Impairment of the p53 pathway is a critical event in cancer. Therefore, reestablishing p53 activity has become one of the most appealing anticancer therapeutic strategies. Here, we disclose the p53-activating anticancer drug (3S)-6,7-bis(hydroxymethyl)-5-methyl-3-phenyl-1H,3H-pyrrolo[1,2-c]thiazole (MANIO). MANIO demonstrates a notable selectivity to the p53 pathway, activating wild-type (WT)p53 and restoring WT-like function to mutant (mut)p53 in human cancer cells. MANIO directly binds to the WT/mutp53 DNA-binding domain, enhancing the protein thermal stability, DNA-binding ability, and transcriptional activity. The high efficacy of MANIO as an anticancer agent toward cancers harboring WT/mutp53 is further demonstrated in patient-derived cells and xenograft mouse models of colorectal cancer (CRC), with no signs of undesirable side effects. MANIO synergizes with conventional chemotherapeutic drugs, and in vitro and in vivo studies predict its adequate drug-likeness and pharmacokinetic properties for a clinical candidate. As a single agent or in combination, MANIO will advance anticancer-targeted therapy, particularly benefiting CRC patients harboring distinct p53 status.
- MeSH
- apoptóza účinky léků genetika MeSH
- cisplatina farmakologie MeSH
- doxorubicin farmakologie MeSH
- fluoruracil farmakologie MeSH
- HCT116 buňky MeSH
- kolorektální nádory farmakoterapie genetika metabolismus patologie MeSH
- kontrolní body buněčného cyklu účinky léků genetika MeSH
- lidé MeSH
- myši nahé MeSH
- myši MeSH
- nádorové buněčné linie MeSH
- nádorový supresorový protein p53 agonisté genetika metabolismus MeSH
- objevování léků MeSH
- proliferace buněk účinky léků MeSH
- protinádorové látky chemická syntéza farmakologie MeSH
- protokoly protinádorové kombinované chemoterapie farmakologie MeSH
- pyrroly chemická syntéza farmakologie MeSH
- regulace genové exprese u nádorů MeSH
- synergismus léků MeSH
- thiazoly chemická syntéza farmakologie MeSH
- vazba proteinů MeSH
- xenogenní modely - testy protinádorové aktivity MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Twelve 7-chloroquinoline derivatives were designed and synthesized using the principle of molecular hybridization through the coupling of 2-[2-(7-chloroquinolin-4-ylthio)-4-methylthiazol-5-yl]acetic acid 1 with various benzoyl hydrazines 2a-l. The synthetic compounds were tested as antimalarials. Some of them showed an efficient in vitro activity as inhibitors of β-hematin formation and an in vivo activity in a murine model, resulting in compounds 8 and 9 as the most active ones with IC50 values of 0.65 ± 0.09 and 0.64 ± 0.16 µM, respectively. The effects of the compounds on the cell viability, cell cycle, and apoptosis induction of A549 and MCF-7 cancer cell lines were also examined. Our data showed that compounds 6 and 12 were the most active agents, decreasing the cell viability of MCF-7 cells with IC50 values of 15.41 and 12.99 µM, respectively. None of the compounds analyzed significantly affected the viability of peripheral blood mononuclear cells. Also, significant induction of apoptosis was observed when both cancer cell lines were incubated with compounds 6 and 12. In MCF-7 cells, treatment with these compounds led to cell cycle arrest in the G0/G1 phase. The results obtained suggest that these structures may be useful in developing new therapies for malaria and cancer treatment.
