1,721,068 research outputs found
Desymmetrisation of meso-methylcyclooctanones. Highly Enantioselective Synthesis of C8 syn-Isoprenoid and syn,syn-Deoxypropionate Subunits from a Bicyclo[3.3.1]nonane Precursor
No full textMicrowave-assisted intramolecular huisgen cycloaddition of azido alkynes derived from α-amino acids
No full textThe intramolecular version of the Huisgen cycloaddition is a potentially useful reaction for the stereocontrolled preparation of 1,5-disubstituted and 1,4,5-trisubstiututed triazoles. When α-azido propargyl esters derived from α-amino acids are submitted to [3 + 2] cycloaddition, the expected 4H-[1,2,3]triazolo[5,1-c][1,4]oxazin-6-ones are not formed; rather, an oligomeric cyclic polyester is obtained via a prevailing intermolecular cycloaddition. We have discovered that propargyl α-azido amides undergo metal-free intramolecular Huisgen cycloaddition in MeCN/H2O under microwave dielectric heating. This reaction provides access to new condensed triazoles that can be considered as conformationally constrained peptidomimetics. Moreover, the following microwave-assisted lactam ring opening provides 1,4-disubstituted and 1,4,5-trisubstituted triazole amino acids. The same kind of compounds are obtained from the ester cycloadduct by reaction with primary amines in the presence of AlMe3. In order to interpretate this unpredictable behavior, an ab initio study of the reaction pathway was undertaken using GAMESS(US) at the B3LYP/6-31G** level of theory. Different relaxed potential energy profiles were obtained for esters and amides, suggesting that the cis-arrangement of the-CO=N-could account for the amide reactivity
In Memory of Maurizio Botta: His Contribution to the Development of Computer-Aided Drug Design
Full text linkMaurizio Botta was born in Manziana, near Rome (Italy), on May 1950. He built his background in chemistry at Sapienza University of Rome, and then, he received his Ph.D. in 1979 at the University of Brunswick (Canada) working at the total synthesis of complex natural products under the supervision of Prof. Karel Wiesner. From 1980 to 1987, he was a Researcher at the Sapienza University of Roma, and thanks to a NATO grant, he spent one year in 1985–1986 working as a postdoctoral associate in the group of Prof. Stephen Hanessian at the University of Montreal (Canada), where he was also invited as a visiting scientist many other times thereafter.(1) In 1987, he became an Associate Professor of medicinal chemistry at the University of Siena (Italy) and then a Full Professor in 2000. His scientific career was objectively successful, as he was author in more than 400 papers and books or book chapters, as well as inventor in more than 25 patents. He was a member of many scientific societies and editorial boards of journals mostly devoted to chemistry, medicinal chemistry and drug design. Particularly, he served as an Associate Editor for ACS Medicinal Chemistry Letters.
Besides his chemical background, in his research life Maurizio was intrigued by multiple fields adjacent to synthetic chemistry, such as biochemistry, biophysics, molecular biology, and computational modeling. This latter captured his attention and was implemented in his research activity as a crucial support to drug design since the beginning of the 1990s. It is worth noting that most of Botta’s publications report on the use of computational tools, mostly relying on (but not limited to) molecular mechanics (MM) approaches to rationalize existing biological data, or to drive the design and synthesis of bioactive compounds. His research initially focused on conformational analysis of small molecules with the double aim to seize the enormous possibilities offered by MM in modeling conformational flexibility detected by NMR spectroscopy, as well as to exploit the active analogue approach (AAA) developed by Prof. Garland Marshall to interpreting pharmacological properties of bioactive compounds.(2) Thanks to the fruitful collaboration with Prof. Kosta Steliou (University of Montreal), near the beginning of the 1990s, his group started to use the VAX version of Model software, implemented with the MMX force field that was especially suitable to modeling molecular systems with π-electron delocalization. In the same years, MacroModel was used to model with high accuracy the flexibility of an increased number of organic molecules thanks to different force fields, while the use of Sybyl was initially related to its graphic potential but would later pave the way to using the CoMFA 3D-QSAR methodology. Since then, the role of computational modeling studies became more and more relevant in the research of Maurizio’s group, up to the publication of papers mostly or exclusively conducted at the theoretical level. The crucial role of theoretical approaches in drug design was highlighted by the successful series of workshops, i.e., the European Workshop in Drug Design (EWDD), held every two years in the lovely location of Certosa di Pontignano in the countryside of Siena (Italy).
