Stereo- and regio-controlled synthesis of bioactive polycyclic molecules based on carbonyl compounds from the oxindole, naphthoquinone and androsterone series

Programme

 

Postdoctoral program

Strategic priority

V. Economic competitiveness and innovative technologies

Code
23.00208.5007.04/PD I
Duration
2023-2024
Institutions

Institute of Chemistry

Laboratories/Centers

Laboratory of Organic Synthesis / Centre of Applied Organic Chemistry

Project manager

Dr. Natalia Susman

Team:

Dr. Natalia Sucman

Abstract

The project is dedicated to obtaining enantiomerically pure compounds with biological properties, which provide greater activity and fewer side effects compared to a racemic or diastereomeric mixture. Target compounds will have a polycyclic structure, will be obtained on the basis of the modification of carbonyl substances and will have applicability in pharmacy and agriculture. The project will be carried out in 4 main stages and will include the synthesis and characterization of oxindole-based compounds, 2-hydroxyjuglone-based compounds, steroid-based compounds, as well as the formation and writing of the doctoral dissertation. In addition, in cooperation with the Rega Medical Research Institute (Leuven, Belgium), Aristotle University (Thessaloniki, Greece), Testimitsanu University of Medicine and Pharmacy (Moldova), Comrat State University (Moldova), the biological properties of the obtained compounds will be investigated. The project will be focused on conductive an exhaustive search of new and more effective drug candidates with the least cytotoxicity. To achieve this goal, two synthetic strategies will be applied. First, a library of analogues of substances similar to known natural and synthetic products will be created. Isatin, naphthoquinone and steroids will be used as the main elements to introduce molecular diversity. Secondly, a new library of mimetic derivatives will be obtained by introducing a new class of kernels for obtaining polycycles. Both strategies will use advanced synthetic approaches to create new bioactive chemical topologies that will bring economic and social benefits. At the final stage of the announced project, the conditions for obtaining the most promising compounds will be optimized and laboratory regulations will be developed to expand production.

Results, activities

Summary of the activity and results obtained in 2023

The project is dedicated to obtaining compounds with biological properties in enantiomerically pure form, ensuring higher bioactivity and fewer side effects compared to racemic or diastereomeric mixtures. The synthesized compounds have a polycyclic structure and were obtained by modifying carbonyl compounds. In 2023, two planned stages were completed, involving the synthesis and characterization of compounds based on oxindole and compounds based on 2-hydroxyjuglone. The stages of 2023 focused on identifying new and more efficient candidates as alternatives to medications. To achieve this goal, two synthetic strategies were applied. Firstly, a library of analogues of substances similar to known natural and synthetic products was created. Isatin and naphthoquinone were used as basic elements to introduce molecular diversity. Secondly, a series of new derivatives were synthesized by introducing new nuclei to obtain polycyclic compounds. Advanced synthetic approaches were used for both strategies. In collaboration with the Rega Institute for Medical Research (Leuven, Belgium), Aristotle University (Thessaloniki, Greece), Ion Cuza University (Iași, Romania), and the Testimițeanu University of Medicine and Pharmacy (Moldova), biological testing of the obtained compounds was conducted.

Summary of the activity and results obtained in 2024

The proposed project for 2024 has the main objective of developing stereo- and regioselective synthesis methods for polycyclic compounds based on carbonyl substances, namely steroids, elucidating the reaction mechanisms, and optimizing the conditions for the preparation of these compounds. The project also aims for the directed synthesis of new substances with high biological potential, relevant to the pharmaceutical and biomedical fields.

The main objectives for the 2024 stage include: 1.Developing a new concept in fine organic synthesis based on the use of carbonyl substances to build chiral molecules for the pharmaceutical and agricultural industries. 2.Gaining fundamental knowledge about the influence of structural, steric, and electronic factors on the chemo-, regio-, and stereoselective formation of C-C, C-N, and C-O bonds in the molecules of oxindole, naphthoquinone, and steroid compounds. 3.Determining the bioactivity of the synthesized compounds through virtual and in vitro testing. 4.Determining the structure and stereochemistry of the new compounds using modern spectral methods and X-ray diffraction.

