New products with preventive and therapeutic potential basing on natural products of vegetal origin and modern methods of organic synthesis

Programme

Research project within the State Program financed by the National Agency for Research and Development of the Republic of Moldova

Strategic priority

I. Health

Strategic direction

3. Pharmaceuticals and nutraceuticals

Code
ANCD/20.80009.8007.03
Duration
2020-2023
Institutions

1. Institute of Chemistry, Laboratory of Natural and Biologically Active Compounds.

2. State University of Medicine and Pharmacy “Nicolae Testemițanu”, Laboratory Tissue Engineering and Cellular Cultures, Department of Pharmaceutical and Toxicological Chemistry, Department of Pharmacognosy and Pharmaceutical Botany, Department of Orthopedics and Traumatology.  

Project manager

Dr. habilitate Veaceslav KULCITKI

Team:

The team of the Institute of Chemistry

  
Corresponding member, dr. habilitate UNGUR Nicon Dr. GIRBU Vladilena
Dr. habilitate ARICU Aculina Dr. LUNGU Lidia
Dr. DRAGALIN Ion Dr. SECARA-KUSNIR Elena
Dr. CIOCARLAN Alexandru Dr. BLAJA Svetlana
Dr. GRINCO Marina CAZACU Cătălina
Dr. CUCICOVA Caleria COCIU Vera 
Dr. MORARESCU Olga BIRCA  Natalia

 

Abstract

Healthcare represents one of the global problems faced by humanity. Intensive industrialization, radical change in living habits and exponential population growth imposed to the society survival solutions which frequently are in disagreement with the sustainability philosophy, especially as regarding healthcare problems. In this context, elaboration of remedies with preventive and therapeutic potential on the basis of accessible vegetal sources represents a reasonable compromise which can contribute to human healthcare with minimal risks for adverse effects and reduced environmental impact. The fundamental scope of the current project represents valorization of vegetal sources available in the Republic of Moldova for the elaboration of novel pharmaceutical remedies and nutraceuticals.
The specific aspect of the project stems on several basic pillars. First of all, the priority will be given to agricultural plant sources. After their basic use substantial wastes are generated, which often contain secondary metabolites with complex structure and relevant biological activity. Currently, the scheme for efficient valorization of such materials are lacking. The spontaneous flora is also interesting from this point of view, but its collection or introduction into agriculture represents an impediment for tangible results within the limited project timeframe. Second, due to the fact that secondary metabolites with relevant activities are as a rule chemically unstable and their content in the host organisms is usually very low, we intend to develop an ample program of chemical modification of natural compounds that are available in preparative amounts from local natural sources with the aim of expanding structural diversity and study the properties of the obtained new compounds. Terpenic compounds will be investigated predominantly due to their wide availability from local raw materials. The study strategy will not be random, but based on a clear principle of biomimetic pharmacophoric groups. Their combination with the terpenic skeleton will contribute to a better biocompatibility of the synthesized compounds. Third, in order to demonstrate the viability of local raw material use for the elaboration and production of pharmaceutical products and nutraceuticals, several most promising vegetal objects will be selected and profoundly studied for the demonstration of their inofensivity and utility of intact natural components, isolated according to elaborated separation schemes in the form of individual fractions. Several pathologies will be targeted, which require remedies possessing antimicrobial, antifungal or antioxidative action. In particular, these are cutaneous lesions following burns and surgical interventions, as well as diabetes complications. In the nearest perspective maladies of central nervous system like Alzheimer and Parkinson will be addressed. The final products will be elaborated taking into consideration the ease of following promotion in different forms, including as nutraceuticals or personal hygiene means.
Project activities represent a profound interdisciplinary character, which imposed creation of a consortium of two partners: Institute of Chemistry and Medical University. Such collaborative projects have been poorly promoted previously within the former Academy of Sciences and under current circumstances represent an efficient tool to furnish viable solutions on the interface of adjacent disciplines.

