were carried out followed by binding free‐energy simulations. Our results indicate that with the antibody modeling approach presented here it is possible to construct accurate homology models for antibodies which correctly describes the antibody‐antigen interactions, and produces absolute binding free‐energies that are comparable with experimental values. In addition, our simulations suggest that the conformations of complementary determining regions (CDRs) may considerably change from the X‐ray configuration upon solvation. In conclusion, here we have introduced an antibody modeling workflow that can be used in studying the interactions between antibody and antigen solely based on an amino acid sequence, which in turn provides novel opportunities to tune the properties of antibodies in different applications. Proteins 2017; 85:322–331. © 2016 Wiley Periodicals, Inc.     

Enantiodiscrimination of methamphetamine by circular dichroism using a porphyrin tweezer

Using exciton‐coupled circular dichroism (ECCD) spectroscopy, our lab was able to differentiate between the two enantiomers of methamphetamine using a commercially available porphyrin tweezer as an achiral host. The host–guest complex formed with (+)‐(S)‐methamphetamine produced a negative bisignate‐shaped ECCD spectrum, whereas the complex formed with (?)‐(R)‐methamphetamine produced a positive one. This sensitive technique could serve as an alternative method for the enantiodiscrimination of chiral methamphetamine, a commonly abused drug in the United States. Chirality 2010. © 2009 Wiley‐Liss, Inc.     

Synthesis and Characterization of Conformationally Rigid Chiral Pyridine–N‐Heterocyclic Carbene‐Based Palladacycles with an Unexpected Pd–N Bond Cleavage

The versatility of a previously developed method for the synthesis of chiral carbene‐based palladacycles is demonstrated through the synthesis of two new chiral pyridine‐functionalized N‐heterocyclic carbene palladacycles with different wingtip groups. The efficiency in their resolution with different counter anions and different chiral amino acid salt auxiliaries has been studied. The absolute stereochemistries of all the chiral compounds were confirmed by single crystal X‐ray crystallography. An unexpected Pd–N bond cleavage that resulted in the racemization of the α‐carbon center in these complexes has also been investigated. Chirality 25:149–159, 2013. © 2013 Wiley Periodicals, Inc.     

Determination of the Absolute Configuration of Two Pairs of C‐8 − C‐9′ Linked Neolignan Enantiomers

Two pairs of new neolignan enantiomers, (±)‐torreyayunan A ( 1a / 1b ) and (±)‐torreyayunan B ( 2a / 2b ), featuring a rare C‐8 ? C‐9′ linked skeleton, were isolated from leaves and twigs of Torreya yunnanensis. Their absolute configuration involving two chiral centers was determined by combined spectral and Density Functional Theory (DFT) calculation. This is the first report of the absolute configuration of this group of neolignans. Chirality 26:825–828, 2014. © 2014 Wiley Periodicals, Inc.     

Amino acids as chiral derivatizing agents for antiproliferative substituted N‐benzyl isoindolinones

The absolute configurations of the diastereomers of novel amino acid ester derivatives of 2,3‐substituted isoindolinones, which are known as apoptosis activators due to their ability to inhibit the MDM2‐p53 PPI, were assigned using NMR and computational methods. Procedures for diastereomer separation and determining the absolute configuration were developed to perform the study. The high significance of N‐benzyl fragment for the determination of the diastereomer absolute configuration by NMR methods was established; it is determined by a number of factors inherent in this fragment and the structural features of the studied substrates. Analysis of the individual isomer activity showed that the target inhibitory effect of S‐ and R‐isoindolinone L‐valinates differs by less than 20%. It can be explained by the presence of a flexible linker between the isoindolinone core and amino acid fragment, which provides the optimal arrangement of the molecule in the hydrophobic cavity of MDM2 for both isomers.     

Semipreparative HPLC enantioseparation,chiroptical properties,and absolute configuration of two novel cyclooxygenase‐2 inhibitors

A direct semipreparative HPLC enantioseparation of two chiral thiazolidinone derivatives having cyclooxygenase‐2 inhibition activity was performed on the Chiralpak IA chiral stationary phase. Semipreparative amounts of enantiopure forms were collected using acetonitrile‐ethanol‐trifluoroacetic acid mixtures as mobile phase. The absolute configuration of both compounds was unequivocally established by single‐crystal X‐ray diffraction method and correlated to the chiroptical properties of isolated enantiomers. Chirality, 2010. © 2009 Wiley‐Liss, Inc.     

Determination of absolute configuration in 4‐aryl‐3,4‐dihydro‐2(1H)‐pyrimidones by high performance liquid chromatography and CD spectroscopy

The absolute configuration of three 4‐aryl‐3,4‐dihydro‐2(1H)‐pyrimidones (Biginelli compounds, DHPMs) was established by comparison of the typical circular dichroism (CD) spectra of individual enantiomers with reference samples of known absolute configuration. The enantiomers were obtained by semipreparative separation of racemic mixtures on a Chiralcel OD‐H chiral stationary phase. The method was used to establish the enantiopreference of various lipases in biocatalytic kinetic resolution experiments employing activated DHPM esters. Chirality 11:659–662, 1999. © 1999 Wiley‐Liss, Inc.     

