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Small Molecules with Spiro-Conjugated Cycles: Advances in Synthesis and Applications, 2nd Edition

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Biochemistry".

Deadline for manuscript submissions: closed (20 February 2025) | Viewed by 8377

Special Issue Editor

Prof. Dr. Elena K. Beloglazkina

E-Mail Website
Guest Editor
Department of Chemistry, M. V. Lomonosov Moscow State University, Leninskie Gory, 1-3, 119991 Moscow, Russia
Interests: cycloaddition reactions; organic ligands; medicinal chemistry; functional organic-inorganic materials
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues, 

Organic spiro derivatives are extremely attractive molecules for the development of novel structural types of biologically active molecules, and for the fabrication of new materials. The rigidity of spiro junctions in molecular frameworks makes it possible to fix the required spatial arrangement of exocyclic substituents, which are crucial to enabling with biological targets and the properties of developed materials. It is also vital that spiro-linked carbo- and heterocyclic compounds can be obtained via various types of cyclization reactions with high regio- and stereoselectivity, as well as atomic precision; such reactions are atom-economical and make it possible to significantly complicate the molecular structure in one synthetic step.

This Special Issue of International Journal of Molecular Sciences focuses on the synthesis and physico-chemical and biological investigation of spiro-conjugated organic compounds, and welcomes both original research articles and review papers addressing with both practical and mechanistic aspects of the preparation and reactivity of title compounds, as well as prospects for their possible application. In its Volume I, 10 papers were published. We sincerely encourage you to read these papers and welcome your contributions to Volume II.

Prof. Dr. Elena K. Beloglazkina
Guest Editor

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

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Keywords

  • bioactivity
  • carbocycles
  • cyclization
  • cycloaddition
  • heterocycles
  • low molecular weight materials
  • spiro-compounds
  • synthetic methods

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Published Papers (6 papers)