Results, activities

The phytochemical study of extractive plant products was carried out. Collected plant material, waste: lavender, sunflower, apple, sea buckthorn, tobacco, spruce. Cultivated plants: mint, lemon balm, rosemary, oregano, sage. Identified substances: oleanolic, ursolic, pomolic, rosmarinic, ent-kaurenoic, ent-trachylobanoic, ent-15-angeloyloxykaurenoic acids, solanesol, polyphenols, flavonoids. Extraction of important metabolites was performed using a non-conventional ultrasound extraction procedure. Major amounts of pomolic acid were found in lavender and apple pomace extracts and rosmarinic acid in Lamiaceae plants. Efficient fractionation schemes and preparative isolation of the compounds of interest from the studied sources were developed. The synthesis of norlabdanic, homodrimanic, drimanic and iononic compounds from the oxidative degradation of sclareol was carried out, including the selective synthesis of manoyloxides and ent-gomeric acids which represent natural compounds. Radical processes for the synthesis of terpene derivatives functionalized with azide, lactam and pyrrolidine groups have been applied to the radical carboazidation of diterpene and sesquiterpene compounds. Transformations based on the conversion of functional groups were carried out for the synthesis of prenylated acylguanidines, scalarane sesterterpenoids functionalized in C and D rings, terpenic derivatives with terpene hybrid structure and amide and thioamide fragments, benzothiazolinic, thiolactamic, aminobenzothiazolic, aminobenzimidazolic, benzimidazolic, phenothiazinic and 1,3,4-thiadiazole heterocycles. The fungicidal and antimicrobial activity studies of terpenic-heterocyclic hybrid compounds, the fungicidal activity tests of oxidized essential oils, the antimicrobial and synergistic activity tests of prenylated acylguanidines were carried out. The studies of the cytotoxic activity against a series of tumor cells of diterpenic compounds with an ent-kauranic skeleton functionalized with azides, amines, lactams, pyrrolidines were carried out. Testing of the activity of stimulating cell multiplication of fibroblast and mesenchymal stem cell cultures of the series of plant extracts obtained within the project was carried out. Testing of the antioxidant activity of most of the plant extracts obtained within the project as well as of the auto-oxidation products of the essential oils was carried out. In vivo testing experiments of selected products from plant sources included the study of burn wounds healing action based on semi-solid preformulations containing plant extracts (4 samples). The burn wound remedial effect has been demonstrated based on histological studies. The insecticidal action of essential oils chemically modified by thionylation and oxidation has been studied. The study of chronic and acute toxicity was carried out, demonstrating the lack of toxicity of lavender extracts. In order to ensure the standardization of extractive products, quantitative analysis of triterpenic acids in lavender and apple extract, quantitative analysis of triterpenic acids and rosmarinic acid in Lamiaceae extracts using the qNMR method, analysis of the total content of phenolic compounds in extracts of lavender and sea buckthorn, analysis of flavonoid content in lavender and sea buckthorn extracts have been performed.

2021

Scientific seminar,
June 4,  2021, 
in virtual format. 

 

The scientific seminar with international participation NEW FRONTIERS IN NATURAL PRODUCT CHEMISTRY is at its VIth edition and this year is dedicated to the memory of the distinguished chemist Pavel VLAD, who would have celebrated the 85th anniversary on June 6, 2021.
The seminar was attended by about 60 researchers from 8 countries (Italy, Germany, Romania, Poland, France, Switzerland, Belgium and the Republic of Moldova).
13 oral scientific reports and 16 poster presentations were presented, which were published in the Book of abstracts, edited in electronic format.

Program
Scientific seminar with international participation (hybrid format): NEW FRONTIERS IN NATURAL PRODUCT CHEMISTRY,
7th edition, October 12-13, 2023

The scientific seminar NEW FRONTIERS IN NATURAL PRODUCT CHEMISTRY is at its VII-th edition with the main aim of establishing an efficient communication between natural product researchers at national and international levels, as well as active promotion of this fascinating research field in the society.