Significant progress was made within the project in 2024. A total of 23 new substances were synthesized and characterized, including compounds with triazole and imidazole rings. Modern spectral methods were used for complete characterization, and their structure and stereochemistry were confirmed by X-ray diffraction. In addition, synthesis conditions for hybrid steroid molecules coupled with 1,2,3-triazole rings were optimized. All synthesized compounds were sent for complex biological testing in collaboration with international institutes. At the Rega Institute (Belgium), they were evaluated for cytotoxicity against eight cancer cell lines, including pancreatic adenocarcinoma, glioblastoma, lung carcinoma, and leukemia. In collaboration with the Institute of Bioorganic Chemistry in Belarus, testing for prostate cancer was performed. Compounds showing high activity against all tested cell lines were identified, confirming their potential as promising anticancer agents.

The obtained results have a significant scientific impact, contributing to the expansion of the steroid compound library with azole fragments, recognized for their anticancer activity. The studies conducted provide a solid foundation for future research in organic and medicinal chemistry. A detailed methodology for obtaining steroid and triazole derivatives has been developed, which can be applied in the synthesis of therapeutic agents with enhanced selective activity.

The project has a social/economic impact, contributing to the identification of more effective and less toxic therapeutic solutions, improving prospects for cancer treatments – a global issue with a major impact on public health and national economies. The synthesis of high-efficiency and low-cost compounds opens opportunities for the development of affordable medicines and the attraction of investments in the pharmaceutical sector.

In this stage, the project results were presented in the form of posters and oral presentations at international and national conferences. Additionally, scientific articles were published in high-impact international journals (Q2) and in collections of national conferences with international participation.

Publications

Monograph
1.SUCMAN, N., MACAEV, F. Steroizi anabolizanți. Chişinău: Editura USM, 2024, 200 p. ISBN 978-9975-62-710-8. https://ichem.md/sites/default/files/2025-01/Steroizi%20anabolzanti%20Macaev%20Sucman.pdf

Chapter in monograph

  1. SUCMAN, Natalia, MAKAEV, Fliur. Photosensitive nanopesticides for environmentally friendly and sustainable agriculture. In: Environmental and Technological Aspects of Redox Processes.  Pennsylvania, SUA: 2023, pp. 188-211. ISBN 979-836930514-0, 979-836930512-6. DOI: 10.4018/979-8-3693-0512-6.ch011


Article in international journals

  1. SUCMAN, N., STINGACI, E., LUPASCU, L., SMETANSCAIA, A., VALICA, V., UNCU, L., SHOVA, S., PETROU, A., GLAMOČLIJA, F., SOKOVIĆ,M., GERONIKAKI, A., MACAEV, F. New 1H-1,2,4-Triazolyl Derivatives as Antimicrobial Agents. In: Chem. Biodiversity, 2024, e202400316. https://doi.org/10.1002/cbdv.202400316 https://www.scimagojr.com/journalsearch.php?q=130069&tip=sid&clean=0.  (IF: 2,9)
  2. SUCMAN, N.S., BILAN, D.YA., COJOCARI, S.V., POGREBNOI, V.S., STÎNGACI, E.P., KHRIPACH, V.A., ZHABINSKII, V.N., TSYBRUK, T.V., GRABOVEC, I.P., PANIBRAT, O.V., PERSOONS, L., SCHOLS, D., FROEYEN, M., SHOVA, S., DE JONGHE, S., MACAEV, F.Z. Steroidal 21-imidazolium salt derivatives: Synthesis and anticancer activity. In: Steroids, 210, 2024, 109475, ISSN 0039-128X. https://doi.org/10.1016/j.steroids.2024.109475 https://www.scimagojr.com/journalsearch.php?q=14805&tip=sid&clean=0.  (IF: 2,1)
     

Article in abstarct books

  1. ЗВЯГИНЦЕВА, М., СУКМАН, Н., МАКАЕВ, Ф. Получение производных класса пиразола гетероциклизации 1,2,4-триазолилэтанонов. În: Integrare prin cercetare și inovare: conferința științifică națională cu participare internațională. Ştiinţe ale naturii și exacte, Chișinău, Republica Moldova, 7-8 noiembrie, 2024, pp. 674-682. https://ichem.md/sites/default/files/2025-01/Conf_USM%207-8%20noiembrie%202024.pdf 


