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Dynamic Stereochemistry of Bioactive Compounds
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Dynamic Stereochemistry of Bioactive Compounds

A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Natural Products Chemistry".

Deadline for manuscript submissions: closed (30 November 2022) | Viewed by 10546

Special Issue Editor

Dr. Vadim V. Negrebetsky

E-Mail Website
Guest Editor
Department of Medicinal Chemistry and Chemical Department, Research Institute of translational medicine, N.I. Pirogov Russian National Research Medical University, Moscow, Russia
Interests: stereodynamic behavior; dynamic stereochemistry; NMR investigation; medicinal chemistry
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Since the first fundamental research of Pasteur, Le Belle, and Van't Hoff, which laid the foundation for modern stereochemistry, including dynamic stereochemistry, this field of knowledge has turned into a multidisciplinary science which is still actively developing. At present, the main one both in importance and in volume has become its area which studies the influence of the spatial structure on the rate and direction of chemical reactions, as well as on the manifested biological activity.

Today, dynamic stereochemistry plays a key role in almost all chemical disciplines, from asymmetric synthesis to the creation of modern drugs (medical chemistry), as well as nanomaterials. Considering the “dynamics” of its development, it is easy to see that the prospects for this direction are far from exhausted. The great interest and activity of researchers has led to the development of new methodologies in the most recent years and laid the fundamental foundations of promising areas of research for many decades to come. An additional incentive for the development of dynamic stereochemistry has been the rapid progress currently being observed in the block of sciences (biology, biochemistry, pharmacology, medical chemistry, etc.) studying the dependence of the therapeutic effect and side effects of drugs on steric factors, as well as the rapid development of chiral technologies in the pharmaceutical industry. Numerous studies in recent years clearly indicate the existence of a close relationship between biological activity and the spatial structure of biologically active compounds. For specialists working in the field of dynamic stereochemistry, it seems obvious that the stereoisomers of the same substance may have different biological activity or even different pharmacological uses. The activity, absorption, transport, biotransformation, and excretion of enantiomers can be fundamentally different. A large number of examples are known when one of the possible enantiomers of a drug compound is toxic or leads to undesirable side effects. Thus, serious malformations in children when taking thalidomide (also known as Contergan, sedative sleeping pills) at the end of the 1950s were caused by the teratogenic nature of its (S) enantiomer. This and other cases have led to increased requirements for the creation of enantiomerically pure compounds. The use of pharmacological agents in a pure spatial form can significantly increase the activity of the drug, reduce the dose, and reduce side effects. The chiral drug market has reached sales of over $90 billion. Current trends in this direction indicate that in the near future, medicinal compounds with internal asymmetry will be produced exclusively in enantiomerically pure form.

This Special Issue on “Dynamic Stereochemistry of Bioactive Compounds” is intended to attract researchers in this field who want to contribute their latest results to the forum of Molecules. It is my hope that a large number of interesting papers will be submitted that will reflect the potential and rapid development in this important area.

We cordially invite researchers working in this field to contribute original research articles, short communications, and critical review articles.

Dr. Vadim V. Negrebetsky
Guest Editor

Manuscript Submission Information

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Keywords

  • Dynamics Stereochemistry
  • Biological activity of stereoisomers
  • Enantiomers of medicines
  • Creation of modern medicines
  • Control of the structure of molecules using external pulses (molecular motors)

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Published Papers (4 papers)