- MeSH
- antimalarika chemická syntéza chemie farmakologie MeSH
- apoptóza účinky léků MeSH
- buňky A549 MeSH
- chinoliny chemická syntéza chemie farmakologie MeSH
- hydraziny chemická syntéza chemie farmakologie MeSH
- inhibiční koncentrace 50 MeSH
- kontrolní body buněčného cyklu účinky léků MeSH
- kyselina octová chemická syntéza chemie farmakologie MeSH
- lidé MeSH
- malárie farmakoterapie MeSH
- MFC-7 buňky MeSH
- modely nemocí na zvířatech MeSH
- myši inbrední BALB C MeSH
- myši MeSH
- protinádorové látky chemická syntéza chemie farmakologie MeSH
- thiazoly chemická syntéza chemie farmakologie MeSH
- viabilita buněk účinky léků MeSH
- vztahy mezi strukturou a aktivitou MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
In this work, 35 new derivatives of betulonic, dihydrobetulonic and ursonic acid were prepared including 30 aminothiazoles and all of them were tested for their in vitro cytotoxic activity in eight cancer cell lines and two non-cancer fibroblasts. Compounds with the IC50 below 5 μM in CCRF-CEM cells and low toxicity in non-cancer fibroblasts (4m, 5c, 5m, 6c, 6m, 7b, and 7c) were further subjected to tests of pharmacological parameters yielding the final set for advanced biological evaluation (4m, 5m, 6m, and 7b). It was proved by several methods, that all of them trigger apoptosis via the intrinsic pathway and derivatives 5m and 7b are the most effective (IC50 2.4 μM and 3.6 μM). They are the best candidates to become potentially new anticancer drugs and will be subjected to in vivo tests in mice. In addition, compounds 6b and 6c deserve more attention because their activity is not limited only to chemosensitive CCRF-CEM cell line. Specifically, compound 6b is highly active against K562 leukemic cell line (0.7 μM) and its IC50 activity in colon cancer HCT116 cell line is 1.0 μM. Compound 6c is active in both normal K562 and resistant K562-TAX cell lines (IC50 3.4 μM and 5.4 μM) and both colon cancer cell lines (HCT116 and HCT116p53-/-, IC50 3.5 μM and 3.4 μM).
- MeSH
- apoptóza účinky léků MeSH
- fibroblasty účinky léků MeSH
- kultivované buňky MeSH
- kyselina olenalová analogy a deriváty chemie farmakologie MeSH
- lidé MeSH
- membránový potenciál mitochondrií účinky léků MeSH
- mikrozomy chemie metabolismus MeSH
- molekulární struktura MeSH
- proliferace buněk účinky léků MeSH
- protinádorové látky chemická syntéza chemie farmakologie MeSH
- screeningové testy protinádorových léčiv MeSH
- terpeny chemická syntéza chemie farmakologie MeSH
- thiazoly chemická syntéza chemie farmakologie MeSH
- triterpeny chemie farmakologie MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- vztahy mezi strukturou a aktivitou MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
By understanding the rampant infections of Mycobacterium tuberculosis (Mtb) and inflammations caused due to the generation of radical species during the Mtb infection, a series of (E)-2-(2-allylidenehydrazinyl)thiazole derivatives, with dual-action properties, was designed. The molecules were designed with a considerable variation in LogP, one of the critical parameters in physicochemical properties, and analyzed for their drug-likeness. For the synthesis, a simple, green, and multicomponent one-pot synthesis method was developed. The in vitro inhibition potentials were evaluated against Mtb H37 Rv by the microplate Alamar Blue assay. The results reveal that compound 6 was potent, with a MIC value of 6.5 µg/ml, and showed better interactions with the KasA protein with binding free energy (ΔG) of -9.4 kcal/mol. Also, the radical scavenging properties were studied to establish the dual-action properties of the molecules. Compound 9 exhibited promising antioxidant and nitric oxide radical scavenging activities, with 81.7% and 81.0%, respectively, at 1,000-μg/ml concentration.