The seminar program includes oral presentations of researchers selected by the Scientific Committee and poster presentations which will be thoroughly reviewed and adapted to the format as an electronic edition.

Program

Book of abstracts
Publications

Chapters in international/national monographs

  1. ARICU, A., CIOCARLAN, A., LUNGU, L., CUCICOVA, C., BLAJA, S., SECARA, E., UNGUR N. Synthesis of Biologically Active Nitrogen and Sulfur-Containing Terpenoids. In: Fundamental and Biomedical Aspects of Redox Processes. IGI Global, 2023, 369-399.
  2. ARÎCU, A., KULCIŢKI, V., UNGUR, N. Sclareolul–materie primă sustenabilă pentru sinteza compușilor terpenici cu valoare adăugată înaltă. In: Chimie ecologică: istorie și realizări: Academicianul Gheorghe Duca, 70 ani de la naștere. Chişinău: 2022, 86-113. ISBN 978-9975-159-05-0. https://ibn.idsi.md/vizualizare_articol/164444.
  3. ARÎCU, A., LUNGU, L., BLAJA, S., CUCICOVA, C., CIOCÂRLAN, A. Sinteza și studiul activității antimicrobiene a compușilor norlabdanici cu unități structurale heterociclice. In: Acad. A. Gulea - Conferinţa Ştiinţifică Naţională cu participare Internaţională: „Materiale Avansate în Biofarmaceutică şi Tehnică”, Chişnău, 2021, 10-34.
  4. UNGUR, N., MORARESCU, O. Sinteza dirijată a unor diterpenoide tetraciclice bioactive din acidul ent-kaur-16-en-19-oic. In: Acad. A. Gulea - Conferinţa Ştiinţifică Naţională cu participare Internaţională: „Materiale Avansate în Biofarmaceutică şi Tehnică”, Chişnău, 2021, 294-313.


Abstract books

  1. ARÎCU, A., KULCIȚKI, V. eds. New frontiers in natural product chemistry. Scientific seminar with international participation, VI-th edition. Book of Abstracts. Chișinău, Institute of Chemistry, 2021. DOI: https://doi.org/10.19261/nfnpc.2021. IBN: https://ibn.idsi.md/ro/collection_view/1058
  2. ARÎCU, A., KULCIȚKI, V. eds. New frontiers in natural product chemistry. Scientific seminar with international participation, VII-th edition. Book of Abstracts. Chișinău, Institute of Chemistry, 2023. DOI: https://doi.org/10.19261/nfnpc.2023. IBN: https://ibn.idsi.md/ro/collection_view/2386


