Partial PPARγ agonists attracted substantially heightened interest as safer thiazolidinediones alternatives. On the other hand, Wnt/β-catenin antagonists have been highlighted as promising strategy ...for type 2 diabetes management via up-regulating PPARγ gene expression. We aimed at synthesizing novel partial PPARγ agonists with β-catenin inhibitory activity which could enhance insulin sensitivity and avoid the side effects of full PPARγ agonists.
We synthesized novel series of α-phthlimido-o-toluoyl-2-aminothiazoles hybrids for evaluating their antidiabetic activity and discovering its mechanistic pathway. We assessed effect of the new hybrids on PPARγ activation using a luciferase reporter assay system. Moreover, intracellular triglyceride levels, gene levels of c/EBPα, PPARγ and PPARγ targets including GLUT4, adiponectin, aP2 were measured in 3T3-L1 cells. Uptake of 2-DOG together with PPARγ and β-catenin protein levels were evaluated in 3T3-L1cells. In addition, molecular docking studies with PPARγ LBD, physicochemical properties and structure activity relationship of the novel hybrids were also studied.
Three of the synthesized hybrids showed partial PPARγ agonistic activity and distinct PPARγ binding pattern. These compounds modulated PPARγ gene expression and PPARγ target genes; and increased glucose uptake in 3T3-L1 and slightly induced adipogenesis compared to rosiglitazone. Moreover, these compounds reduced β-catenin protein level which reflected in increased both PPARγ gene and protein levels that leads to improved insulin sensitivity and increased GLUT4 and adiponectin gene expression.
Our synthesized compounds act as novel partial PPARγ agonists and β-catenin inhibitors that have potent insulin sensitizing activity and mitigate the lipogenic side effects of TZDs.
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•Novel α-phthlimido-o-toluoyl-2-aminothiazole hybrids synthesized and identified•Among new hybrids, 7a,7c and 7g act as partial PPARγ agonist and β-catenin inhibitor.•In 3T3-L1 cells, the new hybrids decreased triglycerides compared to rosiglitazone.•7a,7c and 7g stimulated glucose uptake and adiponectin gene expression in 3T3-L1.•7a,7c and 7g reduced β-catenin protein, while; upregulated PPARγ protein in 3T3-L1.
Topoisomerases II are ubiquitous enzymes with significant genotoxic effects in many critical DNA processes. Additionally, epidermal growth factor receptor (EGFR) plays pivotal role in tumour growth ...and angiogenesis. A novel series of naphtho2',3':4,5thiazolo3,2-
a
pyrimidine hybrids have been designed, synthesised and evaluated for their topo IIα/EGFR inhibitory and apoptotic inducer activities. Cytotoxicity of the synthesised hybrids was evaluated against MCF-7, A549 and HCT-116 cell lines. Of the synthesised hybrids, 6i, 6a and 6c experienced superior cytotoxic activity compared to doxorubicin and erlotinib against the tested cancer cells. The molecular mechanism of these hybrids revealed their ability to successfully inhibit topo IIα and EGFR activities in micromolar concentration and may serve as topo II catalytic inhibitor. Moreover, these hybrids significantly arrested cell cycle at G2/M phase together with increased p53, caspae-7, caspase-9 levels and Bax/Bcl-2 ratio. The synthesised hybrids showed efficient binding pattern in molecular docking study and have acceptable drug likeness characters.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Dipeptidyl peptidase-4 (DPP-4) inhibitors have emerged as anti-hyperglycemic agents that improve glycemic control in type 2 diabetic patients, either as monotherapy or in combination with other ...antidiabetic drugs.
A novel series of dihydropyrimidine phthalimide hybrids was synthesized and evaluated for their in vitro and in vivo DPP-4 inhibition activity and selectivity using alogliptin as reference. Oral glucose tolerance test was assessed in type 2 diabetic rats after chronic treatment with the synthesized hybrids ± metformin. Cytotoxicity and antioxidant assays were performed. Additionally, molecular docking study with DPP-4 and structure activity relationship of the novel hybrids were also studied.
Among the synthesized hybrids,
,
,
,
and
had stronger in vitro DPP-4 inhibitory activity than alogliptin. Moreover, an in vivo DPP-4 inhibition assay revealed that
and
have the strongest and the most extended blood DPP-4 inhibitory activity compared to alogliptin. In type 2 diabetic rats, hybrids
,
and
exhibited better glycemic control than alogliptin, an effect that further supported by metformin combination. Finally,
,
,
and
had the highest radical scavenging activity in DPPH assay.