- MeSH
- antituberkulotika chemická syntéza chemie farmakologie MeSH
- mikrobiální testy citlivosti MeSH
- molekulární modely MeSH
- molekulární struktura MeSH
- Mycobacterium tuberculosis účinky léků MeSH
- racionální návrh léčiv * MeSH
- scavengery volných radikálů chemická syntéza chemie farmakologie MeSH
- thiazoly chemická syntéza chemie farmakologie MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- vztahy mezi strukturou a aktivitou MeSH
- Publikační typ
- časopisecké články MeSH
A total of 41 new triterpenoids were prepared from allobetulone, methyl betulonate, methyl oleanonate, and oleanonic acid to study their influence on cancer cells. Each 3-oxotriterpene was brominated at C2 and substituted with thiocyanate; subsequent cyclization with the appropriate ammonium salts gave N-substituted thiazoles. All compounds were tested for their in vitro cytotoxic activity on eight cancer cell lines and two non-cancer fibroblasts. 2-Bromoallobetulone (2 b) methyl 2-bromobetulonate (3 b), 2-bromooleanonic acid (5 b), and 2-thiocyanooleanonic acid (5 c) were best, with IC50 values less than 10 μm against CCRF-CEM cells (e.g., 3 b: IC50 =2.9 μm) as well as 2'-(diethylamino)olean-12(13)-eno[2,3-d]thiazole-28-oic acid (5 f, IC50 =9.7 μm) and 2'-(N-methylpiperazino)olean-12(13)-eno[2,3-d]thiazole-28-oic acid (5 k, IC50 =11.4 μm). Compound 5 c leads to the accumulation of cells in the G2 phase of the cell cycle and inhibits RNA and DNA synthesis significantly at 1×IC50 . The G2 /M cell-cycle arrest probably corresponds to the inhibition of DNA/RNA synthesis, similar to the mechanism of action of actinomycin D. Compound 5 c is new, active, and nontoxic; it is therefore the most promising compound in this series for future drug development. Methyl 2-bromobetulonate (3 b) and methyl 2-thiocyanometulonate (3 c) were found to inhibit nucleic acid synthesis only at 5×IC50 . We assume that in 3 b and 3 c (unlike in 5 c), DNA/RNA inhibition is a nonspecific event, and an unknown primary cytotoxic target is activated at 1×IC50 or lower concentration.
- MeSH
- apoptóza účinky léků MeSH
- kontrolní body fáze G2 buněčného cyklu účinky léků MeSH
- kontrolní body M fáze buněčného cyklu účinky léků MeSH
- kyselina olenalová analogy a deriváty chemie MeSH
- lidé MeSH
- nádorové buněčné linie MeSH
- protinádorové látky chemická syntéza chemie toxicita MeSH
- screeningové testy protinádorových léčiv MeSH
- thiazoly chemická syntéza chemie toxicita MeSH
- triterpeny chemie MeSH
- vztahy mezi strukturou a aktivitou MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
NAG-thiazoline is a well-established competitive inhibitor of two physiologically relevant glycosidase families-β-N-acetylhexosaminidases (GH20) and β-N-acetylglucosaminidases (GH84). Based on the different substrate flexibilities of these enzyme groups, we designed and synthesized the 4-deoxy derivative of NAG-thiazoline aiming at the selective inhibition of GH20 β-N-acetylhexosaminidases. One GH84 and two GH20 microbial glycosidases were employed as model enzymes for the inhibition assays. Surprisingly, the new compound 4-deoxy-thiazoline exhibited no activity inhibition with either of the enzyme families of interest. Unlike with the substrates, the 4-hydroxyl group of the inhibitor's sugar ring seems to be crucial for binding the inhibitor to the active sites of these enzymes.
- MeSH
- acetylglukosamin analogy a deriváty chemická syntéza chemie metabolismus MeSH
- Bacteroides enzymologie MeSH
- bakteriální proteiny antagonisté a inhibitory metabolismus MeSH
- beta-N-acetylhexosaminidasy antagonisté a inhibitory metabolismus MeSH
- fungální proteiny antagonisté a inhibitory metabolismus MeSH
- houby enzymologie MeSH
- kinetika MeSH
- Streptomyces enzymologie MeSH
- substrátová specifita MeSH
- thiazoly chemická syntéza chemie metabolismus MeSH
- vazba proteinů MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
NAG-thiazoline is a strong competitive inhibitor of GH20 β-N-acetyl- hexosaminidases and GH84 β-N-acetylglucosaminidases. Here, we focused on the design, synthesis and inhibition potency of a series of new derivatives of NAG-thiazoline modified at the C-6 position. Dimerization of NAG-thiazoline via C-6 attached triazole linkers prepared by click chemistry was employed to make use of multivalency in the inhibition. Novel compounds were tested as potential inhibitors of β-N-acetylhexosaminidases from Talaromyces flavus, Streptomyces plicatus (both GH20) and β-N-acetylglucosaminidases from Bacteroides thetaiotaomicron and humans (both GH84). From the set of newly prepared NAG-thiazoline derivatives, only C-6-azido-NAG-thiazoline displayed inhibition activity towards these enzymes; C-6 triazole-substituted NAG-thiazolines lacked inhibition activity against the enzymes used. Docking of C-6-azido-NAG-thiazoline into the active site of the tested enzymes was performed. Moreover, a stability study with GlcNAc-thiazoline confirmed its decomposition at pH < 6 yielding 2-acetamido-2-deoxy-1-thio-α/β-D-glucopyranoses, which presumably dimerize oxidatively into S-S linked dimers; decomposition products of NAG-thiazoline are void of inhibitory activity.
