AIM: This work explores the synthesis of new bi-heterocyclic hybrid compounds based on quinoline ring and investigates their potential as anticancer agents. MATERIALS & METHODS: The novel fused quinoline-thiazolo[3,2-a] benzimidazole-3(2 h)one hybrids were prepared by regioselective nucleophilic ring opening of the corresponding quinolinyl-oxiranes. In vitro cytotoxic activity was evaluated against human lung (A549) and gastric (AGS) cancer cell lines. RESULTS: Global results showed that all tested compounds have promising inhibitory properties. Compounds 17 and 18 bearing two methoxy groups on the quinoline ring have exhibited remarkable and interesting activities. The investigation of the cell death process showed that these compounds activated a caspase-dependent apoptosis pathway. Results were further supported by molecular docking studies. CONCLUSION: Both compounds exhibited good drug-like characteristics, which make them promising drug candidates.

• MeSH
• apoptóza * účinky léků   MeSH
• benzimidazoly * farmakologie   chemie   chemická syntéza   MeSH
• chinoliny * chemie   farmakologie   chemická syntéza   MeSH
• kaspasy * metabolismus   MeSH
• lidé MeSH
• molekulární struktura MeSH
• nádorové buněčné linie MeSH
• proliferace buněk účinky léků   MeSH
• protinádorové látky * farmakologie   chemie   chemická syntéza   MeSH
• screeningové testy protinádorových léčiv MeSH
• simulace molekulového dockingu * MeSH
• thiazoly chemie   farmakologie   chemická syntéza   MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

Interleukin-2-inducible T-cell kinase (ITK) and Bruton's tyrosine kinase (BTK) are two important members of the Tec family with crucial roles in immune system function. Deregulation in ITK and BTK activity is linked to several hematological malignancies, making them key targets for cancer immunotherapy. In this study, we synthesized a series of azaspirooxindolinone derivatives and evaluated their cytotoxic activity against ITK/BTK-negative and positive cancer cell lines, followed by enzymatic inhibition studies to assess the ITK/BTK kinase selectivity of two hit compounds. Several compounds demonstrated selective cytotoxicity against ITK- or BTK-expressing cells. Compound 3d exhibited high cytotoxicity in ITK-positive Jurkat (IC50 = 3.58 μM) and BTK-positive Ramos (IC50 = 3.06 μM) cells, while compound 3j showed strong cytotoxicity in Ramos (IC50 = 1.38 μM) and Jurkat (IC50 = 4.16 μM) cells. Compounds 3a and 3e were selectively cytotoxic in Jurkat cells (IC50 = 9.36 μM and 10.85 μM, respectively), while compounds 3f and 3g were highly cytotoxic in Ramos cells (IC50 = 1.82 μM and 1.42 μM, respectively). None of the active compounds exhibited cytotoxicity in non-cancer cell lines (IC50 > 50 μM), demonstrating their selectivity for malignant cells. Enzyme inhibition assay showed that 3d is a selective ITK inhibitor (IC50 = 0.91 μM) with no detectable BTK inhibition, aligning with its strong activity in ITK-positive cells. In contrast, compound 3j did not inhibit ITK or BTK enzymatically, suggesting an alternative mechanism of action. These findings highlight 3d as a promising ITK inhibitor and warrant further investigation to elucidate its mechanism of action.

• MeSH
• inhibitory proteinkinas * farmakologie   chemická syntéza   chemie   MeSH
• lidé MeSH
• molekulární struktura MeSH
• nádorové buněčné linie MeSH
• oxindoly farmakologie   chemie   chemická syntéza   MeSH
• proliferace buněk účinky léků   MeSH
• proteinkinasa BTK * antagonisté a inhibitory   metabolismus   MeSH
• protinádorové látky * farmakologie   chemická syntéza   chemie   MeSH
• racionální návrh léčiv * MeSH
• screeningové testy protinádorových léčiv * MeSH
• simulace molekulového dockingu MeSH
• spirosloučeniny chemie   farmakologie   chemická syntéza   MeSH
• tyrosinkinasy * antagonisté a inhibitory   metabolismus   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

