Synthesis, characterization and examination of the biological activity of binuclear complexes of copper(II) with S-alkenyl derivatives of thiosalicylic acid

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) spektroskopije, 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

Docking studies, cytotoxicity evaluation and interactions of binuclear copper(ii) complexes with s-isoalkyl derivatives of thiosalicylic acid with some relevant biomolecules

The numerous side effects of platinum based chemotherapy has led to the design of new therapeutics with platinum replaced by another transition metal. Here, we investigated the interactions of previously reported copper(II) complexes containing S-isoalkyl derivatives, the salicylic acid with guanosine-5′-monophosphate and calf thymus DNA (CT-DNA) and their antitumor effects, in a colon carcinoma model. All three copper(II) complexes exhibited an affinity for binding to CT-DNA, but there was no indication of intercalation or the displacement of ethidium bromide. Molecular docking studies revealed a significant affinity of the complexes for binding to the minor groove of B-form DNA, which coincided with DNA elongation, and a higher affinity for binding to Z-form DNA, supporting the hypothesis that the complex binding to CT-DNA induces a local transition from B-form to Z-form DNA. These complexes show a moderate, but selective cytotoxic effect toward colon cancer cells in vitro. Binuclear complex of copper(II) with S-isoamyl derivative of thiosalicylic acid showed the highest cytotoxic effect, arrested tumor cells in the G2/M phase of the cell cycle, and significantly reduced the expression of inflammatory molecules pro-IL-1β, TNF-α, ICAM-1, and VCAM-1 in the tissue of primary heterotopic murine colon cancer, which was accompanied by a significantly reduced tumor growth and metastases in the lung and liver

Interactions of binuclear copper(II) complexes with S-substituted thiosalicylate derivatives with some relevant biomolecules

Interactions of copper(II) complexes which contain S-alkyl derivatives of thiosalicylic acid (alkyl = methyl, ethyl, propyl and butyl; aryl = benzyl), marked as 1–5, with guanosine-5′-monophosphate (5′-GMP) and calf thymus DNA (CT-DNA) were studied. Kinetics of substitution reactions of 1–5 with 5′-GMP and CT-DNA were investigated under pseudo-first-order conditions at 310 K and pH = 7.2 in 25 mM Hepes buffer using stopped-flow method. All complexes have high affinity toward studied bio-molecules. Additionally, interactions with CT-DNA were followed by absorption spectroscopy and fluorescence quenching measurements. The results indicate that complexes bind to DNA exhibiting high binding constants (Kb = 104 M−1). During the examination of competitive reactions with ethidium bromide (EB), results showed that complexes can replace EB-bound DNA. In addition, a new crystal structure of the binuclear Cu(II) complex with S-substituted thiosalicylate derivative has been reported. In the present series of Cu(II) complexes the crystal structure is the first example of a complex comprising an S-aryl derivative of thiosalicylate ligand. Through comparative study of structural properties of six molecules from four crystal structures we examined the structural variations, potentially important for biological activity of these complexes. © 2019, © 2019 Informa UK Limited, trading as Taylor & Francis Group