5-Keto-3-cyano-2,4-diaminothiophenes as selective maternal embryonic leucine zipper kinase inhibitors

Boutard, Nicolas; Sabiniarz, Aleksandra; Czerwińska, Klaudia; Jarosz, Małgorzata; Cierpich, Anna; Kolasińska, Ewa; Wiklik, Katarzyna; Gluza, Karolina; Commandeur, Claude; Buda, Anna; Stasiowska, Agata; Bobowska, Aneta; Galek, Mariusz; Fabritius, Charles-Henry; Bugaj, Marta; Palacz, Edyta; Mazan, Andrzej; Zarębski, Adrian; Krawczynska, Karolina; Zurawska, Malgorzata; Zawadzki, Przemysław; Milik, Mariusz; Węgrzyn, Paulina; Dobrzańska, Monika; Brzózka, Krzysztof; Kowalczyk, Piotr

doi:10.1016/j.bmcl.2018.12.051

Cited by 6 publications

(3 citation statements)

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“…Taking together, the optimal reduction of CRC incidence, morbidity, and mortality will require concerted efforts to develop novel drug candidates that are capable of eliminating oxidative stress, eradicating bacteria, and/or inhibiting protumorigenic LDHA and PDK1 enzymes. In this regard, thiophene derivatives are extensively explored in the field of drug design and development as antioxidant, antibacterial, and anticancer agents. − In particular, 4,5,6,7-tetrahydrobenzo[ b ]thiophene derivatives have been recognized as promising anticancer agents . Many of them (Figure ) have produced their antiproliferative effects through targeting metalloproteinases 2 and 9 (MMP 2 and 9), HIF-1α and the vascular endothelial growth factor receptor, the epidermal growth factor receptor (EGFR), human EGFR-related receptor 2 (HER2), and the colon cancer-related genes, namely, collagen type X α1 (COL10A1) and collagen type XI α1 (COL11A1) …”

Section: Introductionmentioning

confidence: 99%

Synthesis, Biological, and Molecular Docking Studies on 4,5,6,7-Tetrahydrobenzo[b]thiophene Derivatives and Their Nanoparticles Targeting Colorectal Cancer

et al. 2021

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Initiation of colorectal carcinogenesis may be induced by chromosomal instability caused by oxidative stress or indirectly by bacterial infections. Moreover, proliferating tumor cells are characterized by reprogrammed glucose metabolism, which is associated with upregulation of PDK1 and LDHA enzymes. In the present study, some 4,5,6,7-tetrahydrobenzo[b]thiophene derivatives in addition to Fe 3 O 4 and Fe 3 O 4 /SiO 2 nanoparticles (NPs) supported with a new Schiff base were synthesized for biological evaluation as PDK1 and LDHA inhibitors as well as antibacterial, antioxidant, and cytotoxic agents on LoVo and HCT-116 cells of colorectal cancer (CRC). The results showed that compound 1b is the most active as PDK1 and LDHA inhibitor with IC 50 values (μg/mL) of 57.10 and 64.10 compared to 25.75 and 15.60, which were produced by the standard inhibitors sodium dichloroacetate and sodium oxamate, respectively. NPs12a,b and compound 1b exhibited the strongest antioxidant properties with IC 50 values (μg/mL) of 80.0, 95.0, and 110.0 μg/mL, respectively, compared to 54.0 μg/mL, which was produced by butylated hydroxy toluene. Moreover, NPs12a and carbamate derivative 3b exhibited significant cytotoxic activities with IC 50 values (μg/mL) of 57.15 and 81.50 (LoVo cells) and 60.35 and 71.00 (HCT-116 cells). Thus, NPs12a and compound 3b would be considered as promising candidates suitable for further optimization to develop new chemopreventive and chemotherapeutic agents against these types of CRC cell lines. Besides, molecular docking in the colchicine binding site of the tubulin (TUB) domain revealed a good binding affinity of 3b to the protein; in addition, the absorption, distribution, metabolism, and excretion (ADME) analyses showed its desirable drug-likeness and oral bioavailability characteristics.

