Synthesis, antiproliferative activity, and lipophilicity of new quinoline-4- carboxylic acid derivatives as potential dihydroorotate dehydrogenase inhibitors

[M. M. Petrović]

[7], 138 str.

U okviru ove doktorske disertacije opisani su sinteza, strukturna karakterizacija, 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 kao potencijalni inhibitori dihidroorotat dehidrogenaze (hDHODH) čoveka. Samim tim, određene su njihove inhibitorne aktivnosti, a dobijeni rezultati IC50 vrednosti upoređeni sa poznatim inhibitorima, Brequinar-om i/ili Leflunomide-om. U okviru svake serije je za određena jedinjenja zapažena dobra inhibitorna aktivnost, a posebno su odličnu enzimsku inhibiciju ispoljili odgovarajući derivati koji pripadaju serijama A i V. Citotoksičnost jedinjenja serija A i V je testirana in vitro na ćelijskim linijama karcinoma dojke (MCF-7), pluća (A549) i melanoma (A375), dok je citotoksična aktivnost jedinjenja serije B ispitana na MCF-7 i ćelijskoj liniji akutne monocitne leukemije (THP-1). U cilju određivanja selektivnosti i terapeutskog potencijala, testirana je i njihova toksičnost na ćelijskoj liniji keratinocita kože čoveka (HaCaT). Dodatno, određena je lipofilnost svih derivata i izražena preko logD7,4 vrednosti, a u okviru V serije je određena i rastvorljivost. U oba slučaja, neka jedinjenja su pokazala bolje farmakološke osobine od referentnih. Pored toga, studija molekulskog dokinga je prikazala najznačajnije interakcije koje ostvaruju novosintetizovani derivati sa enzimom.

In this doctoral thesis, the synthesis, structural characterization, inhibitory activity against the enzyme dihydroorotate dehydrogenase, as well as the cytotoxic potential, lipophilicity, and molecular docking studies of quinoline-4-carboxylic acid derivatives were described. Three series containing a total of 48 compounds were synthesized, the first two series are derivatives of 2-substituted quinoline-4-carboxylic acid (А and Б), while the third series consists of 2,3-disubstituted quinoline-4-carboxylic acid derivatives (В). Human dihydroorotate dehydrogenase (hDHODH) was clearly recognized as the ideal target for these compounds. Consequently, enzyme screening was conducted and obtained IC50 results were compared with prominent inhibitors, Brequinar and/or Leflunomide. A certain number of compounds in each series showed good inhibitory activity, while some derivatives from the A and В series exhibited excellent enzyme inhibition. The cytotoxicity of series A and В was evaluated in vitro on breast (MCF-7), lung (A549) and melanoma (A375) cancer cell lines. In the case of series Б, the cytotoxic potential was tested on MCF-7 and acute monocytic leukemia (THP-1) cell lines. In order to evaluate the selectivity and therapeutic potential of these compounds, their toxicity to the human skin keratinocyte cell line (HaCaT) was also examined. Additionally, lipophilicity study was conducted, and the results were expressed as logD7.4 values, while solubility assay was performed for all derivatives of В series. In both cases, certain derivatives showed better pharmacological properties than a reference compounds. Besides, molecular docking study revealed the most important interactions of newly synthesized compounds with the enzyme.

Organska sinteza, Doebner-ova reakcija, Pfitzinger-ova ciklizaciona reakcija, Strukturna karakterizacija, Hinolin-4-karboksilna kiselina, Enzimska inhibicija, Humana dihidroorotat dehidrogenaza (hDHODH), Citotoksičnost, Lipofilnost, Molekulski doking

Organic synthesis, Doebner reaction, Pfitzinger cyclization reaction, Structural characterization, Quinoline-4-carboxylic acid, Enzyme inhibition, Human dihydroorotate dehydrogenase (hDHODH), Cytotoxicity, Lipophilicity, Molecular docking

547.831(043.3)

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