Articles in international journals

  1. ANTOCI, V., CUCU, D., ZBANCIOC, Gh., MOLDOVEANU, C., MANGALAGIU, V., AMARIUCAI-MANTU, D., ARICU, A, MANGALAGIU I. I. Bis-(imidazole/benzimidazole)-pyridine derivatives: synthesis, structure and antimycobacterial activity. In: Future Medicinal Chemistry, Part XII, 2020, 12(3), 207-222. https://doi.org/10.4155/fmc-2019-0063 (FI 4.2).
  2. MORARESCU, O., GRINCO, M., KULCIŢKI, V., BARBA, A., GARBUZ, O., GUDUMAC, V., GULEA, A., UNGUR, N. A straightforward synthesis of natural oxygenated ent-kaurenoic acid derivatives. In: Synthetic communications, 2020, 50. https://doi.org/10.1080/00397911.2020.1821225 (FI 2.1).
  3. ZINICOVSCAIA, I., GUNDORINA, S., VERGEL, C., GROZDOV, D., CIOCARLAN, A., ARICU, A., DRAGALIN, I., CIOCARLAN, N. Elemental analysis of Lamiaceae medicinal and aromatic plants growing in the Republic of Moldova using neutron activation analysis. In: Phytochemistry Letters. 2020, 35, 119–127. https://doi.org/10.1016/j.phytol.2019.10.009 (FI 1.7).
  4. LUNGU, L., CIOCARLAN, A., SMIGON, C., OZER, I., SHOVA, S., GUTU, I., VORNICU, N., MANGALAGIU, I., D'AMBROSIO, M., ARICU, A. Synthesis and evaluation of biological activity of homodrimane sesquiterpenoids bearing 1,3,4-oxadiazole or 1,3,4-thiadiazole units. In: Chemistry of Heterocyclic Compounds, 2020, 56(5), 578-585. https://doi.org/10.1007/s10593-020-02703-7 (FI 1.5).
  5. ARICU, A., KUCHKOVA, K., SECARA-CUSHNIR, E., BARBA, A., UNGUR, N., VORNICU, N. Synthesis and antimicrobial activity of new drimane and homodrinane sesquiterpenoids with oxadiazole and thiadiazole fragments. In: Chemistry of Natural Compounds, 2020, 56(4), 656-662. https://doi.org/10.1007/s10600-020-03115-x (FI 0.8).
  6. CIOCARLAN, A., LUNGU, L., BLAJA, S., DRAGALIN, I., ARICU, A. The use of some non-conventional methods in chemistry of bicyclohomofarnesenic methyl esters. In: Chemistry Journal of Moldova, 2020, 15(2), 69-77. https://doi.org/10.19261/cjm.2020.791. IBN: https://ibn.idsi.md/ro/vizualizare_articol/118145
  7. CIOCARLAN, A., LUPASCU, L., ARICU, A., DRAGALIN, I., POPESCU, V., GEANA, E.I., IONETE, R.E., VORNICU, N., DULIU, O.G., HRISTOZOVA, G. AND ZINICOVSCAIA, I. Chemical composition and assessment of antimicrobial activity of lavender essential oil and some by-products. In: Plants, 2021, 10(9), 1829.  https://doi.org/10,3390/plants1091829 (FI 4.5). IBN: https://ibn.idsi.md/ro/vizualizare_articol/138166
  8. PRUTEANU, E., GÎRBU, V., UNGUR, N., PERSOONS, L., DAELEMANS, D., RENAUD, P., KULCIȚKI, V. Preparation of antiproliferative terpene-alkaloid hybrids by free radical-mediated modification of ent-kauranic derivatives. In: Molecules, 2021, 26(15), 4549. https://doi.org/10.3390/molecules26154549 (FI 4.6).
  9. GEANĂ, E.-I., CIUCURE, C.T., IONETE, R.E., CIOCARLAN, A., ARICU, A., FICAI, A., ANDRONESCU, E. Profiling of phenolic compounds and triterpene acids in different apple (Malus domestica Borkh.) cultivars. In: Foods, 2021, 10(2), 267-282.  https://doi.org/10.3390/foods10020267 (FI 5.2).  IBN: https://ibn.idsi.md/ro/vizualizare_articol/126448
  10. MORARESCU, O., GRINCO, M., KULCIŢKI, V., SHOVA, S., UNGUR, N. An Alternative Approach towards C-12 Functionalized Scalaranic Sesterterpenoids. Synthesis of 17-Oxo-20-norscalaran-12α,19-O-lactone. In: Marine Drugs, 2021, 19(11), 636.  https://doi.org/10.3390/md19110636 (FI 5.4).
  11. PRUTEANU, E., TAPPIN, N.D., GÎRBU, V., MORARESCU, O., DÉNÈS, F., KULCIŢKI, V., RENAUD, P. Forskolin Editing via Radical Iodo-and Hydroalkylation. In: Synthesis, 2021, 53(07), 1247-1261. https://doi.org/10.1055/s-0040-1706003 (FI 2.6).  IBN: https://ibn.idsi.md/ro/vizualizare_articol/125941
  12. BLAJA, S.P., LUNGU, L.V., KUCHKOVA, K.I., CIOCARLAN, A.G., BARBA, A.N., VORNICU, N., ARICU, A.N. Norlabdane Compounds Containing Thiosemicarbazone or 1,3-Thiazole Fragments: Synthesis and Antimicrobial Activity. In: Chemistry of Natural Compounds, 2021, 57(1), 101-110. https://doi.org/10.1007/s10600-021-03292-3 (FI 0.8). IBN: https://ibn.idsi.md/ro/vizualizare_articol/126852
