Potent human dihydroorotate dehydrogenase inhibitory activity of new quinoline-4-carboxylic acids derived from phenolic aldehydes: Synthesis, cytotoxicity, lipophilicity and molecular docking studies

Petrović, Milena M.; Roschger, Cornelia; Chaudary, Sidrah; Zierer, Andreas; Mladenović, Milan; Jakovljević, Katarina; Marković, Violeta; Botta, Bruno

doi:10.1016/j.bioorg.2020.104373

Cited by 9 publications

(12 citation statements)

References 31 publications

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“…On the basis of these results, more potent inhibitors of DHODH are being developed for treatment of rheumatoid arthritis and SARS-CoV-2 (ReF. 205 ) as well as cancer [206][207][208] . Another DHODH inhib itor, AG-636 (ReF.…”

Section: ();mentioning

confidence: 99%

Targeting cancer metabolism in the era of precision oncology

Stine¹,

Schug

Salvino

et al. 2021

Nat Rev Drug Discov

627

402

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Before Sidney Farber published his seminal paper in 1948 in The New England Journal of Medicine describing anti-folate-induced remissions 1 , childhood acute lymphocytic leukaemia (ALL) was universally fatal. Thirty years before this article was published, Otto Warburg's determination to conquer cancer led him to discover that many tumours used aerobic glycolysis (also known as the Warburg effect) to convert almost all glucose to lactate even in the presence of oxygen 2 . Aerobic glycolysis, however, has never been successfully exploited clinically, particularly as the use of 2-deoxyglucose, which inhibits glycolysis, was proved to have undesirable side effects and limited efficacy in humans 3 . Farber noted the clinical 'accelerated phenomenon' among 11 children treated with an active form of folate, pteroyltriglutamic acid, which was thought to have broad anticancer activity, and thus sought folate antagonists as therapeutic agents. Working with chemist Yellapragada Subbarow, the anti-folate aminopterin was synthesized, and Farber was able to induce remissions in children with ALL, thus providing the foundation for cancer chemotherapy 4 . Today, another folate antagonist, methotrexate, is still used in the multi-chemotherapy treatment of childhood ALL and, used together with l-asparaginase, induces a remarkable 90% cure rate. Indeed, many anti-metabolite drugs, particularly those targeting nucleotide metabolism, have been approved and used in the clinic (Table 1). The recent approval of drugs that target mutant isocitrate dehydrogenases in acute myeloid leukaemias (AMLs) (Table 1) provides a milestone in targeting cancer metabolism with precision and establishes that metabolic therapy can be highly effective.Warburg's and Farber's ideas were conceptually displaced in the 1980s as oncogenes and tumour suppressors became recognized as targets in human cancer treatments. Molecular biology took centre stage, and the drive to target oncogenes began with vigour, resulting in many effective anticancer kinase drugs that displaced interest in targeting metabolism. However, the links between oncogenes, tumour suppressors and metabolism began to emerge in the 1990s, ushering in a resurgence of interest in cancer metabolism [5][6][7] . More recently, the success of immunotherapy underscores the importance of non-cancer-cell autonomous components of the tumour immune microenvironment (TIME) [8][9][10] , which is a neoplastic hub of metabolically active cells comprising tumour cells, immune cells, stromal cells and blood and lymph vessel cells, all of which are involved in tumour growth. In this regard, targeting cancer metabolism must be based on a thorough understanding of how inhibiting specific metabolic pathways affects the TIME cells, which can either dampen or promote tumour progression. In this Review, we cover the fundamentals of cancer metabolism and focus on recent small-molecule drug discovery efforts to target cancer.

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Section: ();mentioning

confidence: 99%

Targeting cancer metabolism in the era of precision oncology

Stine¹,

Schug

Salvino

et al. 2021

Nat Rev Drug Discov

627

402

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“…Lipophilicity can be determined by two coefficients: partition coefficient (logP) or distribution coefficient (logD) that is an appropriate description of lipophilicity for our synthesized compounds, as it reflects the partition that includes both unionized and ionized forms due to the presence of an ionizable carboxylic group. [16,17] Moderate lipophilic characteristics of the drugs (logD 7.4 = 0-3) demonstrate a very good balance between permeability and solubility, while the negative values of logD 7.4 result in reduced permeability through biological membranes. Highly lipophilic substances (logD 7.4 > 3.5) have poor aqueous solubility.…”