Di(1‐naphthyl) methanol ester of carboxylic acids for absolute stereochemical determination

The absolute stereochemistry of chiral carboxylic acids is determined as a di(1‐naphthyl)methanol ester derivative. Computational scoring of conformations favoring either P or M helicity of the naphthyl groups, capable of exciton‐coupled circular dichroic coupling, leads to a predicted stereochemistry for the derivatized carboxylic acids.     

Circular dichroism spectroscopic study of non‐covalent interactions of poly‐L‐glutamic acid with a porphyrin derivative in aqueous solutions

The interactions of poly‐L ‐glutamic acid and a cationic porphyrin derivative in aqueous solutions were studied by the combination of vibrational circular dichroism (VCD) and electronic circular dichroism (ECD) spectroscopies. It was found that non‐covalent interactions between both agents influence the structure of the polymeric matrix and the guest porphyrins and vice versa, but the physico‐chemical properties of the solutions, especially the pH and the relative permittivity of the solvent, play a key role in the structure of the polypeptide part of the formed complexes. It was shown that the interaction with porphyrins prevents the precipitation of poly‐L ‐glutamic acid in aqueous solution at acidic pH. In special conditions, the porphyrins attached to the polypeptide probably possess face‐to‐face interaction as demonstrated by the enhancement of the characteristic ECD signal and the appearance of sidebands on its short and long wavelength sides. Copyright © 2005 European Peptide Society and John Wiley & Sons, Ltd.     

Application of NMR spectroscopy for assignment of the absolute configuration of 8‐tert‐butyl‐2‐hydroxy‐7‐methoxy‐8‐methyl‐9‐oxa‐6‐azaspiro[4.5]dec‐6‐en‐10‐one

In order to assign the absolute configurations of 8‐tert‐butyl‐2‐hydroxy‐7‐methoxy‐8‐methyl‐9‐oxa‐6‐azaspiro[4.5]dec‐6‐en‐10‐one ( 2a , 2b ), their esters ( 5a , 5b , 5c , 5d ) with (R)‐ or (S)‐2‐methoxyphenylacetic acid ( 4a , 4b ) have been synthesized. The absolute configurations of these compounds have been determined on the basis of NOESY correlations between the protons of the tert‐butyl group and the cyclopentane fragment of the molecules. The crucial part of this analysis was assignment of the absolute configuration at C‐5. Additionally, by calculation of the chemical shift anisotropy, δ^RS, for the relevant protons, it was also possible to confirm the absolute configurations at the C‐2 centres of compounds 2a , 2b and 5a , 5b , 5c , 5d . Chirality, 25:422–426, 2013.© 2013 Wiley Periodicals, Inc.     

Predicting binding modes of reversible peptide‐based inhibitors of falcipain‐2 consistent with structure–activity relationships

Falcipain‐2 (FP‐2) is a major hemoglobinase of Plasmodium falciparum, considered an important drug target for the development of antimalarials. A previous study reported a novel series of 20 reversible peptide‐based inhibitors of FP‐2. However, the lack of tridimensional structures of the complexes hinders further optimization strategies to enhance the inhibitory activity of the compounds. Here we report the prediction of the binding modes of the aforementioned inhibitors to FP‐2. A computational approach combining previous knowledge on the determinants of binding to the enzyme, docking, and postdocking refinement steps, is employed. The latter steps comprise molecular dynamics simulations and free energy calculations. Remarkably, this approach leads to the identification of near‐native ligand conformations when applied to a validation set of protein‐ligand structures. Overall, we proposed substrate‐like binding modes of the studied compounds fulfilling the structural requirements for FP‐2 binding and yielding free energy values that correlated well with the experimental data. Proteins 2017; 85:1666–1683. © 2017 Wiley Periodicals, Inc.     

Synthesis,HPLC Enantioresolution,and X‐ray Analysis of a New Series of C5‐methyl Pyridazines as N‐Formyl Peptide Receptor (FPR) Agonists

The synthesis of three racemates and the corresponding non‐chiral analogues of a C5‐methyl pyridazine series is described here, as well as the isolation of pure enantiomers and their absolute configuration assignment. In order to obtain optically active compounds, direct chromatographic methods of separation by HPLC‐UV were investigated using four chiral stationary phases (CSPs: Lux Amylose‐2, Lux Cellulose‐1, Lux Cellulose‐2 and Lux Cellulose‐3). The best resolution was achieved using amylose tris(5‐chloro‐2‐methylphenylcarbamate) (Lux Amylose‐2), and single enantiomers were isolated on a semipreparative scale with high enantiomeric excess, suitable for biological assays. The absolute configuration of optically active compounds was unequivocally established by X‐ray crystallographic analysis and comparative chiral HPLC‐UV profile. All compounds of the series were tested for formyl peptide receptor (FPR) agonist activity, and four were found to be active, with EC₅₀ values in the micromolar range. Chirality 25:400–408, 2013. © 2013 Wiley Periodicals, Inc.