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Research

22 pages, 5720 KiB  
Article
Pyridine Carboxamides Based on Sulfobetaines: Design, Reactivity, and Biological Activity
by Eugene P. Kramarova, Sophia S. Borisevich, Edward M. Khamitov, Alexander A. Korlyukov, Pavel V. Dorovatovskii, Anastasia D. Shagina, Konstantin S. Mineev, Dmitri V. Tarasenko, Roman A. Novikov, Alexey A. Lagunin, Ivan Boldyrev, Aiarpi A. Ezdoglian, Natalia Yu. Karpechenko, Tatiana A. Shmigol, Yuri I. Baukov and Vadim V. Negrebetsky
Molecules 2022, 27(21), 7542; https://doi.org/10.3390/molecules27217542 - 3 Nov 2022
Cited by 4 | Viewed by 1882
Abstract
The synthesis of the products of the 1,3-propanesultone ring opening during its interaction with amides of pyridinecarboxylic acids has been carried out. The dependence of the yield of the reaction products on the position (ortho-, meta-, para-) of the [...] Read more.
The synthesis of the products of the 1,3-propanesultone ring opening during its interaction with amides of pyridinecarboxylic acids has been carried out. The dependence of the yield of the reaction products on the position (ortho-, meta-, para-) of the substituent in the heteroaromatic fragment and temperature condition was revealed. In contrast to the meta- and para-substituted substrates, the reaction involving ortho-derivatives at the boiling point of methanol unexpectedly led to the formation of a salt. On the basis of spectroscopic, X-Ray, and quantum-chemical calculation data, a model of the transition-state, as well as a mechanism for this alkylation reaction of pyridine carboxamides with sultone were proposed in order to explain the higher yields obtained with the nicotinamide and its N-methyl analog compared to ortho or meta parents. Based on the analysis of ESP maps, the positions of the binding sites of reagents with a potential complexing agent in space were determined. The in silico evaluation of possible biological activity showed that the synthetized compounds revealed some promising pharmacological effects and low acute toxicity. Full article
(This article belongs to the Special Issue Dynamic Stereochemistry of Bioactive Compounds)
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16 pages, 2656 KiB  
Article
Bispidine Platform as a Tool for Studying Amide Configuration Stability
by Dmitry P. Krut’ko, Alexey V. Medved’ko, Konstantin A. Lyssenko, Andrei V. Churakov, Alexander I. Dalinger, Mikhail A. Kalinin, Alexey O. Gudovannyy, Konstantin Y. Ponomarev, Eugeny V. Suslov and Sergey Z. Vatsadze
Molecules 2022, 27(2), 430; https://doi.org/10.3390/molecules27020430 - 10 Jan 2022
Cited by 9 | Viewed by 2552
Abstract
In this work, the solution conformations of seventeen 3,7-diacyl bispidines were studied by means of NMR spectroscopy including VT NMR experiments. The acyl groups included alkyl, alkenyl, aryl, hetaryl, and ferrocene moieties. The presence of syn/anti-isomers and their ratios were estimated, and some [...] Read more.
In this work, the solution conformations of seventeen 3,7-diacyl bispidines were studied by means of NMR spectroscopy including VT NMR experiments. The acyl groups included alkyl, alkenyl, aryl, hetaryl, and ferrocene moieties. The presence of syn/anti-isomers and their ratios were estimated, and some reasons explaining experimental facts were formulated. In particular, all aliphatic and heterocyclic units in the acylic R(CO) fragments led to an increased content of the syn-form in DMSO-d6 solutions. In contrast, only the anti-form was detected in DMSO-d6 and CDCl3 in the case when R = Ph, ferrocenyl, (R)-myrtenyl. In the case of a chiral compound derived from the natural terpene myrtene, a new dynamic process was found in addition to the expected inversion around the amide N-C(O) bond. Here, rotation around the CO-C=C bond in the acylic R fragment was detected, and its energy was estimated. For this compound, ΔG for amide N-C(O) inversion was found to be equal to 15.0 ± 0.2 kcal/mol, and for the rotation around the N(CO)–C2′ bond, it was equal to 15.6 ± 0.3 kcal/mol. NMR analysis of the chiral bispidine-based bis-amide was conducted for the first time. Two X-ray structures are reported. For the first time, the unique syn-form was found in the crystal of an acyclic bispidine-based bis-amide. Quantum chemical calculations revealed the unexpected mechanism for amide bond inversion. It was found that the reaction does not proceed as direct N-C(O) bond inversion in the double-chair (CC) conformation but rather requires the conformational transformation into the chair–boat (CB) form first. The amide bond inversion in the latter requires less energy than in the CC form. Full article
(This article belongs to the Special Issue Dynamic Stereochemistry of Bioactive Compounds)
