Proiect PN-III-P4-ID-PCE-2020-1028 :   Project timespan   Project team   Abstract   Budget   Results  
Contract:PCE 220/2021

Title: Tailoring Organochalcogen (Se, Te) Based Compounds with Potential as Antitumor Agents

Project timespan
2021 -- 2023

Abstract
The goal of this proposal is to obtain new organochalcogen compounds and metal complexes which can act as efficient antitumor and chemopriventive agents. Our objectives are: (i) to design organochalcogen derivatives of type R2E2, RR'E, R2E (E = Se,Te; R,R' = organic groups with donor atoms capable for intra- or intermolecular interactions) and their metal (Au,Ag,Zn,Sn,Bi) complexes, with potential as antioxidant, antitumor and chemopreventive agents, (ii) to study their solution behavior and solid state structure, (iii) to assay their antitumor activity against commercial tumor cell lines, (iv) to find an optimized strategy, based on experimental evidence and theoretical approach (DFT, QSAR) for highly active species with low toxicity, (v) to investigate the relation structure-antioxidant activity-antitumor properties for selected classes of compounds and (vi) to identify the interaction mechanism at cell level. The proposed organochalcogen compounds are flexible, potential tridentate systems, containing, besides Se or Te, other functionalities (pyrazole (pz), phenylthiazole (Phtz), amino, imino, COOH, OH) which share with the central chalcogen or the metal their donation ability and the own biological properties. The chosen ligands and their metal complexes are very attractive both for fundamental research and as promising active antitumor agents. The project combines research excellence and complementarity and is essentially based on inter- and multidisciplinary studies.

Budget
Budget chapter (expenses) 2021 (lei) 2022 (lei) 2023 (lei) Total
1 Salaries 180000 210000 210000 600000
2 Logistics 208293 54162 87734 350189
2.1 Capital expenses 120000 20000 0 140000
2.2 Stocks expenses 88293 34162 87734 210189
3 Mobility 0 28000 22000 50000
4 Overhead (23%) 61707 62598 73538 197843
5 Total 450000 354760 393272 1198032