The aim of this paper is to honor the memory of Prof. Maurizio Botta and to briefly overview the major contributions he gave to the field of computer-aided drug design, chemical information, and modeling. Works that represented a milestone in his research strategy are briefly overviewed herein, grouped on the basis of the topic. Finally, a note to the EWDD series is provided
3D-QSAR using pharmacophore-based alignment and virtual screening for discovery of novel MCF-7 cell line inhibitors
No full textThe development of a novel approach for the prediction of antiestrogenic activity is described, bringing up to date a previous pharmacophore study. Software Phase has been used to derive a 3D-QSAR model based, as alignment rule, on a pharmacophore built on three compounds highly active against MCF-7 cell line. Five features comprised the pharmacophore: two hydrogen-bond acceptors, one hydrogen-bond donor, and two aromatic rings. The sequential 3D-QSAR yielded a test set q2 equal to 0.73 and proved to be predictive with respect to an external test set of 21 compounds (r2 = 0.69). The model was used to detect new MCF-7 inhibitors through 3D-database searching and identified fourteen compounds that were subsequently tested in vitro against the MCF-7 human breast adenocarcinoma cell line. Eleven out of the fourteen compounds exhibited inhibitory activity with IC50 values ranging between 30 and 186 μM. The results of the study confirmed the fundamental validity of the chosen approach as a hit discovery tool. © 2013 Elsevier Masson SAS. All rights reserved
Structural flexibility of hyaluronan oligomers as probed by molecular modeling
No full textIn the last few years, molecular modeling studies have been published that are devoted to a better understanding of the structural flexibility of hyaluronan (HA). Further conformational investigations, however, are needed on this polysaccharide, such as the application of statistical methods to perform enhanced one-step conformational analyses of its subunits. Moreover, the adjustment of assisted model building and energy refinement (AMBER) force field could provide the appropriate computational tool to study the interactions of HA and its derivatives with proteins. The present paper reports a combined Monte Carlo (MC) and molecular dynamics (MD) approach applied to the conformational study of HA, using an adjusted version of AMBER force field and the generalized Born solvent-accessible surface area (GB/SA) continuum solvation model. The MC approach turned out to be extremely effective to outline a conformational survey of the disaccharides constituting HA. Complete sets of conformations of the monomers were provided for the first time, some of which had never been predicted. MD technique, integrating the MC results, correctly reproduced the unusual stiffness of HA and predicted the existence of a minor skew-boat conformation of the β-D-glucuronic moiety. The computational approach, as a whole, improved the comprehension of the dynamic behavior of HA and offered a clear causal explanation of the relative dynamics of the glycosidic linkages
Chair-boat equilibrium as driving force in epimerization of 3,7-dimethylbicyclo[3.3.1]nonan-2,9-dione derivatives. Stereocontrolled synthesis of the 3-exo,7-exo- and 3-endo,7-exo-dimethylbicyclo[3.3.1]nonan-9-ones
No full textMolecular mechanics calculations and experimental H-1 NMR data are in close agreement and show that the epimerization equilibrium at C-3 Of 3,7-dimethylbicyclo[3.3.1]nonan-2,9-diones is shifted toward the 3-endo-epimer in order to reach the lowest energy chair-boat conformation. Introduction of a 1.3-dioxolane moiety at C-9 results in reversal of the equilibrium, in protic solvents, leading mainly to the 3-exo-epimer in the most stable chair-chair conformation. These results have been applied to the stereocontrolled synthesis of the title compounds
Desymmetrisation of meso-methyleyclooctanones. Highly enantioselective synthesis of C-8 syn-isoprenoid and syn,syn-deoxypropionate subunits from a bicyclo[3.3.1]nonane precursor
No full textThe methyl esters of 3R,7S-dimethyl- and 3R,5R,7S-trimethyl-8-hydroxyoctanoic acids have been prepared in good yields and with e.e. >98% by chemical elaboration of the known exo,exo-3,7-dimethylbicyclo[3.3.1]nonan-9-one, the key step involving the desymmetrisation of the intermediate meso-ketones cis-3,7-dimethyl- and cis,cis-3,5,7-trimethyl-cyclooctanone through the corresponding chiral enolates generated by the lithium amide of the (+)bis[(R)-(1-phenylethylamine)]. The very high enantioselectivity observed might be related to the conformational features of the eight-membered rin
CONFORMATIONAL EFFECTS ON THE STEREOCHEMICAL COURSE OF THE NABH4 REDUCTION OF SUBSTITUTED BICYCLO[3.3.1]NONAN-2-ONES
No full textMolecular mechanics calculations for the 1-substituted bicyclo[3.3.1]nonan-2-ones 2a-d show that the amount of the chair-boat conformation increases as the size of the substituent at C1 increases. This result sharply fits with the stereochemical course of NaBH4 reductions of ketones 2a-d if axial attack on the chair-boat conformation and equatorial attack on the chair-chair one are assumed to be preferential
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
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