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30 pages, 6430 KiB  
Article
Nucleophilic Substitution at Tetracoordinate Phosphorus. Stereochemical Course and Mechanisms of Nucleophilic Displacement Reactions at Phosphorus in Diastereomeric cis- and trans-2-Halogeno-4-methyl-1,3,2-dioxaphosphorinan-2-thiones: Experimental and DFT Studies
by Marian Mikołajczyk, Barbara Ziemnicka, Jan Krzywański, Marek Cypryk and Bartłomiej Gostyński
Molecules 2021, 26(12), 3655; https://doi.org/10.3390/molecules26123655 - 15 Jun 2021
Cited by 6 | Viewed by 2851
Abstract
Geometrical cis- and trans- isomers of 2-chloro-, 2-bromo- and 2-fluoro-4-methyl-1,3,2-dioxaphosphorinan-2-thiones were obtained in a diastereoselective way by (a) sulfurization of corresponding cyclic PIII-halogenides, (b) reaction of cyclic phosphorothioic acids with phosphorus pentachloride and (c) halogen–halogen exchange at PIV [...] Read more.
Geometrical cis- and trans- isomers of 2-chloro-, 2-bromo- and 2-fluoro-4-methyl-1,3,2-dioxaphosphorinan-2-thiones were obtained in a diastereoselective way by (a) sulfurization of corresponding cyclic PIII-halogenides, (b) reaction of cyclic phosphorothioic acids with phosphorus pentachloride and (c) halogen–halogen exchange at PIV-halogenide. Their conformation and configuration at the C4-ring carbon and phosphorus stereocentres were studied by NMR (1H, 31P) methods, X-ray analysis and density functional (DFT) calculations. The stereochemistry of displacement reactions (alkaline hydrolysis, methanolysis, aminolysis) at phosphorus and its mechanism were shown to depend on the nature of halogen. Cyclic cis- and trans-isomers of chlorides and bromides react with nucleophiles (HO−, CH3O−, Me2NH) with inversion of configuration at phosphorus. DFT calculations provided evidence that alkaline hydrolysis of cyclic thiophosphoryl chlorides proceeds according to the SN2-P mechanism with a single transition state according to the potential energy surface (PES) observed. The alkaline hydrolysis reaction of cis- and trans-fluorides afforded the same mixture of the corresponding cyclic thiophosphoric acids with the thermodynamically more stable major product. Similar DFT calculations revealed that substitution at phosphorus in fluorides proceeds stepwise according to the A–E mechanism with formation of a pentacoordinate intermediate since a PES with two transition states was observed. Full article
(This article belongs to the Special Issue Dynamic Stereochemistry of Bioactive Compounds)
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14 pages, 3246 KiB  
Article
pH-Dependent Photoinduced Interconversion of Furocoumaric and Furocoumarinic Acids
by Vladislav V. Skarga, Anton A. Matrosov, Artemiy I. Nichugovskiy, Vadim V. Negrebetsky, Mikhail A. Maslov, Ivan A. Boldyrev and Mikhail V. Malakhov
Molecules 2021, 26(9), 2800; https://doi.org/10.3390/molecules26092800 - 10 May 2021
Cited by 5 | Viewed by 2290
Abstract
Photo-controlled or photo-regulated molecules, especially biologically active and operating in physiological conditions, are in steady demand. Herein, furocoumaric and furocoumarinic acids being (Z/E)-isomers relative to each other were obtained in two stages starting from psoralen: the alkaline solvolysis of psoralen led [...] Read more.
Photo-controlled or photo-regulated molecules, especially biologically active and operating in physiological conditions, are in steady demand. Herein, furocoumaric and furocoumarinic acids being (Z/E)-isomers relative to each other were obtained in two stages starting from psoralen: the alkaline solvolysis of psoralen led to furocoumaric acid, which was further Z → E photoisomerized (365 nm) to furocoumarinic acid. The kinetics of Z → E photoisomerization was monitored by HPLC and UV-vis spectrophotometry. Photophysical characteristics in the aqueous phase for both acids, as well as the reversibility of (Z/E) photoisomerization process, were also assessed. Furocoumarinic acid was found to be visibly fluorescent at pH 2.0–12.0, with the maxima of fluorescence emission spectra being pH-dependent. The reverse E → Z photoisomerization predicted by quantum chemistry calculations as energetically favorable for the monoanionic form of furocoumarinic acid was proved in the experiment while being complicated by pyrone ring closure back to psoralen in acidic and neutral conditions. The preparative synthesis of furocoumarinic acid outlined in this work is particularly valuable in view of a wide range of pharmacological effects previously predicted for this compound. Full article
(This article belongs to the Special Issue Dynamic Stereochemistry of Bioactive Compounds)
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