Section: Lipophilicity and Solubility Studiesmentioning

confidence: 99%

“…The SB analysis of targeted hDHODH inhibitors, by means of the same experimental setup as described elsewhere, [17,22] resolved the compounds' activity in terms of individual molecular determinants contribution, thus providing a three-dimensional extension of the above-conducted SAR studies and was able to discriminate compounds by means of decreasing-like potency. All the in silico resolved bioactive conformations of targeted hDHODH inhibitors were comparable with the previously experimentally determined crystal structures of either clinical drug leflunomide (viz.…”

Section: Structure-based (Sb) Sar Studiesmentioning

confidence: 99%

“…All the compounds (Figure 2, Supporting Information: Figures S1-S13) occupied the narrow tunnel of hDHODH within the N-terminus, thus preventing ubiquinone as the second cofactor from easily approaching the flavin mononucleotide (FMN) as a cofactor for the redox reaction within the redox site. [17,22] Adopting their bioactive conformations, compounds filled up the tunnel's subsite 1, almost exclusively complied of α helices comprising hydrophobic residues Leu42, Met43, Leu46, Gln47, Ala55, Leu58, Phe62, Leu68, Phe98, and Leu359, involved in the hDHODHmembrane association and alleviating the acceptance of ubiquinone, as well as the redox site and sub-sites formed of Gln47, Arg136, Val134, Val143, Tyr356, Thr360. [17,22] Hence, the bioactive conformation of the ligand found in the 3F1Q complex emerged as a consequence of water-mediated hydrogen bonds formed between the nitrile portion and the Arg136 and Gln47, as well as the direct hydrogen bond (d HB = 2.781 Å) between the carbonyl portion and the hydroxyl of Tyr356 (Figure 2a).…”

Section: Structure-based (Sb) Sar Studiesmentioning

confidence: 99%

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Synthesis and biological evaluation of new quinoline‐4‐carboxylic acid‐chalcone hybrids as dihydroorotate dehydrogenase inhibitors

Petrović

Roschger

Lang

et al. 2022

Archiv der Pharmazie

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Fourteen novel quinoline-4-carboxylic acid-chalcone hybrids were obtained via Claisen-Schmidt condensation and evaluated as potential human dihydroorotate dehydrogenase (hDHODH) inhibitors. The ketone precursor 2 was synthesized by the Pfitzinger reaction and used for further derivatization at position 3 of the quinoline ring for the first time. Six compounds showed better hDHODH inhibitory activity than the reference drug leflunomide, with IC 50 values ranging from 0.12 to 0.58 μM.The bioactive conformations of the compounds within hDHODH were resolved by means of molecular docking, revealing their tendency to occupy the narrow tunnel of hDHODH within the N-terminus and to prevent ubiquinone as the second cofactor from easily approaching the flavin mononucleotide as a cofactor for the redox reaction within the redox site. The results of the 3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assay revealed that 4d and 4h demonstrated the highest cytotoxic activity against the A375 cell line, with IC 50 values of 5.0 and 6.8 µM, respectively. The lipophilicity of the synthesized hybrids was obtained experimentally and expressed as logD 7.4 values at physiologicalpH while the solubility assay was conducted to define physicochemical characteristics influencing the ADMET properties. K E Y W O R D S chalcones, dihydroorotate dehydrogenase, hDHODH inhibitors, quinoline-4-carboxylic acid 1 | INTRODUCTION Dihydroorotate dehydrogenase (DHODH) is located in the inner mitochondrial membrane and represents one of the most important flavin-dependent enzymes, playing a significant role in the de novo biosynthesis of pyrimidine nucleotides. The fourth step of this biosynthesis pathway is catalyzed by DHODH, a rate-limitingenzyme responsible for the oxidation of dihydroorotate to orotate. [1] Considering the importance of pyrimidine nucleotides for cellular metabolism, especially in tumor cell proliferation and their requirement for the biosynthesis of macromolecules such as DNA, RNA, phospholipids, and glycoproteins, inhibition of this enzyme has gained a lot of attention in recent decades. [2] Furthermore, DHODH was noted as an ideal target for the treatment of various diseases and these facts encouraged many scientists to design novel inhibitors that will disrupt the function of the enzyme consequently causing the deficiency of essential pyrimidine nucleotides. Accordingly, a variety of specific inhibitors with a wide range of heterocyclic scaffolds and diverse