Results

The implementation of the project: January 2021 – December 2023
The activities developed during the implementation of this project were dedicated to the fulfilment of the objectives proposed in the approved application (contract 220/2021), as followings:
  • The synthesis and structural characterization of new homo- and heteroleptic diorganochalcogen compounds of type RR'Se (R = R' = Me2C(OH)CH2, 2-(Me2NCH2)C6H4, CH2phtz, CH2CH2pz; R ≠ R', R = 2-(Me2NCH2)C6H4, R' = Me2C(OH)CH2, (CF3)2C(OH)CH2); R = 2-(Me2NCH2)C6H4, R = 2-(Et2NCH2)C6H4, 2-[O(CH2CH2)2NCH2]C6H4, 2-[MeN(CH2CH2)2NCH2]C6H4; R' = CH2phtz, CH2CH2pz;
  • The synthesis and structural characterization of new compounds of type 2,6-[(2-Me2NCH2C6H4)SeCH2]2C5H3N, 2,6-[(2-Et2NCH2C6H4)SeCH2]2C5H3N, 2,6-[SeCH2C(OH)(CH3)2]C5H3N and 2,6-{[HOC(CH3)2CH2]SeCH2}2C5H3N;
  • The synthesis and structural characterization of diorganochalcogenides of type {2-(PhE)C6H4CH2}2Se (E = S, Se), (2-BrC6H4CH2)2E (E = S, Se), (2-MeC6H4CH2)2E (E = S, Se);
  • The synthesis and structural characterization of diorganodichalcogenides of type R2E2, respectively [2,6-(Me2NCH2)C6H3]2Se2, [2-{(OCH2)2CH}C6H4]2Te2, [2-(OCH2)C6H4]2Te2, [2-{2-C6H4-(4H)-oxazol-5-one}C6H4]2E2 (E = Se, Te);
  • The synthesis and structural characterization of the macrocyclic compounds [12]aneNS2E (E = O, S, Se);
  • The synthesis and structural characterization of Ag(I) complexes with homo- or heteroleptic ligands of type RR'E (E = S, Se, Te) or with pyridine derivatives, as those mentioned above; In all reactions silver salts of type AgX (X = OTf, NO3, ClO4) were used as starting materials.
  • The synthesis and structural characterization of organoselenolates of diorgano- and triorganoSn(IV) with pzCH2H2Se− ligands or ligands of type [(EPPh2)2N] (E = S, Se);
  • The synthesis and structural characterization of group 12 metals, respectively [M2Cl4{[2-{2-C6H4-(4H)-oxazol-5-one}C6H4]2Se2}] (M = Zn, Cd, Hg), {[12]aneNS2Se}2+2[ZnCl3]−, [{2,6-(Me2NCH2)C6H3}Se][CdCl3];
  • The synthesis and structural characterization of Bi(III) complexes, e.g. [CH3OCH2CH2N(CH2C6H4)2Bi]2Se;
  • All compounds were structurally investigated, both in solution and in solid state, by spectroscopic methods (multinuclear NMR, ESI MS or APCI MS and IR spectroscopy). For the silver complexes the molar conductivities were determined, when their behaviour as 1:1 electrolytes was established.
    For selected complexes the molecular and the crystal structures were determined by single-crystal X-ray diffraction. Mono- or dinuclear species were identified and in most cases supramolecular networks were formed by secondary interactions;
  • Investigations upon the catalitic activity of the diorganoselenides in the oxidation reaction of PhSH to PhSSPh. A mechanism including the intermediary formation of the RR'Se=O species was established by using NMR and UV-Vis spectroscopies. The 1H NMR spectra revealed the formation of hypervalent species in solution, based on N→Se intramolecular interactions. The probability of such N→Se intramolecular interactions in the diorganoselenoxides, as well as their strength, were investigated at theoretical level, by DFT calculations.
  • Studies upon the antiproliferative activity of the diorganochalcogen ligands and their silver complexes. The silver complexes showed a better activity than the free ligands, and, moreover, better when compared with that of the standard drug Dacarbazine.
Articles
  1. Silver(I) complexes based on diorganoselenium(II) ligands with amino or hydroxo functionalities,
    M. David, R. Mitea, A. Silvestru, J. Mol. Struct., 2021, 1246, 131243.
    DOI: 10.1016/j.molstruc.2021.131243

  2. New mercury(II) complexes of polydentate ligands,
    C. Șalgău, A. Dobri, A. Silvestru Studia Univ. “Babes-Bolyai”, Chemia, LXVI, 2021, 3, 175-185.
    DOI: 10.24193/subbchem.2021.3.10

  3. Silver(I) and gold(I) complexes of multidentate ligands based on functionalized pyridine,
    D. Dumitraș, A. Pop, A. Silvestru, Polyhedron, 2022, 220, 115801.
    DOI: 10.1016/j.poly.2022.115801

  4. New ionic [{2-(Me2NCH2)C6H4}(R)Sn{(EPPh2)2N}][(EPPh2)2N] (R = 2-(Me2NCH2)C6H4, nBu; E = O, S, Se) compounds. Solution behavior and solid state structure,
    E Denes, L. Marangiu, M. Arca, V. Lippolis, A. Silvestru, J. Organomet. Chem., 2022, 963, 122282.
    DOI: 10.1016/j.jorganchem.2022.122282

  5. Group 12 metal complexes of mixed thia/aza and thia/oxa/aza macrocyclic ligands,
    A. M. Hodorogea, A. Silvestru, V. Lippolis, A. Pop, Polyhedron, 2022, 216, 115650.
    DOI: 10.1016/j.poly.2022.115650

  6. Homoleptic and heteroleptic diorganoselenides containing pyrazole functionalities. Synthesis, characterization, and antioxidant activity,
    R. A. Popa, A. Nicoară, M. Arca, V. Lippolis, A. Pintus, A. Silvestru, Appl. Organomet. Chem., 2022, 36, e6894.
    DOI: 10.1002/aoc.6894

  7. On the coordination behaviour of diorganoselenium ligands based on amino and azole functionalities: silver(I) complexes with relevance for biological applications,
    R. A. Popa, M. David, E. Licarete, M. Banciu, A. Silvestru, New J. Chem., 2022 , 46, 23019-23029.
    DOI: 10.1039/D2NJ04812D