  13. ARÎCU, A. The natural product chemistry of terpenoids - a tribute to the remarkable legacy of academician Pavel Vlad. In: Chemistry Journal of Moldova. 2021, 16(1), 8-29. https://doi.org/10.19261/cjm.2021.856.  IBN: https://ibn.idsi.md/ro/vizualizare_articol/134250
  14. CIOCARLAN A., LUPASCU L., ARICU A., DRAGALIN I., CIOCARLAN N., ZINICOVSCAIA I., SLANINA V., YUSHIN N. Chemical composition of the essential oil and antimicrobial properties of crude extract from Tanacetum corymbosum (L.). In: Chemistry Journal of Moldova, 2021, 16(2), 83-90. https://doi.org/10.19261/cjm.2021.877.
  15. CIOCARLAN, A. (+)-Larixol and larixyl acetate: syntheses, phytochemical studies and biological activity assessments. In: Chemistry Journal of Moldova. 2021, 16(1), 30-45. https://doi.org/10.19261/cjm.2021.836 IBN: https://ibn.idsi.md/ro/vizualizare_articol/134251
  16. MORARESCU, O., TRAISTARI, M., BARBA, A., DUCA, G., UNGUR, N. AND KULCIȚKI, V. One-step selective synthesis of 13-epi-manoyl oxide. In: Chemistry Journal of Moldova, 2021, 16(1), 99-104. http://dx.doi.org/10.19261/cjm.2021.820.
  17. MORARESCU, O., GRINCO, M., KULCITKI, V. et al. Synthesis of highly functionalized biologically active tetracyclic diterpenoids from ent-kaur-16-en-19-oic acid under modified Prévost-Woodward reaction conditions. In: Russian Journal of Organic Chemistry, 2021, 57, 1931–1939. https://doi.org/10.1134/S1070428021120058 (FI 0.8).
  18. CIOCARLAN A., HRISTOZOVA G., ARICU A., DRAGALIN I., ZINICOVSCAIA I., YUSHIN N., GROZDOV D., POPESCU V. Determination of the elemental composition of aromatic plants cultivated industrially in the Republic of Moldova using neutron activation analysis. In: Agronomy, 2021, 11(5), 1011-1030. https://doi.org/10.3390/agronomy11051011 (FI 3.7).
  19. LUNGU, L., CUCICOVA, C., BLAJA, S., CIOCARLAN,  A., DRAGALIN,  I., VORNICU,  N., GEANA, E., MANGALAGIU, I.I., ARICU, A. Synthesis of homodrimane sesquiterpenoids bearing 1,3-benzothiazole unit and their Antimicrobial activity evaluation. In: Molecules, 2022, 27, 5082-5096. https://doi.org/10.3390/molecules27165082 (FI 4.6).
  20. CIOCARLAN, A., DRAGALIN, I., ARICU, A., LUPASCU, L., CIOCARLAN, N., VERGEL, K., DULIU, O.G., HRISTOZOVA, G., ZINICOVSCAIA, I. Chemical profile, elemental composition, and antimicrobial activity of plants of the Teucrium (Lamiaceae) genus growing in Moldova. In: Agronomy, 2022, 12(4), 772-788. https://doi.org/10.3390/agronomy12040772 (FI 3.7).
  21. CIOCARLAN, A. From (-)-sclareol to norlabdane heterocyclic hybrid compounds. In: Chemistry Journal of Moldova, 2022, 17(2), 30-45. http://dx.doi.org/10.19261/cjm.2022.958.
  22. GIRBU, V., ORGAN, A., GRINCO, M., COTELEA, T., UNGUR, N., BARBA, A., KULCITKI, V. Identification, Quantitative Determination and Isolation of Pomolic Acid from Lavender (Lavandula Angustifolia Mill.) Wastes. In: Sustainable Chemistry and Pharmacy, 2023, 33, 101140. https://doi.org/10.1016/j.scp.2023.101140 (FI 6.0).
  23. BLAJA S., LUNGU L., CIOCARLAN A., VORNICU N., ARICU A. Synthesis and evaluation of antimicrobial activity of tetranorlabdane compounds bearing 1,3,4-thiadiazole units. In: Chemistry Journal of Moldova, 2023, 18(1), 86-91.   https://doi.org/10.19261/cjm.2022.1026.
  24. LUNGU, L, BLAJA, S., CUCICOVA, C., CIOCARLAN, A., BARBA, A., KULCIȚKI, V. SHOVA, S., VORNICU, N., GEANA, E.-I., MANGALAGIU, I.I., ARICU, A. Synthesis and antimicrobial activity evaluation of homodrimane sesquiterpenoids with benzimidazole unit. In: Molecules, 2023, 28(3), 933, 1-14. https://doi.org/10.3390/molecules28030933 (FI 4.6).
  25. GRINCO, M., MORARESCU, O., LEMBO, F., UNGUR, N., TURCO, L., CORETTI, L., CARBONE, M., CELENTANO, C., CIAVATTA, M. L., MOLLO, E., KULCITKI, V., BUOMMINO, E. Synthesis and antimicrobial properties of guanidine-functionalized labdane type diterpenoids. In: European Journal of Medicinal Chemistry, 2024, 264, 115981. https://doi.org/10.1016/j.ejmech.2023.115981 (FI 6.7).