In the complex network of cellular physiology, the maintenance of cellular proteostasis emerges as a critical factor for cell survival, particularly under stress conditions. This homeostasis is largely governed by a sophisticated network of molecular chaperones and co-chaperones, among which Bcl-2-associated athanogene 3 (BAG3), able to interact with the ATPase domain of Heat Shock Protein 70 (HSP70), plays a pivotal role. The BAG3-HSP70 functional module is not only essential for cellular homeostasis but is also involved in the pathogenesis of various diseases, including cancer, neurodegenerative disorders, and cardiac dysfunction, making it an attractive target for therapeutic intervention. Inspired by our continuous interest in the development of new chemical platforms able to interfere with BAG3 protein, herein we report the discovery of compound 16, the first-in-class BAG3/HSP70 dual modulator, obtained by combining the multicomponent Ugi reaction with the alkyne-azide Huisgen procedure in a sequential tandem reaction approach. Through a combination of biophysical analysis, biochemical assays, and cell-based studies, we elucidated the mechanism of action of this inhibitor and assessed its potential as a therapeutic agent. Hence, this study can open new avenues for the development of novel anticancer strategies that leverage the simultaneous disruption of multiple chaperone pathways.

• MeSH
• adaptorové proteiny signální transdukční * metabolismus   antagonisté a inhibitory   MeSH
• lidé MeSH
• molekulární chaperony metabolismus   antagonisté a inhibitory   chemie   MeSH
• molekulární struktura MeSH
• nádorové buněčné linie MeSH
• proliferace buněk účinky léků   MeSH
• proteiny regulující apoptózu * metabolismus   antagonisté a inhibitory   MeSH
• proteiny tepelného šoku HSP70 * antagonisté a inhibitory   metabolismus   MeSH
• protinádorové látky * farmakologie   chemie   chemická syntéza   MeSH
• screeningové testy protinádorových léčiv MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

The novel diiron amine complexes [Fe2Cp2(CO)(NH2R')(μ-CO){μ-CN(Me)(Cy)}]CF3SO3 [R' = H, 3; Cy, 4; CH2CH2NH2, 5; CH2CH2NMe2, 6; CH2CH2(4-C6H4OMe), 7; CH2CH2(4-C6H4OH), 8; Cp = η5-C5H5, Cy = C6H11 = cyclohexyl] were synthesized in 49-92 % yields from [Fe2Cp2(CO)2(μ-CO){μ-CN(Me)(Cy)}]CF3SO3, 1a, using a straightforward two-step procedure. They were characterized by IR and multinuclear NMR spectroscopy, and the structure of 7 was confirmed through X-ray diffraction analysis. Complexes 3-8 and the acetonitrile adducts [Fe2Cp2(CO)(NCMe)(μ-CO){μ-CN(Me)(R)}]CF3SO3 (R = Cy, 2a; Me, 2b; Xyl = 2,6-C6H3Me2, 2c) were assessed for their water solubility, octanol-water partition coefficient and stability in physiological-like solutions. The in vitro antiproliferative activity of 2a-c and 3-8 was tested on seven human cancer cell lines (A2780, A2780R, PC3, A549, MCF7, HOS and HT-29), while the selectivity was evaluated using normal MRC-5 cells. Overall, the complexes exhibited variable cytotoxicity, with IC50 values reaching the low micromolar range for 3, 7 and 8 in A2780 and A2780R cells, along with significant selectivity. Targeted experiments covered cell cycle modification, induction of cell death, mitochondrial membrane potential, ROS production and interaction with DNA and bovine serum albumin (BSA) as a model protein. The interaction of 3 with BSA was further investigated through computational studies. Results showed a negligible increase in intracellular ROS levels (except for 2b) and insignificant changes in mitochondrial membrane potential.