  8. New organobismuth(III) compounds based on a tetrahydro dibenzo[c,f][1,5]azabismocine heterocyclic framework,
    L. Corjuc, C. Silvestru, A. Silvestru, Rev. Roum. Chim., 2023 , 68(5-6), 209-215.
    DOI: 10.33224/rrch.2023.68.5-6.02

  9. Silver(I) complexes with diorganochalcogen ligands of type (2-MeC6H4CH2)2E (E = S, Se). Synthesis, structure and antiproliferative activity,
    L. Corjuc, A. Pop, E. Licarete, M. Banciu, A. Silvestru, Inorg. Chim. Acta, 2024 , 565, 121972.
    DOI: 10.1016/j.ica.2024.121972

  10. Silver(I) complexes with diorganochalcogen ligands of type (2-BrC6H4CH2)2E (E = S, Se). Synthesis, structure and reactivity,
    L. Corjuc, A. Pop, A. Silvestru, Polyhedron, in preparation.

  11. Di- and triorganotin(IV) complexes with organoselenolato ligands. Synthesis and structure,
    M. Tamas, R. A. Popa, A. Silvestru, J. Organomet. Chem., in preparation.

  12. On the reactivity of diorganoselenides of type RR'Se (R = aryl, R' = alkyl) towards group 11 metals. Synthesis, structure and antiproliferative activity,
    R. A. Popa, M. David, A. Silvestru, J. Mol. Struct., in preparation.

Conferences
  1. Organochalcogen compounds with relevance for biology. Structure and reactivity,
    A. Silvestru,
    at Simpozionul cu participare internațională – Noi tendințe și strategii în chimia materialelor avansate, cu relevanță în sisteme biologice, tehnică și protecția mediului, Timișoara, October 7-8, 2021 (oral presentation).

  2. Silver Complexes with Diorganochalcogen Ligands of Type (2-XC6H4CH2)2E (E = S, Se; X = Br, CH3),
    A. L. Corjuc, A. Silvestru,
    at Zilele Academice Clujene, Cluj-Napoca, October 21-22, 2021 (oral presentation).

  3. Diorganoselenides and their late d-metal complexes. Synthesis and structural characterization,
    M. David, R.-A. Popa, R. Mitea, A. Silvestru,
    at Zilele Academice Clujene, Cluj-Napoca, October 21-22, 2021 (oral presentation).

  4. Novel Silver(I) Complexes of Organoselenium Ligands Bearing Organic Groups with Pendant Arms and Pyrazole or Phenylthiazole Moieties,
    R. A. Popa, A. Silvestru,
    at Zilele Academice Clujene, Cluj-Napoca, October 21-22, 2021 (oral presentation).

  5. Organoselenium ligands and their silver(I) complexes. Synthesis and structural characterization,
    A.-M. Lazăr, Maria David, A. Pop,
    at 17th International Conference Students for Students, Cluj-Napoca, April 21-23, 2021 (oral presentation).

  6. Hypercoordinated organoselenium ligands and their reactivity towards group 12 metals,
    C. E. Șalgău, A. Silvestru,
    at 17th International Conference Students for Students, Cluj-Napoca, April 21-24, 2021 (oral presentation).

  7. Organoselenium pincer ligands and their reactivity towards late transition metals,
    D. Dumitraș, A. Silvestru,
    at 17th International Conference Students for Students, Cluj-Napoca, April 21-24, 2021 (oral presentation).

  8. Synthesis and structural characterization of group 11 metal complexes of [2-(Me2NCH2)C6H4]2Se,
    M. David, A. Silvestru,
    at 17th International Conference Students for Students, Cluj-Napoca, April 21-24, 2021 (oral presentation).

  9. Group 11 metal complexes based on diorganoselenium ligands,
    M. David, R.-A. Popa,
    at Sesiunea de Comunicări Științifice Studențești, ediția a XVI-a, May 28-29, 2021 (oral presentation).

  10. Structural aspects in mercury complexes with organoselenium ligands,
    C. E. Șalgău, A. Silvestru,
    at Sesiunea de Comunicări Științifice Studențești, ediția a XVI-a, May 28-29, 2021 (oral presentation).

  11. Diorganoselenium ligands based on amino and azole functionalities: Synthesis, structure, coordination behaviour and relevance for biological applications,
    R.-A. Popa, E. Licarete, M. Banciu, A. Silvestru,
    at ICCBIC XXVIII, Smolenice, Slovakia, June 2022 (oral presentation).

  12. Silver(I) complexes of diorganochalcogen (S, Se) ligands. Synthesis, structure and specific properties,
    A. L. Corjuc, M. David, D. Dumitraș, A. Silvestru,
    at ICCBIC XXVIII, Smolenice, Slovakia, June 2022 (oral presentation).

  13. Novel silver(I) complexes of a diorganoselenium ligand with phenylthiazole functionalities. Synthesis, structure and potential applications,
    M. David, A. Silvestru,
    at 18th International Conference Students for Students, Cluj-Napoca, April, 2022 (oral presentation).

  14. Organochalcogen compounds with relevance for biology, organic synthesis and nanomaterials,
    A. Silvestru,
    at A XXXVI-a Conferință Națională de Chimie, Călimănești-Căciulata, October, 2022 (invited lecture).

  15. Diorganochalcogenides with alcoxo functionalities and their silver(I) complexes,
    M. Tamas, R. Mitea, A. Silvestru,
    at A XXXVI-a Conferință Națională de Chimie, Călimănești-Căciulata, October, 2022 (poster presentation).

  16. Synthesis, structural characterization and antiproliferative activity assay of a diorganoselenide ligand and its silver(I) complexes,
    M. David, A. Silvestru,
    at A XXXVI-a Conferință Națională de Chimie, Călimănești-Căciulata, October, 2022 (oral presentation).

  17. Complecși de zinc și cadmiu hipercoordinați cu liganzi organoselenolato. Sinteză și caracterizare structurală,
    C. E. Șalgău, A. Pop, A. Silvestru,
    at A XXXVI-a Conferință Națională de Chimie, Călimănești-Căciulata, October, 2022 (poster presentation).

  18. NMR spectroscopy – a versatile tool for GPx mimetic studies,
    R.-A. Popa, A. Silvestru,
    at CEUM 2022, Warsaw, Poland, September, 2022 (poster presentation).

  19. Group 11 metal complexes of diorganoselenium ligands. Synthesis, structure and specific properties,
    A. Silvestru,
    at ICCST 15, Florianopolis, Brazil, Nov.-Dec. 2022 (invited lecture).

  20. New organoselenium compounds - synthesis, structural characterization and reactivity,
    A. Pop,
    at ICCST 15, Florianopolis, Brazil, Nov.-Dec. 2022 (poster presentation).

  21. Synthesis and structural characterization of new diorganoselenides and their silver(I) complexes. Antiproliferative activity assay,
    M. David, A. Silvestru,
    at 19th International Conference Students for Students, Cluj-Napoca, April 26-30, 2023 (oral presentation).

  22. Cadmium complexes with organoselenolato ligands. Synthesis and structural characterization,
    C. Șalgău, A. Pop, A. Silvestru,
    at IRICCCE IV, Debrecen, Hungary, June 01-03, 2023 (poster presentation).

  23. Structural aspects in silver complexes with diorganochalcogen ligands of type (2-XC6H4CH2)2E, (E = S, Se; X = Br, CH3),
    L. Corjuc, A. Silvestru,
    at IRICCCE IV, Debrecen, Hungary, June 01-03, 2023 (poster presentation).

  24. Diorganotin(IV) complexes with organoselenolato ligands,
    M. Tamas, R. A. Popa, A. Silvestru,
    at IRICCCE IV, Debrecen, Hungary, June 01-03, 2023 (poster presentation).

  25. Synthesis, structural characterization, and reactivity of organoselenium compounds,
    D. Dumitraș, E. Gal, A. Pop,
    at Se2023 International Conference, Daejeon, Korea, June 26-29, 2023 (oral presentation).

  26. Diorganoselenides and their metal complexes. Synthesis, structure and relevance for biological applications,
    A. Silvestru,
    at Se2023 International Conference, Daejeon, Korea, June 26-29, 2023 (invited presentation).

For information about unpublished results contact Prof. Dr. Anca Silvestru at anca.silvestru@ubbcluj.ro.