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“…The inhibiton of human dihydroorotate dehydrogenase (hDHODH) activity by synthesized compounds (5a-5t) as well as cytotoxicity against HaCat cell line were determined according to previosly reported procedure [1].…”

Section: Inhibition Of Hdhodh and Cytotoxicitymentioning

confidence: 99%

Low cytotoxic quinoline-4-carboxylic acids derived from vanillin precursors as potential human dihydroorotate dehydrogenase inhibitors

Petrović

Roschger

Chaudary

et al. 2021

Bioorganic & Medicinal Chemistry Letters

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Melting points were determined on a Mel-Temp capillary melting points apparatus, model 1001, and are uncorrected. Elemental (C, H, N, S) analysis of the samples was carried out in the Center for Instrumental Analysis, Faculty of Chemistry, Belgrade. IR spectra were obtained on a Perkin Elmer Spectrum One FT-IR spectrometer with a KBr disc. 1 H and 13 C-NMR spectra were recorded on a Varian Gemini 200 MHz spectrometer. UV-Vis spectra were recorded on a double beam UV-Vis spectrophotometer model Cary 300 (Agilent Technologies, Santa Clara, USA) with 1.0 cm quartz cells. General procedure for the synthesis of 4a-tTo the aqueous solution of NaOH (21.887 mmol, 3.8 mL of distilled H2O) monochloroacetic acid (10.94 mmol, 1033.83mg) and vanillin (9.48 mmol, 1442.38 mg) were added, and the reaction mixture was refluxed for 100 minutes. Afterwards, the mixture in the flask was cooled to room temperature, 15 mL of distilled H2O was added and the solution was acidified with 2M HCl to pH 2, whereby a beige precipitate was formed. The suspension was cooled in the refrigerator for 2 h, the precipitate was filtrated, washed with a small amount of cold water and dried over anhydrous CaCl2. The crude product was purified by dissolving in hot distilled water. After cooling in a refrigerator for 2 h, brown-yellow crystals were formed. The compound was filtered off, dried over anhydrous CaCl2 and used for further synthesis. In the next step, the compound 2 (2.857 mmol, 600.49 mg) was measured into a 50 mL flask, followed by the addition of dry, freshly distilled CH2Cl2 (14.28 mL), SOCl2 (28.57 mmol, 2.07 mL) and 4 drops of DMF. After 12 h of stirring at room temperature, the solvent was evaporated under reduced pressure, and the excess of SOCl2 was removed by azeotropic distillation with toluene.Then, a corresponding amine (2.857 mmol), NaHCO3 (5.714 mmol, 479.85 mg) and dry CH2Cl2 (14.28 mL) were added to the formed acid chloride, without its previous isolation, and the reaction mixture was further stirred at room temperature for additional 4.5 h. After completion, CH2Cl2 was evaporated under reduced pressure, 28.60 mL of distilled water was added to the residue, and the pH was adjusted to 10 by addition of solid Na2CO3. In the case of compounds S4 4b, 4i and 4t this suspension was left overnight at room temperature, vigorously stirred for 20 minutes the next day and then filtered. In all other cases after pH adjustment, the suspension was stirred for 20 minutes and filtered. With exception of 4o, which was obtained with satisfactory purity and used for further synthesis without purification, all other 4a-t derivatives were purified by dissolving in an appropriate solution of hot aqueous ethanol, and left overnight in the refrigerator. Compounds 4a-g, 4j, 4l, 4n, 4r and 4s-t were recrystallized from 50% aqueous solution of EtOH, 4i from 55%, 4m and 4p from 60% EtOH, while 4h and 4k were purified by recrystallization from 65% EtOH. Derivatives 4a-t were obtained in satisfactory yields ranging from 42 to 78%. General procedure for the...

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Potent human dihydroorotate dehydrogenase inhibitory activity of new quinoline-4-carboxylic acids derived from phenolic aldehydes: Synthesis, cytotoxicity, lipophilicity and molecular docking studies

Cited by 9 publications

References 31 publications

Targeting cancer metabolism in the era of precision oncology

Targeting cancer metabolism in the era of precision oncology

Synthesis and biological evaluation of new quinoline‐4‐carboxylic acid‐chalcone hybrids as dihydroorotate dehydrogenase inhibitors

Low cytotoxic quinoline-4-carboxylic acids derived from vanillin precursors as potential human dihydroorotate dehydrogenase inhibitors

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