• MeSH
• aminy chemie   farmakologie   MeSH
• komplexní sloučeniny chemie   farmakologie   chemická syntéza   MeSH
• lidé MeSH
• ligandy MeSH
• molekulární struktura MeSH
• nádorové buněčné linie MeSH
• proliferace buněk * účinky léků   MeSH
• protinádorové látky * farmakologie   chemie   chemická syntéza   MeSH
• screeningové testy protinádorových léčiv * MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• vztahy mezi strukturou a aktivitou MeSH
• železo chemie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Starting from benzyl 30-oxobetulinate and 30-oxobetulin diacetate, substituted dienes were synthesized and subjected to Diels-Alder reaction, yielding a variety of triterpenoid phthalates, phthalimides, and related derivatives. A total of 55 new compounds were prepared and tested for in vitro cytotoxic activity against eight cancer cell lines and two non-cancerous cell lines. Four compounds with IC50 values of 5 μM or lower were selected for further investigation. These compounds induced apoptosis in CCRF-CEM cells in a concentration-dependent manner, accompanied by mitochondrial depolarization and altered expression of key proteins involved in mitochondrial apoptosis. The compounds also disrupted DNA replication and transcriptional activity. Modulation of key proliferation pathways, including PI3K/Akt and STAT3, further supported the antiproliferative potential of these derivatives. Considering their high cytotoxicity and antiproliferative activity in CCRF-CEM cells, compounds 19, 26, 28, and 30 have been identified as promising candidates for further development.

• MeSH
• apoptóza * účinky léků   MeSH
• ftalimidy * farmakologie   chemie   chemická syntéza   MeSH
• lidé MeSH
• mitochondrie * účinky léků   metabolismus   MeSH
• molekulární struktura MeSH
• nádorové buněčné linie MeSH
• proliferace buněk * účinky léků   MeSH
• protinádorové látky * farmakologie   chemie   chemická syntéza   MeSH
• screeningové testy protinádorových léčiv * MeSH
• triterpeny * farmakologie   chemie   chemická syntéza   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

Herein, we describe and investigate biological activity of three octahedral ruthenium(II) complexes of the type [Ru(C∧N)(phen)2]+, RuL1-RuL3, containing a π-expansive cyclometalating substituted benzo[g]quinoxaline ligand (C∧N ligand) (phen = 1,10-phenanthroline). Compounds RuL1-RuL3 in cervical, melanoma, and colon human cancer cells exhibit high phototoxicity after irradiation with light (particularly blue), with the phototoxicity index reaching 100 for the complex RuL2 in most sensitive HCT116 cells. RuL2 accumulates in the cellular membranes. If irradiated, it induces lipid peroxidation, likely connected with photoinduced ROS generation. Oxidative damage to the fatty acids leads to the attenuation of the membranes, the activation of caspase 3, and the triggering of the apoptotic pathway, thus implementing membrane-localized photodynamic therapy. RuL2 is the first photoactive ruthenium-based complex capable of killing the hardly treatable colon cancer stem cells, a highly resilient subpopulation within a heterogeneous tumor mass, responsible for tumor recurrence and the metastatic progression of cancer.

• MeSH
• apoptóza účinky léků   MeSH
• buněčná membrána účinky léků   metabolismus   MeSH
• chinoxaliny * chemie   farmakologie   chemická syntéza   MeSH
• fotochemoterapie * MeSH
• fotosenzibilizující látky * farmakologie   chemie   chemická syntéza   terapeutické užití   MeSH
• komplexní sloučeniny * farmakologie   chemie   chemická syntéza   terapeutické užití   MeSH
• lidé MeSH
• nádorové buněčné linie MeSH
• nádorové kmenové buňky * účinky léků   patologie   MeSH
• nádory tračníku * farmakoterapie   patologie   MeSH
• protinádorové látky * farmakologie   chemie   chemická syntéza   terapeutické užití   MeSH
• reaktivní formy kyslíku metabolismus   MeSH
• ruthenium * chemie   farmakologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