Hybrids
,
and
are potent DPP-4 inhibitors which may be beneficial for T2DM treatment.
Herein, modifications to the previously reported BIBR1591 were conducted to obtain bioisosteric candidates with improved activities. The % inhibition of the newly afforded candidates against the ...telomerase target was investigated. Notably, 6f achieved superior telomerase inhibition (63.14%) compared to BIBR1532 and BIBR1591 (69.64 and 51.58%, respectively). In addition, 8a and 8b showed comparable promising telomerase inhibition with 58.65 and 55.57%, respectively, which were recorded to be frontier to that of BIBR1591. 6f, 8a, and 8b were tested against five cancer cell lines related to the lung and liver subtypes. Moreover, 6f was examined on both cell cycle progression and apoptosis induction in HuH7 cancer cells. Furthermore, the in vivo antitumor activity of 6f was further assessed in female mice with solid Ehrlich carcinoma. In addition, molecular docking and molecular dynamics simulations were carried out. Collectively, 6f, 8a, and 8b could be considered potential new telomerase inhibitors to be subjected to further investigation and/or optimization.
In order to develop novel anticancer HDAC/tubulin dual inhibitors, a novel series of α-phthalimido-substituted chalcones-based hybrids was synthesized and characterized by IR,
H NMR,
C NMR, mass ...spectroscopy and X-ray analysis.
All the synthesized compounds were evaluated for their in vitro anticancer activity against MCF-7 and HepG2 human cancer cell lines using MTT assay. To explore the mechanism of action of the synthesized compounds, in vitro
-tubulin polymerization and HDAC 1 and 2 inhibitory activity were measured for the most potent anticancer hybrids. Further, cell cycle analysis was also evaluated.
The trimethoxy derivative
showed the most potent anticancer activity, possessed the most potent
-tubulin polymerase and HDAC 1 and 2 inhibitory activity and efficiently induced cell cycle arrest at both G2/M and preG1phases in the MCF-7 cell line.
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•Novel series of bis-quinolinylquinones 3a-d and 4b,e,f were synthesized and identified by different spectroscopic techniques.•Targeting ERK2, compounds 3a, 3b and 4f inhibited Ets-1 ...(Avian erythroblastosis virus E26 (v-ets) oncogene homolog-1) phosphorylation by ERK2 in a dose dependent manner. Molecular docking supported the binding pattern of some new compounds towards ATP-binding of ERK2•Compound 4f showed the ability to inhibit ERK2 in vitro with ATP-competitive inhibition mechanism. Further structure improvement is recommended to enhance its mammalian cell internalization.•The cytotoxic effect of compound 3d was apparent across all tumor cell lines tested, except leukemia, with 47 out of the 52 non-leukemic cell lines showing negative growth percentages.•NCI in vitro five dose testing revealed that compounds 3b and 3d represent promising lead anticancer compounds with GI50 values ranging between (0.31–3.04 µM), and (0.26–0.93 µM), respectively.
Two novel series of N-2,3-bis(6-substituted-4-hydroxy-2-oxo-1,2-dihydroquinolin-3-yl)naphthalene-1,4-diones 3a-d and substituted N-(methyl/ethyl)bisquinolinone triethyl-ammonium salts 4e,f were successfully synthesized. The synthesized compounds were targeted as new candidates to extracellular signal-regulated kinases 1/2 (ERK1/2) with considerable antineoplastic activity. The synthesis involved the reactions of 2 equivalents of 4-hydroxy-2(1H)-quinolinones 1a-f and one equivalent of 1,4-naphthoquinone (2) in a mixture of ethanol/dimethylformamide (1:1) as a solvent and 0.5 mL Et3N. In the reaction of 6-methyl-4-hydroxyquinolone 1b with 2, a side product 4b of the second series was obtained. In general, the presence of free NH-quinolone gave a single compound of the first series, whereas reaction of N-methyl/ethyl-quinolones 1e,f with 2 enhanced the formation of compounds of the second series. The structures of the new compounds were proved by different spectroscopic techniques such as IR, NMR (2D-NMR) and mass spectra, elemental analysis, and X-ray crystallography. To further elucidate the mechanism of action of these newly synthesized compounds, compounds 3a, 3b, 4e and 4f were selected to investigate for their MAP Kinases pathway inhibition together with molecular docking using ATP-binding site of ERK2. The results revealed that compounds 3a, 3b and 4f inhibited ETS-1 phosphorylation by ERK2 in a dose dependent manner. Also, compound 4f showed highest potency for ERK2 inhibition with ATP-competitive inhibition mechanism which was confirmed by the formation of three hydrogen bond in the molecular docking studies. The synthesized compounds were then tested for their in vitro anticancer activity against the NCI-60 panel of tumor cell lines. Interestingly, the selected compounds displayed from modest to strong cytotoxic activities. Compound 3b demonstrated broad spectrum anti-tumor activity against the nine tumor sub-panels tested, while compound 3d proved to be lethal to most of the cancer cell lines as shown by their promising GI50 and TGI values in NCI in vitro five dose testing. These results revealed that the synthesized compounds can potentially serve as leads for the development of novel chemotherapeutic agents and structure improvement will be necessary for some derivatives for enhancing their cellular activities and pharmacokinetic profile.