- MeSH
- acetylglukosamin analogy a deriváty chemická syntéza chemie farmakologie MeSH
- beta-N-acetylhexosaminidasy antagonisté a inhibitory chemie metabolismus MeSH
- glykosidhydrolasy antagonisté a inhibitory chemie metabolismus MeSH
- katalytická doména MeSH
- molekulární konformace MeSH
- molekulární modely MeSH
- stabilita léku MeSH
- thiazoly chemická syntéza chemie farmakologie MeSH
- vazba proteinů MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
A series of novel cholinesterase inhibitors based on 2-substituted 6-fluorobenzo[d]thiazole were synthesised and characterised by IR, (1)H, (13)C and (19)F NMR spectroscopy and HRMS. Purity was checked by elemental analyses. The novel carbamates were tested for their ability to inhibit acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). The toxicity of the most active compounds was investigated using a standard in vitro test with HepG2 cells, and the ratio between biological activity and toxicity was determined. In addition, the toxicity of the most active compounds was evaluated against MCF7 cells using the xCELLigence system. Structure-activity relationships reflecting the dependence of cholinesterase inhibitors on the lipophilicity of the compounds as well as on the Taft polar and steric substituent constants are discussed. The specific orientation of the inhibitors in the binding site of acetylcholinesterase was determined using molecular docking of the most active compound.
- MeSH
- acetylcholinesterasa metabolismus MeSH
- buňky Hep G2 MeSH
- butyrylcholinesterasa metabolismus MeSH
- cholinesterasové inhibitory chemická syntéza chemie farmakologie toxicita MeSH
- halogenace MeSH
- karbamáty chemická syntéza chemie farmakologie toxicita MeSH
- lidé MeSH
- nádorové buněčné linie MeSH
- simulace molekulového dockingu MeSH
- thiazoly chemická syntéza chemie farmakologie toxicita MeSH
- viabilita buněk účinky léků MeSH
- vztahy mezi strukturou a aktivitou MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
A series of novel sulfonamides containing 5-chloro-2-hydroxybenzaldehyde or 5-chloro-2-hydroxybenzoic acid scaffolds were designed, synthesized and characterized by IR, (1)H NMR and (13)C NMR. All ten target synthesized derivatives and starting sulfonamides were evaluated in vitro for the activity against Gram-positive and Gram-negative bacteria, fungi, Mycobacterium tuberculosis, Mycobacterium avium and Mycobacterium kansasii. The most active compound against methicillin-sensitive and methicillin-resistant Staphyloccoccus aureus was 5-chloro-N-{4-[N-(4,6-dimethylpyrimidin-2-yl)sulfamoyl]phenyl}-2-hydroxybenzamide with MIC 15.62-31.25 μmol/L. 4-Amino-N-(thiazol-2-yl)benzenesulfonamide and 4-(5-chloro-2-hydroxybenzylideneamino)-N-(thiazol-2-yl)benzenesulfonamide have shown the best activity against M. kansasii at the concentrations of 1-4 μmol/L. The efficacy against other strains was weaker and the studied derivatives exhibited almost none antifungal potency.
- MeSH
- antiinfekční látky chemická syntéza farmakologie MeSH
- Bacteria účinky léků MeSH
- benzamidy chemická syntéza farmakologie MeSH
- houby účinky léků MeSH
- magnetická rezonanční spektroskopie MeSH
- mikrobiální testy citlivosti MeSH
- molekulární struktura MeSH
- spektrofotometrie infračervená MeSH
- sulfonamidy chemická syntéza chemie farmakologie MeSH
- thiazoly chemická syntéza farmakologie MeSH
- vztahy mezi strukturou a aktivitou MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
5-(Substituted amino)-1,2,3,4-thiatriazoles 15a–15i were conveniently synthesized in 73–97% yields in a one-pot procedure from bis(1H-benzotriazol-1-yl)methanethione and amines.