Articles in national journals

  1. COJOCARU-TOMA, M., ANCUCEANU, R., DINU, M., CIOBANU, N., CIOBANU, C., COTELEA, T., JIAN, M., COBZAC, V., NACU, V., TOMA, M. M. Viability and cytotoxicity evaluation on isolated hepatocytes of some species rich in polyphenolic compounds. In: Advansed Nano-Bio Materials and Devices –AdvNanoBioM&D, 2020, 4(2), 580-585. ISSN: 2559-1118
  2. DRAGALIN, I., MELNIC, V., PELEAH, E. Polichimismul intraspecific mentha spicata. In: Studia Universitatis Moldaviae. Seria Ştiinţe reale şi ale naturii. 2020, 6 (136), 60-63. https://doi.org/10.5281/zenodo.4431568. IBN: https://ibn.idsi.md/ro/vizualizare_articol/120149
  3. ORGAN, A., GÎRBU, V., COJOCARU-TOMA, M., KULCIŢKI, V., COTELEA T., UNGUR, N. Therapeutic potential and preventive effects of major triterpenic secondary metabolites from Lavandula angustifolia. In: Revista Farmaceutică a Moldovei, 2021, 45(1), 79-81. IBN: https://ibn.idsi.md/ro/vizualizare_articol/138710