A group of novel nitric oxide (NO) donating chalcone derivatives was prepared by binding various amino chalcones with different NO donating moieties including; nitrate ester, oximes and furoxans. ...Most of the prepared compounds showed significant anti-inflammatory activity using carrageenan-induced rat paw edema method compared with indomethacin. The prepared compounds exhibited more protection than indomethacin in regard to gastric toxicity. Histopathological investigation confirmed the beneficial effects of the NO releasing compounds in reducing ulcer formation. The incorporation of the NO-donating group into the parent chalcone derivatives caused a moderate increase in the anti-inflammatory activity with a marked decrease in gastric ulcerations compared to their parent chalcone derivatives.
A group of nitric oxide (NO) donating chalcone derivatives was prepared by binding amino chalcones with different NO-donating moieties including; nitrate esters, oximes and furoxans. Screening of the ...anticancer activity of the target compounds revealed that the selected NO-donating compounds exhibited from mild to strong cytotoxic activity. The NO/chalcone hybrids 3a and 3b exhibited remarkable activity against different types of cancer cell lines especially against the colon and melanoma cancer cell lines. The nitrate ester 3a exhibited moderate selectivity toward colon cancer subpanel with selectivity ratio of 5.87 at TGI level.
The prepared chalcone/NO hybrids 3a and 3b exhibited remarkable cytotoxic activity against various cancer cell lines. The nitrate ester 3a achieved maximum inhibitory activity with moderate selectivity toward colon cancer subpanel. Display omitted
► A group of chalcone/NO-donating hybrids were prepared and identified by different spectroscopic techniques. ► The tested NO-donating compounds exhibited from mild to strong cytotoxic activity. ► The nitrate ester 3a exhibited moderate selectivity toward colon cancer subpanel with selectivity ratio of 5.87 at TGI level. ► The novel synthesized NO-donating hybrids represent a significant strategy against cancer.
Ulcerative colitis (UC) is a chronic inflammatory bowel disease of unknown etiology that increases the risk of developing colorectal cancer and imposes a lifelong healthcare burden on millions of ...patients worldwide. Current treatment strategies are associated with significant risks and have been shown to be fairly effective. Hence, discovering new therapies that have better efficacy and safety profiles than currently exploited therapeutic strategies is challenging. It has been well delineated that NF‐κB/Nrf2 crosstalk is a chief player in the interplay between oxidative stress and inflammation. Ambroxol hydrochloride, a mucolytic agent, has shown antioxidant and anti‐inflammatory activity in humans and animals and has not yet been examined for the management of UC. Therefore, our approach was to investigate whether ambroxol could be effective to combat UC using the common acetic acid rat model. Interestingly, a high dose of oral ambroxol (200 mg/kg/day) reasonably improved the microscopic and macroscopic features of the injured colon. This was linked to low disease activity and a reduction in the colonic weight/length ratio. In the context of that, ambroxol boosted Nrf2 activity and upregulated HO‐1 and catalase to augment the antioxidant defense against oxidative damage. Besides, ambroxol inactivated NF‐κB signaling and its consequent target pro‐inflammatory mediators, IL‐6 and TNF‐α. In contrast, IL‐10 is upregulated. Consistent with these results, myeloperoxidase activity is suppressed. Moreover, ambroxol decreased the susceptibility of the injured colon to apoptosis. To conclude, our findings highlight the potential application of ambroxol to modify the progression of UC by its anti‐inflammatory, antioxidant, and antiapoptotic properties.
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