Naslov (srp)

Sinteza, antiproliferativna aktivnost novih derivata hinolin-4-karboksilne kiseline kao potencijalnih inhibitora dihidroorotat dehidrogenaze

Autor

Petrović, Milena, 1995-

Doprinosi

Joksović, Milan, 1963-
Trifunović, Snežana, 1968-
Misirlić Denčić, Sonja, 1975-
Damljanović, Ivan, 1979-

Opis (eng)

In this doctoral thesis, the synthesis, structural characterization, inhibitory activityagainst the enzyme dihydroorotate dehydrogenase, as well as the cytotoxic potential,lipophilicity, and molecular docking studies of quinoline-4-carboxylic acid derivatives weredescribed. Three series containing a total of 48 compounds were synthesized, the first twoseries are derivatives of 2-substituted quinoline-4-carboxylic acid (А and Б), while the thirdseries consists of 2,3-disubstituted quinoline-4-carboxylic acid derivatives (В). Humandihydroorotate dehydrogenase (hDHODH) was clearly recognized as the ideal target for thesecompounds. Consequently, enzyme screening was conducted and obtained IC50 results werecompared with prominent inhibitors, Brequinar and/or Leflunomide. A certain number ofcompounds in each series showed good inhibitory activity, while some derivatives from the Aand В series exhibited excellent enzyme inhibition. The cytotoxicity of series A and В wasevaluated in vitro on breast (MCF-7), lung (A549) and melanoma (A375) cancer cell lines. Inthe case of series Б, the cytotoxic potential was tested on MCF-7 and acute monocyticleukemia (THP-1) cell lines. In order to evaluate the selectivity and therapeutic potential ofthese compounds, their toxicity to the human skin keratinocyte cell line (HaCaT) was alsoexamined. Additionally, lipophilicity study was conducted, and the results were expressed aslogD7.4 values, while solubility assay was performed for all derivatives of В series. In bothcases, certain derivatives showed better pharmacological properties than a referencecompounds. Besides, molecular docking study revealed the most important interactions ofnewly synthesized compounds with the enzyme.

Opis (srp)

U okviru ove doktorske disertacije opisani su sinteza, strukturnakarakterizacija, inhibitorna aktivnost prema enzimu dihidroorotat dehidrogenazi,kao i citotoksični potencijal, lipofilnost, i molekulski doking derivata hinolin4-karboksilne kiseline. Sintetizovane su tri serije koje ukupno sadrže 48 jedinjenja,od kojih prve dve serije predstavljaju derivate 2-supstituisane-hinolin-4-karboksilne kiseline (A i B), dok treću čine derivati 2,3-disupstituisane hinolin4-karboksilne kiseline (V). Sva sintetizovana jedinjenja su prepoznata kaopotencijalni inhibitori dihidroorotat dehidrogenaze (hDHODH) čoveka. Samimtim, određene su njihove inhibitorne aktivnosti, a dobijeni rezultati IC50 vrednostiupoređeni sa poznatim inhibitorima, Brequinar-om i/ili Leflunomide-om. U okvirusvake serije je za određena jedinjenja zapažena dobra inhibitorna aktivnost, a posebnosu odličnu enzimsku inhibiciju ispoljili odgovarajući derivati koji pripadajuserijama A i V. Citotoksičnost jedinjenja serija A i V je testirana in vitro naćelijskim linijama karcinoma dojke (MCF-7), pluća (A549) i melanoma (A375), dok jecitotoksična aktivnost jedinjenja serije B ispitana na MCF-7 i ćelijskoj linijiakutne monocitne leukemije (THP-1). U cilju određivanja selektivnosti iterapeutskog potencijala, testirana je i njihova toksičnost na ćelijskoj linijikeratinocita kože čoveka (HaCaT). Dodatno, određena je lipofilnost svih derivata iizražena preko logD7,4 vrednosti, a u okviru V serije je određena i rastvorljivost. Uoba slučaja, neka jedinjenja su pokazala bolje farmakološke osobine od referentnih.Pored toga, studija molekulskog dokinga je prikazala najznačajnije interakcije kojeostvaruju novosintetizovani derivati sa enzimom.

Opis (srp)

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Jezik

srpski

Datum

2023

Licenca

Ovo delo je licencirano pod uslovima licence
Creative Commons CC BY-SA 3.0 AT - Creative Commons Autorstvo - Deliti pod istim uslovima 3.0 Austria License.

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