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Research

23 pages, 6777 KiB  
Article
Study of Cytotoxicity of 3-Azabicyclo[3.1.0]hexanes and Cyclopropa[a]pyrrolizidines Spiro-Fused to Acenaphthylene-1(2H)-one and Aceanthrylene-1(2H)-one Fragments Against Tumor Cell Lines
by Anton A. Kornev, Stanislav V. Shmakov, Alexandra M. Gryschenko, Yulia A. Pronina, Alexander I. Ponyaev, Alexander V. Stepakov and Vitali M. Boitsov
Int. J. Mol. Sci. 2025, 26(8), 3474; https://doi.org/10.3390/ijms26083474 - 8 Apr 2025
Viewed by 317
Abstract
A series of 3-azabicyclo[3.1.0]hexanes and cyclopropa[a]pyrrolizidines spiro-fused to acenaphthylene-1(2H)-one and aceanthrylene-1(2H)-one frameworks have been studied for their in vitro antiproliferative activity against human erythroleukemia (K562), cervical carcinoma (HeLa), melanoma (Sk-mel-2), osteosarcoma (U2OS), as well as murine melanoma [...] Read more.
A series of 3-azabicyclo[3.1.0]hexanes and cyclopropa[a]pyrrolizidines spiro-fused to acenaphthylene-1(2H)-one and aceanthrylene-1(2H)-one frameworks have been studied for their in vitro antiproliferative activity against human erythroleukemia (K562), cervical carcinoma (HeLa), melanoma (Sk-mel-2), osteosarcoma (U2OS), as well as murine melanoma (B16) cell lines. Using confocal microscopy, it was found that cultivation with the tested spiro-fused compounds led to the disappearance of stress fibers (granular actin was distributed diffusely in the cytoplasm in up to 56% of treated cells) and decrease in filopodia-like deformations (up to 69% after cultivation), which indirectly suggests a decrease in cell motility. The human melanoma cell line scratch test showed that these cells lose their ability to move after cultivation with the tested spiro-fused compounds and do not fill the scratched strip. This was also supported by docking simulations with actin-related targets (PDB ID: 8DNH, 2Q1N). Using flow cytometry, the impact on the mitochondrial membrane potential showed that the tested compounds led to a significant increase in the number of cells with decreased mitochondrial membrane potential from 10% for the control up to 55–80% for the cyclopropa[a]pyrrolizidine adducts. The obtained results support the antitumor effect of the tested spiro-compounds and encourage the extension of the study in order to improve their anticancer activity as well as reduce their toxicological risks. Full article
(This article belongs to the Special Issue Small Molecules with Spiro-Conjugated Cycles: Advances in Synthesis and Applications, 2nd Edition)
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19 pages, 4660 KiB  
Article
You Win Some, You Lose Some: Modifying the Molecular Periphery of Nitrofuran-Tagged Diazaspirooctane Reshapes Its Antibacterial Activity Profile
by Lyubov Vinogradova, Kristina Komarova, Alexey Lukin, Maxim Zhuravlev, Dmitry Deniskin, Anastasia Poliakova, Mikhail Chudinov, Maxim Gureev, Marine Dogonadze, Tatiana Vinogradova, Elizaveta Rogacheva, Lyudmila Kraeva, Yuri Porozov and Viktor Korzhikov-Vlakh
Int. J. Mol. Sci. 2025, 26(1), 207; https://doi.org/10.3390/ijms26010207 - 29 Dec 2024
Viewed by 1060
Abstract
The use of the concept of privileged structures significantly accelerates the search for new leads and their optimization. 6-(methylsulfonyl)-8-(4-methyl-4H-1,2,4-triazol-3-yl)-2-(5-nitro-2-furoyl)-2,6-diazaspiro[3.4]octane 1 has been identified as a lead, with MICs of 0.0124–0.0441 μg/mL against MTb multiresistant strains. Several series of structural analogues have [...] Read more.
The use of the concept of privileged structures significantly accelerates the search for new leads and their optimization. 6-(methylsulfonyl)-8-(4-methyl-4H-1,2,4-triazol-3-yl)-2-(5-nitro-2-furoyl)-2,6-diazaspiro[3.4]octane 1 has been identified as a lead, with MICs of 0.0124–0.0441 μg/mL against MTb multiresistant strains. Several series of structural analogues have been synthesized, including variations in the periphery and simplifications of their scaffolds. All synthesized compounds were tested against the MTb H37Rv strain and ESKAPE panel of pathogens using serial broth dilutions. However, an attempt to optimize structure of 1 did not lead to the development of more active compounds which can work against MTb, but to substances with high activity against S. aureus. Induced-fit docking and MM-GBSA calculations determined a change in the likely biotarget from deazaflavin-dependent nitroreductase to azoreductases. The privileged nature of the scaffold was demonstrated by the detection of a different type of activity. Full article
(This article belongs to the Special Issue Small Molecules with Spiro-Conjugated Cycles: Advances in Synthesis and Applications, 2nd Edition)
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18 pages, 1718 KiB  
Article
Biological Activity Evaluation of Phenolic Isatin-3-Hydrazones Containing a Quaternary Ammonium Center of Various Structures
by Margarita Neganova, Yulia Aleksandrova, Alexandra Voloshina, Anna Lyubina, Nurbol Appazov, Sholpan Yespenbetova, Zulfiia Valiullina, Aleksandr Samorodov, Sergey Bukharov, Elmira Gibadullina, Anipa Tapalova and Andrei Bogdanov
Int. J. Mol. Sci. 2024, 25(20), 11130; https://doi.org/10.3390/ijms252011130 - 17 Oct 2024
Viewed by 1521
Abstract
A series of new isatin-3-hydrazones bearing different ammonium fragments was synthesized by a simple and easy work-up reaction of Girard’s reagents analogs with 1-(3,5-di-tert-butyl-4-hydroxybenzyl)isatin. All derivatives have been shown to have antioxidant properties. In terms of bactericidal activity against gram-positive bacteria, [...] Read more.
A series of new isatin-3-hydrazones bearing different ammonium fragments was synthesized by a simple and easy work-up reaction of Girard’s reagents analogs with 1-(3,5-di-tert-butyl-4-hydroxybenzyl)isatin. All derivatives have been shown to have antioxidant properties. In terms of bactericidal activity against gram-positive bacteria, including methicillin-resistant strains of Staphylococcus aureus, the best compounds are 3a, 3e, and 3m, bearing octyl, acetal, and brucine ammonium centers, respectively. In addition, brucine and quinine derivatives 3l, and 3j exhibit platelet antiaggregation activity at the level of acetylsalicylic acid, and this series of isatin derivatives does not adversely affect the hemostasis system as a whole. Thus, all the obtained results can lay the groundwork for future pharmaceutical developments for the creation of effective antibacterial drugs with reduced systemic toxicity due to the presence of antioxidant properties. Full article