The potential as a cancer therapeutic target of the recently reported hotspot binding region close to Lys508 of the β-catenin armadillo repeat domain was not exhaustively explored. In order to get more insight, we synthesized novel N-(heterocyclylphenyl)benzenesulfonamides 6-28. The new compounds significantly inhibited Wnt-dependent transcription as well as SW480 and HCT116 cancer cell proliferation. Compound 25 showed binding mode consistent with this hotspot binding region. Compound 25 inhibited the growth of SW480 and HCT116 cancer cells with IC50's of 2 and 0.12 μM, respectively, and was superior to the reference compounds 5 and 5-FU. 25 inhibited the growth of HCT-116 xenografted in BALB/Cnu/nu mice, reduced the expression of the proliferation marker Ki67, and significantly affected the expression of cancer-related genes. After incubation with human and mouse liver microsomes, 25 showed a higher metabolic stability than 5. Compound 25 aims to be a promising lead for the development of colorectal cancer anticancer therapies.

• MeSH
• beta-katenin * metabolismus   antagonisté a inhibitory   MeSH
• HCT116 buňky MeSH
• jaterní mikrozomy metabolismus   MeSH
• lidé MeSH
• myši inbrední BALB C * MeSH
• myši nahé MeSH
• myši MeSH
• nádorové buněčné linie MeSH
• proliferace buněk * účinky léků   MeSH
• protinádorové látky * farmakologie   chemická syntéza   chemie   MeSH
• sulfonamidy * farmakologie   chemie   chemická syntéza   MeSH
• vztahy mezi strukturou a aktivitou MeSH
• xenogenní modely - testy protinádorové aktivity MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Given the significant prevalence of FLT3 receptor and its mutations in acute myeloid leukemia (AML) pathogenesis, we present a novel series of furo[2,3-d]pyrimidin-1,3,4-thiadiazole-urea derivatives, designed to exhibit FLT3-ITD inhibitory activity. These compounds demonstrated cytotoxicity in FLT3-ITD expressing AML cell lines MOLM-13 and MV4-11 in the nanomolar range, with significant selectivity over the K562 cell line. In-depth evaluations of example compound 49 revealed its efficacy in suppressing FLT3 phosphorylation and the downstream signaling molecules, including STAT5 and ERK1/2. Notably, compound 49 demonstrated cytotoxic effects in Ba/F3 cells expressing FLT3-ITD or FLT3-ITD-F691L mutant, exceeding the potency of both sorafenib and quizartinib. Molecular docking studies suggest that this compound binds to the active site of FLT3 in a type II manner. The study suggests that substituted furo[2,3-d]pyrimidines could be useful additions to the growing field of FLT3-targeted therapy for AML. These compounds have the potential to serve as novel FLT3-ITD inhibitors and may offer insights for developing future therapeutic strategies in AML.

• MeSH
• akutní myeloidní leukemie farmakoterapie   patologie   metabolismus   MeSH
• inhibitory proteinkinas * farmakologie   chemie   chemická syntéza   MeSH
• lidé MeSH
• molekulární struktura MeSH
• nádorové buněčné linie MeSH
• proliferace buněk účinky léků   MeSH
• protinádorové látky * farmakologie   chemie   chemická syntéza   MeSH
• pyrimidiny chemie   farmakologie   chemická syntéza   MeSH
• screeningové testy protinádorových léčiv * MeSH
• simulace molekulového dockingu * MeSH
• thiadiazoly * chemie   farmakologie   chemická syntéza   MeSH
• tyrosinkinasa 3 podobná fms * antagonisté a inhibitory   metabolismus   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