Abstracts

  1. GORINCIOI, E., POGREBNOI, V., SUCMAN, N., MACAEV, F. 6-(2,4-Dichlorobenzoyl)-7-(2,4-dichlorophenyl)indolo[3,4-jk]phenanthridin-5(4H)-one as a specific DNA binder recognizing two different G-quadruplex topologies. In: International symposium on non-canonical nucleic acids ANNA-2024, 24-26 October 2024, Portoroz, Slovenia. Book of abstracts, p. 52. https://www.slonmr.si/anna_2024/ANNA2024BookOfAbstracts.pdf. https://www.way2drug.com/dr/BCADD2024/content/eposter/ysceposter/posters/Chiobanu_N.pdf
  2. SUCMAN, N. Analysis of the addition of 2-hydroxyjuglone and hydroxycitronellal by NMR În: Central European NMR Symposium & Bruker Users Meeting, 18 – 19 September 2024, University of Rijeka, Rijeka, Croatia, p. 55. https://ceum2024.hkd.hr/CEUM2024_Book_of_Abstracts.pdf
  3. SUCMAN, N., POGREBNOI, V., BILAN, D., COJOCARI, S., MACAEV F. Juglone and butylamine reaction products: isolation and structural characterization. În: Central European NMR Symposium & Bruker Users Meeting, 18 – 19 September 2024, University of Rijeka, Rijeka, Croatia, p. 56. https://ceum2024.hkd.hr/CEUM2024_Book_of_Abstracts.pdf
  4. STINGACI, E.P., PETUHOV, O., SUCMAN, N.S., ȘTEFANEȚ, T., VALICA, V., MACAEV, F.Z. Thermogravimetric analysis of isatin β-ethyleneketals: implications for psychotropic drug development În: 10th International Conference on Materials Science and Condensed Matter Physics (MSCMP), 1-4 October 2024, Chisinau, Moldova. Book of abstracts, ISBN 978-9975-62-763-4, p. 128. https://mscmp.usm.md/wp-content/uploads/2024/10/MSCMP2024_Book_Abstracts.pdf
  5. GORINCIOI, E., POGREBNOI, V., IUNAC, D., BALAN, G., ROTARU, A., SUCMAN, N., MACAEV, F.  Antimicrobial, antiproliferative and DNA-interacting properties of 6-(2,4-dichlorobenzoyl)-7-(2,4-dichlorophenyl)indolo[3,4-jk]phenanthridin-5(4H)-one. În: 10th International Conference on Materials Science and Condensed Matter Physics (MSCMP), 1-4 October 2024, Chisinau, Republic of Moldova. Book of abstracts, ISBN 978-9975-62-763-4, p. 107. https://mscmp.usm.md/wp-content/uploads/2024/10/MSCMP2024_Book_Abstracts.pdf
  6. GORINCIOI, E., SUCMAN, N., POGREBNOI, V., MACAEV, F. 6-(2,4-Dichlorobenzoyl)-7-(2,4-dichlorophenyl)indolo[3,4-jk]phenanthridin-5(4H)-one presents anticancer and targeting the non-canonical dna structures effects. În: Al X-lea congres al farmaciștilor din Republica Moldova cu participare internațională, 22 noiembrie 2024, pp. 75-76. https://drive.google.com/file/d/1QVHD460TGa9zZSH1Q_gu581f6v0mHWZE/view
  7. SUCMAN, N., STÎNGACI, E., BILAN, D., MACAEV, F. Sinteza steroizilor noi cu fragment azolic pentru dezvoltarea medicamentelor împotriva cancerului.  În: Al X-lea congres al farmaciștilor din Republica Moldova cu participare internațională, 22 noiembrie 2024, Chișinău, Republica Moldova, pp. 72-73. https://drive.google.com/file/d/1QVHD460TGa9zZSH1Q_gu581f6v0mHWZE/view
  8. SUCMAN, N., MACAEV, F. Sinteza și evaluarea derivaților de naftochinonă pentru aplicații anticancerigene. În: Al X-lea congres al farmaciștilor din Republica Moldova cu participare internațională, 22 noiembrie 2024, Chișinău, Republica Moldova, pp. 66-67. https://drive.google.com/file/d/1QVHD460TGa9zZSH1Q_gu581f6v0mHWZE/view