Patents

  1. KULCIŢKI, V., UNGUR, N., GRINCO, M., BUOMMINO E., LEMBO, F. Derivați guanidinici ai acizilor ent-gomerici cu proprietăți antimicrobiene și efect sinergistic în terapia combinată. Cerere de brevet de invenție (7114/2022.11.18)
  2. CIOCARLAN, A., POPESCU, V., LUPAȘCU, L., DRAGALIN, I., LUNGU, L., BLAJA, S., ARICU, A. Forma oxidată a uleiului volatil de coriandru cu proprietăți antifungice și antibacteriene. Cerere de brevet de invenție (7168/11.04.2023).
  3. CIOCARLAN, A., POPESCU, V., LUPAȘCU, L., DRAGALIN, I., LUNGU, L., BLAJA, S., ARICU, A., LUPAŞCU, G., GAVZER, S. Utilizarea formei oxidate a uleiului volatil de coriandru în calitate de inhibitor contra fungilor Fusarium avenaceum şi Fusarium equiseti. Cerere de brevet de invenție (7250/06.10.2023).
  4. KULCIŢKI, V., GIRBU, V., PRUTEANU, E., RENAUD, PH., DAELEMANS, D., MOLLO, E., DEFRANOUX, F., UNGUR, N. Metil ent-17-amino-kauran-19-oat cu activitate citotoxică selectivă. Brevet de invenție MD 4718 B1. In: BOPI, 10/2020, p. 47-48. http://agepi.gov.md/ro/bopi/10-2020.
  5. ARÎCU, A., CIOCARLAN, A., LUNGU, L., BLAJA, S., VORNICU, N.  5-(Homodrim-6,8-dien-11-il)-1,3,4-tiadiazol-2(3 H )-imină cu proprietăţi antifungice. Brevet de invenție 4765 B1, In: BOPI, 08/2021, p. 58-59. http://agepi.gov.md/sites/default/files/bopi/BOPI_08_2021.pdf
  1. ARÎCU, A., CIOCÂRLAN,  A.,  LUNGU, L., BLAJA, S., VORNICU, N. (Z/E )-2-(1-((1R,2R,8aS)-2-hidroxi-2,5,5,8a-tetrametildecahidronaftalen-1-il)propan-2-iliden)hidrazincarbotioamidă pentru utilizare în calitate de remediu antifungic. Brevet de invenție 4769. B1. In: BOPI, 10/2021, p. 44-45. http://agepi.gov.md/sites/default/files/bopi/BOPI_10_2021.pdf 
  2. KULCIŢKI, V., GIRBU, V., PRUTEANU, E., RENAUD, PH., DAELEMANS, D., UNGUR, N. Metil ent-15-hidroxi-16-azido-17-carboximetoximetilkauranoat cu activitate citotoxică selectivă. Brevet de invenție MD4785 (13) B1. In: BOPI, 2022, (1), p. 47-48. https://www.agepi.gov.md/sites/default/files/bopi/BOPI_01_2022.pdf#page=7.
  3. KULCIŢKI V., GÎRBU V., PRUTEANU E., RENAUD P., DAELEMAS D., UNGUR N. Noi spiro γ-lactame, derivate ale acidului ent-kaurenoic, cu activitate citotoxică selectivă. Brevet de invenție MD4786 (13) B1. In: BOPI, 2022, (1), p. 48-49. https://www.agepi.gov.md/sites/default/files/bopi/BOPI_01_2022.pdf#page=7.
  4. KULCIŢKI, V., GIRBU, V., PRUTEANU, E., RENAUD, PH., DAELEMANS, D., UNGUR, N. Ester metilic al acidului (16R)-spiro[pirolidin-2´, 16-ent-17-norkauran]-19-oic cu activitate citotoxică selectivă. Brevet de invenție MD4792 (13) B1. In: BOPI, 2022, (2), p. 57-58. https://www.agepi.gov.md/sites/default/files/bopi/BOPI_02_2022.pdf#page=7.
  5. KULCIŢKI, V., GIRBU, V., PRUTEANU, E., RENAUD, PH., DAELEMANS, D., UNGUR, N. Utilizarea metil ent-16-azido-17-carboxietoximetilkauranoatului în calitate de inhibitor selectiv al proliferării limfomului non-Hodgkin. Brevet de invenție MD4805 (13) B1. In: BOPI, 2022, (5), p. 55-56.
    https://www.agepi.gov.md/sites/default/files/bopi/BOPI_05_2022.pdf#page=7.
  6. LUNGU, L., CIOCARLAN, A., CUCICOVA, C., BLAJA, S., ARICU, A., VORNICU, N. 2-Amino-1-∆8,9-biciclohomofarnesenoil)-benzimidazol pentru utilizare în tratamentul afecțiunilor provocate de fungi și bacterii. Hotărâre AGEPI de acordare a BI nr. 10344 din 2023.10.25).