(This article belongs to the Special Issue Small Molecules with Spiro-Conjugated Cycles: Advances in Synthesis and Applications, 2nd Edition)
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11 pages, 1759 KiB  
Communication
Concise and Free-Metal Access to Lactone-Annelated Pyrrolo[2,1-a]isoquinoline Derivatives via a 1,2-Rearrangement Step
by Arina Y. Obydennik, Alexander A. Titov, Anna V. Listratova, Tatiana N. Borisova, Victor B. Rybakov, Leonid G. Voskressensky and Alexey V. Varlamov
Int. J. Mol. Sci. 2024, 25(2), 1085; https://doi.org/10.3390/ijms25021085 - 16 Jan 2024
Viewed by 1287
Abstract
Here, An efficient approach to obtaining previously unknown furo[2′,3′:2,3]pyrrolo[2,1-a]isoquinoline derivatives from readily available 1-R-1-ethynyl-2-vinylisoquinolines is described. The reaction features a simple procedure, occurs in hexaflouroisopropanol and does not require elevated temperatures. It has been found that the addition of glacial acetic [...] Read more.
Here, An efficient approach to obtaining previously unknown furo[2′,3′:2,3]pyrrolo[2,1-a]isoquinoline derivatives from readily available 1-R-1-ethynyl-2-vinylisoquinolines is described. The reaction features a simple procedure, occurs in hexaflouroisopropanol and does not require elevated temperatures. It has been found that the addition of glacial acetic acid significantly increases the yields of the target spirolactone products. Using trifluoroethanol instead of hexaflouroisopropanol results in the formation of pyrido[2,1-a]isoquinolines. Full article
(This article belongs to the Special Issue Small Molecules with Spiro-Conjugated Cycles: Advances in Synthesis and Applications, 2nd Edition)
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25 pages, 4695 KiB  
Article
[3+2]-Cycloaddition of Nitrile Imines to Parabanic Acid Derivatives—An Approach to Novel Spiroimidazolidinediones
by Juliana V. Kuznetsova, Varvara T. Tkachenko, Lada M. Petrovskaya, Maria E. Filkina, Dmitry E. Shybanov, Yuri K. Grishin, Vitaly A. Roznyatovsky, Viktor A. Tafeenko, Anna S. Pestretsova, Vera A. Yakovleva, Vadim S. Pokrovsky, Maxim E. Kukushkin and Elena K. Beloglazkina
Int. J. Mol. Sci. 2024, 25(1), 18; https://doi.org/10.3390/ijms25010018 - 19 Dec 2023
Cited by 5 | Viewed by 2099
Abstract
Approximately 1,3-Dipolar cycloaddition of imidazolidine derivatives containing exocyclic double bonds is a convenient method of creating spiro-conjugated molecules with promising anticancer activity. In this work, the derivatives of parabanic acid (2-thioxoimidazolidine-4,5-diones and 5-aryliminoimidazolidine-2,4-diones) were first investigated as dipolarophiles in the reactions with nitrile [...] Read more.
Approximately 1,3-Dipolar cycloaddition of imidazolidine derivatives containing exocyclic double bonds is a convenient method of creating spiro-conjugated molecules with promising anticancer activity. In this work, the derivatives of parabanic acid (2-thioxoimidazolidine-4,5-diones and 5-aryliminoimidazolidine-2,4-diones) were first investigated as dipolarophiles in the reactions with nitrile imines. The generation of nitrile imines was carried out either by the addition of tertiary amine to hydrazonoyl chlorides «drop by drop» or using the recently proposed diffusion mixing technique, which led to ~5–15% increases in target compound yields. It was found that the addition of nitrile imines to C=S or C=N exocyclic double bonds led to 1,2,4-thiazolines or triazolines and occurred regioselectively in accordance with the ratio of FMO coefficients of reactants. The yield of the resulting spiro-compound depended on the presence of alkyl substituents in the nitrile imine structure and was significantly decreased in reactions with imines with strong electron donor or electron-withdrawing groups. Some of the obtained compounds showed reasonable in vitro cytotoxicity. IC50 values were calculated for HCT116 (colon cancer) cells using the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) test. Full article
(This article belongs to the Special Issue Small Molecules with Spiro-Conjugated Cycles: Advances in Synthesis and Applications, 2nd Edition)
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22 pages, 2901 KiB  
Article
Diastereoselective Synthesis of Dispiro[Imidazothiazolotriazine-Pyrrolidin-Oxindoles] and Their Isomerization Pathways in Basic Medium
by Alexei N. Izmest′ev, Dmitry B. Vinogradov, Angelina N. Kravchenko, Natalya G. Kolotyrkina and Galina A. Gazieva
Int. J. Mol. Sci. 2023, 24(22), 16359; https://doi.org/10.3390/ijms242216359 - 15 Nov 2023
Cited by 1 | Viewed by 1168
Abstract
Highly diastereoselective methods for the synthesis of two series of regioisomeric polynuclear dispyroheterocyclic compounds with five or six chiral centers, comprising moieties of pyrrolidinyloxindole and imidazo[4,5-e]thiazolo[3,2-b]-1,2,4-triazine of linear structure or imidazo[4,5-e]thiazolo[2,3-c]-1,2,4-triazine of angular structure, have [...] Read more.
Highly diastereoselective methods for the synthesis of two series of regioisomeric polynuclear dispyroheterocyclic compounds with five or six chiral centers, comprising moieties of pyrrolidinyloxindole and imidazo[4,5-e]thiazolo[3,2-b]-1,2,4-triazine of linear structure or imidazo[4,5-e]thiazolo[2,3-c]-1,2,4-triazine of angular structure, have been developed on the basis of a [3+2] cycloaddition of azomethine ylides to functionalized imidazothiazolotriazines. Depending on the structure of the ethylenic component, cycloaddition proceeds as an anti-exo process for linear derivatives, while cycloaddition to angular ones resulted in a syn-endo diastereomer. Novel pathways of isomerization for the synthesized anti-exo products upon treatment with sodium alkoxides have been found, which resulted in two more series of diastereomeric dispiro[imidazothiazolotriazine-pyrrolidin-oxindoles] inaccessible with the direct cycloaddition reaction. For the first series, the inversion of the configuration of one stereocenter, i.e., C-4′ atom of the pyrrolidine cycle, (epimerization) was established. For the second one, configuration of the obtained diastereomer formally corresponded to the syn-endo approach of the azomethine ylide in the case of cycloaddition to the ethylenic component. Full article
(This article belongs to the Special Issue Small Molecules with Spiro-Conjugated Cycles: Advances in Synthesis and Applications, 2nd Edition)
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