  9. DUCA, G., SUCMAN, N., MACAEV, F. Synthesis of spirooxindoles and study of their antiviral activity. In: Proceedings Of International Congress “By Promoting Excellence We Prepare The Future” - Selection Of Abstracts. 2 - 5 March 2023 Iaşi, România, p. 370. https://ijmd.ro/2023/proceedings-of-international-congress-by-promoting-excellence-we-prepare-the-future-selection-of-abstracts-2-5-march-2023/
  10. COJOCARI, S., BILAN, D., SUCMAN, N., STĂNGACI, E., MACAEV, F.. Transforming the five-membered ring d in a pregnenolone derivative into a six-membered ring through skeletal rearrangement. In: New frontiers in natural product chemistry, 12-13 octombrie 2023, Chișinău, Republica Moldova, p. 29. DOI: 10.19261/nfnpc.2023.ab22
  11. BILAN, D., COJOCARI, S., POGREBNOI, V., SUCMAN, N., MACAEV, F. The opening of dehydropregnenolone epoxide leading to the non-saturated skeletal rearrangement product. In: New frontiers in natural product chemistry, 12-13 octombrie 2023, Chișinău, Republica Moldova, p. 30. DOI: 10.19261/nfnpc.2023.ab23
  12. SUCMAN, N. Nucleophilic addition of pyridine amines to the double bond of in situ generated morita-baylis-hillman adducts from indole-2,3-dione. In: New frontiers in natural product chemistry, 12-13 octombrie 2023, Chișinău, Republica Moldova. p. 26. DOI: 10.19261/nfnpc.2023.ab19
  13. SUCMAN, N. Diastereoselective synthesis of a novel cyclic derivative based on 2,3-indolinedione. In: New frontiers in natural product chemistry, 12-13 octombrie 2023, Chișinău, Republica Moldova. p. 25. DOI: 10.19261/nfnpc.2023.ab18
  14. POGREBNOI, V., SUCMAN, N., MACAEV, F. The amides of dehydroabietic acid in synthesys of spiropyranes with the participation of carbonyl compounds.  In: New frontiers in natural product chemistry, 12-13 octombrie 2023, Chișinău, Republica Moldova. p. 23. DOI: 10.19261/nfnpc.2023.ab16
  15. POGREBNOI, V., SUCMAN, N., MAKAEV, F. The spirocyclopropane with fragments of dehydroabietic acid and aminooxindole. In: New frontiers in natural product chemistry, 12-13 octombrie 2023, Chișinău, Republica Moldova. p. 22. DOI: 10.19261/nfnpc.2023.ab15
  16. SUCMAN, N., COJOCARI, S., BILAN, D., MACAEV, F. Applying NMR for the detection of unusual reaction products of steroids. În: “BOOK OF ABSTRACTS”, Central European NMR Symposium & Bruker Users Meeting, 13-15 September 2023, Praga, Cehia,  P.32
  17. SUCMAN, N., COJOCARI, S., BILAN, D., POGREBNOI, V., MACAEV, F. Applying NMR for ascertaining the product's structure of unexpected dehydropregnenolone moiety skeletal rearrangement. În: “BOOK OF ABSTRACTS”, Central European NMR Symposium & Bruker Users Meeting, 13-15 September 2023, Praga, Cehia, P.32
  18. SUCMAN, N., CALINICENCO, S., MACAEV, F. Using NMR analysis to identify unconventional adducts of indole-2,3-dione. În: “BOOK OF ABSTRACTS”, Central European NMR Symposium & Bruker Users Meeting, 13-15 September 2023, Praga, Cehia,  p. 31


Patent

  1. MACAEV, F., KHRIPACH ,Vladimir, STÂNGACI, Eugenia, ZHABINSKII, Vladimir, SUCMAN, Natalia, HRABAVETS, Iryna, BILAN, Dmitrii, TSYBRUK, Tatsiana, COJOCARI, Sergiu. Clorură de 3-(2-((3S,10R,13S)-3-hidroxi-10,13-dimetil-2,3,4,7,8,9,10,11,12,13,14,15-dodecahidro-1H-ciclopenta[a]fenantren-17-il)-2-oxoetil)-1-vinil-1H-imidazol-3-iu cu activitate antitumorală împotriva cancerului de prostate. Brvet de invenție MD 4894 B1 din 2024.05.31. https://www.db.agepi.md/Inventions/details/a%202023%200010/LinkTitluAcc