Geldanamycin remains a driver in the medicinal chemistry of heat shock protein 90 (Hsp90) inhibition, even half a century after its original isolation from nature. This Perspective focuses on the properties of the benzoquinone ring of the natural product that enable a range of functionalization reactions to take place. Therefore, inherent reactivity at C-17, where the methoxy group serves as a vinylogous ester, and at C-19 that demonstrates nucleophilic, enamide-type character toward electrophiles, and also as a conjugate acceptor to react with nucleophiles, has facilitated the synthesis of semisynthetic derivatives. Thus, a range of C-17-substituted amine derivatives has been investigated in oncology applications, with a number of compounds in this series reaching clinical trials. In contrast, the 19-position of geldanamycin has received less attention, although 19-substituted derivatives offer promise with markedly reduced toxicity compared to geldanamycin itself, while retaining Hsp90 inhibitory activity albeit with diminished potency in cellular studies.

• MeSH
• benzochinony * chemie   farmakologie   chemická syntéza   MeSH
• farmaceutická chemie metody   MeSH
• lidé MeSH
• makrocyklické laktamy * chemie   farmakologie   chemická syntéza   MeSH
• proteiny tepelného šoku HSP90 * antagonisté a inhibitory   metabolismus   MeSH
• protinádorové látky farmakologie   chemie   chemická syntéza   MeSH
• vztahy mezi strukturou a aktivitou MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

A series of new unique acetylene derivatives of 8-hydroxy- and 8-methoxyquinoline- 5-sulfonamide 3a-f and 6a-f were prepared by reactions of 8-hydroxy- and 8-methoxyquinoline- 5-sulfonyl chlorides with acetylene derivatives of amine. A series of new hybrid systems containing quinoline and 1,2,3-triazole systems 7a-h were obtained by reactions of acetylene derivatives of quinoline-5-sulfonamide 6a-d with organic azides. The structures of the obtained compounds were confirmed by 1H and 13C NMR spectroscopy and HR-MS spectrometry. The obtained quinoline derivatives 3a-f and 6a-f and 1,2,3-triazole derivatives 7a-h were tested for their anticancer and antimicrobial activity. Human amelanotic melanoma cells (C-32), human breast adenocarcinoma cells (MDA-MB-231), and human lung adenocarcinoma cells (A549) were selected as tested cancer lines, while cytotoxicity was investigated on normal human dermal fibroblasts (HFF-1). All the compounds were also tested against reference strains Staphylococcus aureus ATCC 29213 and Enterococcus faecalis ATCC 29212 and representatives of multidrug-resistant clinical isolates of methicillin-resistant S. aureus (MRSA) and vancomycin-resistant E. faecalis. Only the acetylene derivatives of 8-hydroxyquinoline-5-sulfonamide 3a-f were shown to be biologically active, and 8-hydroxy-N-methyl-N-(prop-2-yn-1-yl)quinoline-5-sulfonamide (3c) showed the highest activity against all three cancer lines and MRSA isolates. Its efficacies were comparable to those of cisplatin/doxorubicin and oxacillin/ciprofloxacin. In the non-cancer HFF-1 line, the compound showed no toxicity up to an IC50 of 100 μM. In additional tests, compound 3c decreased the expression of H3, increased the transcriptional activity of cell cycle regulators (P53 and P21 proteins), and altered the expression of BCL-2 and BAX genes in all cancer lines. The unsubstituted phenolic group at position 8 of the quinoline is the key structural fragment necessary for biological activity.

• MeSH
• antibakteriální látky * farmakologie   chemie   chemická syntéza   MeSH
• chinoliny * chemie   farmakologie   chemická syntéza   MeSH
• Enterococcus faecalis účinky léků   MeSH
• lidé MeSH
• mikrobiální testy citlivosti * MeSH
• molekulární struktura MeSH
• nádorové buněčné linie MeSH
• protinádorové látky * farmakologie   chemie   chemická syntéza   MeSH
• racionální návrh léčiv MeSH
• Staphylococcus aureus účinky léků   MeSH
• sulfonamidy * farmakologie   chemie   chemická syntéza   MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH