Sinteza, karakterizacija i ispitivanje biološke aktivnosti binuklearnih kompleksa bakra(II) sa S-alkenil derivatima tiosalicilne kiseline
Synthesis, characterization and examination of the biological activity of binuclear complexes of copper(II) with S-alkenyl derivatives of thiosalicylic acid
Author
Tomović, Dušan Lj.Mentor
Radić, Gordana P.Committee members
Arsenijević, Nebojša N.Sabo, Tibor J.
Jevtić, Verica V.
Bogojeski, Jovana V.
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Show full item recordAbstract
Uvod: U ovoj Doktorskoj disertaciji ispitivane su kinetička, antimikrobna i
antitumorska aktivnost novosintetisanih binuklearnih kompleksa bakra(II) sa S-alkenil
derivatima tiosalicilne kiseline. Istraživanja u ovoj oblasti su fokusirana na
pronalaženje biološki aktivnih kompleksnih jedinjenja. Tiosalicilna kiselina i njeni
derivati su veoma interesantni kao ligandi, jer pokazuju veliku raznolikost u mogućnostima
za koordinovanje.
Materijal i metode: U okviru ovog istraživanja opisani su postupci sinteze Salkenil derivata tiosalicilne kiseline (alkenil = propenil- i izobutenil-) i odgovarajućih
binuklearnih kompleksa bakra(II). Sastav nagrađenih jedinjenja potvrđen je na osnovu
rezultata elementalne mikroanalize. Struktura sintetisanih bidentatnih liganada
okarakterisana je na osnovu rezultata infracrvene (IR) i nuklearno-magnetno-rezonancione
spektroskopije
(1H i 13C NMR), dok je struktura odgovarajućih kompleksa pretpostavljena na osnovu rezultata
infracrvene (IR) spektro...skopije, magnetnih merenja i molarne provodljivosti. Stvarna
struktura sintetisanog kompleksa bakra(II), predviđena je na osnovu rezultata rendgenske
strukturne analize. Antimikrobna aktivnost je ispitivana mikrodilucionom metodom sa
resazurinom. Supstitucione reakcije su praćene u prisustvu guanozin-5’-
-monofosfata, kao i CT-DNK (DNK iz timusa govečeta). Citotoksična aktivnost
novosintetisanih jedinjenja je ispitivana pomoću MTT kolorimetrijske tehnike.
Rezultati: Potvrđena je stvarna struktura binuklearnog kompleksa bakra(II) sa
S-izobutenil derivatom tiosalicilne kiseline. Među Gram-pozitivnim bakterijama,
Staphylococcus aureus ATCC® 25923 je pokazao najveću otpornost, dok je najosetljiviji bio
Bifidobacterium animalis subsp. lactis. Kompleksi bakra(II) pokazali su nisku antifungalnu
aktivnost. Reakcije supstitucije ispitivanih kompleksa bile su veoma brze, a pokazano je da
mogu interagovati sa ST-DNK. Bakar(II)-kompleksi su pokazali neznatno nižu citotoksičnost
u poređenju sa cisplatinom. Njihov citotoksični efekat pri koncentracijama od
250 do 1000 μM na HCT-116 ćelije je kao efekat cisplatine.
Zaključak: Otkriće kompleksa bakra(II) sa antimikrobnom i antitumorskom
aktivnošću može bitno podstaći dalja istraživanja u oblasti koordinovanja bakar(II)-jona sa
ligandima od farmakološkog značaja, koji će imati širi spektar dejstva u medicinskoj primeni sa prihvatljivim krajnjim ishodom lečenja.
Introduction: This PhD thesis covers the examination of the kinetic, antimicrobial and
anticancer activities of the newly synthesized binuclear complexes of copper(II) with S-alkenyl
derivatives of thiosalicylic acid. Researches in this area are focused on finding biologically active
complex compounds. Thiosalicylic acid and its derivatives are very interesting as ligands because they
manifest a great diversity in coordination possibilities.
Materials and methods: This study described the methods for the synthesis of the
S-alkenyl derivatives of thiosalicylic acid (alkenyl = propenyl- and isobutenyl-) and the corresponding
binuclear complexes of copper(II). The composition of the obtained compounds was confirmed by the
results of the elemental microanalysis. The structure of synthesized bidentate ligands was
characterized by the results of infrared (IR) and nuclear-magnetic-resonance spectroscopy
(1H and 13C NMR), while the structure of the corresponding complexes was assumed... by the results of
infrared (IR) spectroscopy, magnetic measurements and molar conductivity. The real structure of the
synthesized complex copper(II) was predicted by the results of the X-ray structural analysis. Тhe
antimicrobial activity was examined by the microdilution method with resazurin. The substitution
reactions were monitored in the presence of guanosine-5'-monophosphate, as well as
CT-DNА (calf thymus DNA). The cytotoxic activity of the newly obtained compounds was examined
by MTT colorimetric technique.
Results: The real structure of the binuclear complex of copper(II) with
S-isobutenyl derivative of thiosalicylic acid was confirmed. Among Gram-positive bacteria,
Staphylococcus aureus ATCC® 25923 manifested the highest resistance, while Bifidobacterium
animalis subsp. lactis was the most sensitive one. Copper(II)-complexes manifested a low antifungal
activity. Substitution reactions of the tested complexes were very fast, and it was shown that they
could interact with СT-DNA. Copper(II)-complexes displayed slightly lower cytotoxicity compared to
cisplatin. Copper(II)-complexes with S-alkenyl derivatives of thiosalicylic acid (for concentrations
from 250 to 1000 μM) had cytotoxic effect on HCT-116 cells as cisplatin.
Conclusion: The discovery of the copper(II)-complexes with antimicrobial and anticancer
activity can significantly stimulate further research in the field of copper(II) coordination with ligands
of pharmacological significance, which will have a wider spectrum of effects in medical applications
with the acceptable final outcome of a treatment.
Faculty:
Универзитет у Крагујевцу, Факултет медицинских наукаDate:
20-11-2018Projects:
- Preclinical investigation of bioactive substances (RS-MESTD-Integrated and Interdisciplinary Research (IIR or III)-41010)
- Synthesis, modeling, physicochemical and biological properties of organic compounds and related metal complexes (RS-MESTD-Basic Research (BR or ON)-172016)