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Section: Introductionmentioning

confidence: 99%

Synthesis, Biological, and Molecular Docking Studies on 4,5,6,7-Tetrahydrobenzo[b]thiophene Derivatives and Their Nanoparticles Targeting Colorectal Cancer

et al. 2021

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“…[3][4][5][6] 3-Cyano-2,4-diaminothiophenes were identified as maternal embryonic leucine zipper kinase (MELK) inhibitors. [7] Moreover, thiophene derivatives find large application in coordination chemistry, [8,9] material science [10][11][12][13][14][15][16][17][18][19][20] and as potential intermediate in organic synthesis. [8,9] In addition, the imidazole ring is commonly existing in many synthetic and natural products.…”

Section: Introductionmentioning

confidence: 99%

Synthesis of new heterocycles festooned with thiophene and evaluating their antioxidant activity

Abed

Hammouda

Ismail

et al. 2020

Journal of Heterocyclic Chem

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The chemical performance of 5-bromo-2-(bromoacetyl)-thiophene (1) was tested toward the reaction with numerous bi-nucleophilic reagents (namely; 2-aminobenzothiazoles, 2-aminothiazole, 2-aminotetrazole, 2-aminotriazole, 2-aminopyridines, 2-aminobenzimidazole and o-phenylenediamine). Therefore, a series of bridged nitrogen heterocycles bearing thiophene moiety 3, 5, 7, 9, 11, 13 and 15, respectively was synthesized. In addition, the reaction of 5-bromo-2-(bromoacetyl)-thiophene with the thiocarbamoyl compounds 17, 19 and/or 24 afforded the corresponding thienyl-thiazoles 18 or dithien-2-yl ketones 20 and 25, based on the reaction conditions. Treatment of 1 with 2-mercapto-4,6-dimethylnicotinonitrile was achieved to obtain the target dithien-2-yl ketone 28. The new synthesized scaffolds were examined for their antioxidant activity by means of ABTS antioxidant assay. The thienyl-thiazole scaffold 18c and 2-((2-[thiophen-2-yl]-2-oxoethyl)thio)nicotinonitrile derivative 27 displayed a reasonable radical scavenging activity.

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“…A number of studies have relied upon OTS as a means to investigate the biological function of MELK; however, these results must be interpreted with caution due to the poor selectivity of this inhibitor. More recently, additional MELK inhibitors have been developed, including MELK-T1 (39), NVS-MELK8a (8a) (44), HTH-01-091 (HTH) (15), IN17 (45), and others (8,46). 8a and HTH in particular appear to have more favorable selectivity profiles than OTS based upon kinase activity profiling assays (15,44).…”

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confidence: 99%

Mass spectrometry–based selectivity profiling identifies a highly selective inhibitor of the kinase MELK that delays mitotic entry in cancer cells

McDonald

Grant

East

et al. 2020

Journal of Biological Chemistry

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The maternal embryonic leucine zipper kinase (MELK) has been implicated in the regulation of cancer cell proliferation. RNAi-mediated MELK depletion impairs growth and causes G2/M arrest in numerous cancers, but the mechanisms underlying these effects are poorly understood. Furthermore, the MELK inhibitor OTSSP167 has recently been shown to have poor selectivity for MELK, complicating the use of this inhibitor as a tool compound to investigate MELK function. Here, using a cell-based proteomics technique called multiplexed kinase inhibitor beads/mass spectrometry (MIB/MS), we profiled the selectivity of two additional MELK inhibitors, NVS-MELK8a (8a) and HTH-01-091. Our results revealed that 8a is a highly selective MELK inhibitor, which we further used for functional studies. Resazurin and crystal violet assays indicated that 8a decreases triple-negative breast cancer cell viability, and immunoblotting revealed that impaired growth is due to perturbation of cell cycle progression rather than induction of apoptosis. Using double-thymidine synchronization and immunoblotting, we observed that MELK inhibition delays mitotic entry, which was associated with delayed activation of Aurora A, Aurora B, and cyclin-dependent kinase 1 (CDK1). Following this delay, cells entered and completed mitosis. Using live-cell microscopy of cells harboring fluorescent proliferating cell nuclear antigen, we confirmed that 8a significantly and dose-dependently lengthens G2 phase. Collectively, our results provide a rationale for using 8a as a tool compound for functional studies of MELK and indicate that MELK inhibition delays mitotic entry, likely via transient G2/M checkpoint activation.

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5-Keto-3-cyano-2,4-diaminothiophenes as selective maternal embryonic leucine zipper kinase inhibitors

Cited by 6 publications

References 53 publications

Synthesis, Biological, and Molecular Docking Studies on 4,5,6,7-Tetrahydrobenzo[b]thiophene Derivatives and Their Nanoparticles Targeting Colorectal Cancer

Synthesis, Biological, and Molecular Docking Studies on 4,5,6,7-Tetrahydrobenzo[b]thiophene Derivatives and Their Nanoparticles Targeting Colorectal Cancer

Synthesis of new heterocycles festooned with thiophene and evaluating their antioxidant activity

Mass spectrometry–based selectivity profiling identifies a highly selective inhibitor of the kinase MELK that delays mitotic entry in cancer cells

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