Design,synthesis, evaluation,and molecular docking of ursolic acid derivatives containing a nitrogen heterocycle as anti-inflammatory agents

Ursolic acid derivatives containing oxadiazole, triazolone, and piperazine moieties were synthesized in an attempt to develop potent anti-inflammatory agents. Structures of the synthesized compounds were elucidated by ¹H NMR, ¹³C NMR, and HRMS. Most of the synthesized compounds showed pronounced anti-inflammatory effects at 100?mg/kg. In particular, compound 11b, which displayed the most potent anti-inflammatory activity of all of the compounds prepared, with 69.76% inhibition after intraperitoneal administration, was more potent than the reference drugs indomethacin and ibuprofen. The cytotoxicity of the compounds was also assessed by the 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) assay, and no compounds showed any appreciable cytotoxic activity (IC₅₀ >100?μmol/L). Furthermore, molecular docking studies of the synthesized compounds were performed to rationalize the obtained biological results. Overall, the results indicate that compound 11b could be a therapeutic candidate for the treatment of inflammation.     

Design,synthesis and biological evaluation of glutamic acid derivatives as anti-oxidant and anti-inflammatory agents

A series of glutamic acid derivatives was synthesized and evaluated for their antioxidant activity and stability. We found several potent and stable glutamic acid derivatives. Among them, compound 12b exhibited good in vitro activity, chemical stability and cytotoxicity. A prototype compound 12b showed an anti-inflammatory effect in LPS-stimulated RAW 264.7 cell lines and in a zebrafish model.     

Design,synthesis and biological evaluation of matrine derivatives as potential anticancer agents

Using matrine (1) as the lead compound, a series of new 14-(N-substituted-2-pyrrolemethylene) matrine and 14-(N-substituted-indolemethylene) matrine derivatives was designed and synthesized for their potential application as anticancer agents. The structure of these compounds was characterized by ¹H NMR, ¹³C NMR and ESI-MS spectral analyses. The target compounds were evaluated for their in vitro cytotoxicity against three human cancer cell lines (SMMC-7721, A549 and CNE2). The results revealed that compound A6 and B21 displayed the most significant anticancer activity against three cancer cell lines with IC₅₀ values in range of 3.42–8.05?μM, which showed better activity than the parent compound (Matrine) and positive control Cisplatin. Furthermore, the Annexin V-FITC/PI dual staining assay revealed that compound A6 and B21 could significantly induce the apoptosis of SMMC-7721 and CNE2 cells in a dose-dependent manner. The cell cycle analysis also revealed that compound A6 could cause cell cycle arrest of SMMC-7721 and CNE2 cells at G2/M phase.     

Non-acidic 1,3,4-trisubstituted-pyrazole derivatives as lonazolac analogs with promising COX-2 selectivity,anti-inflammatory activity and gastric safety profile

Twelve new compounds of 1,3,4-trisubstituted-pyrazole derivatives possessing two cyclooxygenase-2 (COX-2) pharmacophoric moieties (SO₂Me or/and SO₂NH₂) 11a-c, 12a-c, 13a-c and 14a-c were designed and synthesized to be evaluated for their COX inhibition, anti-inflammatory activity, ulcerogenic liability. All compounds were more selective for COX-2 isozyme and showed good in vivo anti-inflammatory activity. The bisaminosulphonyl derivatives (14a-c) were the most COX-2 selective compounds (S.I. = 9.87, 9.50 and 9.22 respectively) and showed good anti-inflammatory potency (ED₅₀ = 15.06, 42.51 and 50.43 μmol/kg respectively) in comparison with celecoxib (COX-2 S.I. = 8.61, ED₅₀ = 82.2 μmol/kg). Also, compounds 14a-c were less ulcerogenic (ulcer indexes = 2.72–3.72) than ibuprofen (ulcer index = 20.25) and comparable to celecoxib (ulcer index = 2.93). In addition, to explain the preferential (COX-2) inhibitory and selectivity, the designed compounds were subjected to molecular docking studies. It was found that compound 14c with the highest COX-2 activity and selectivity exhibited a binding pattern and interactions similar to that of celecoxib with formation of more hydrogen-bond features.     

Synthesis and anti-inflammatory evaluations of β-lapachone derivatives

β-Lapachone (β-LAPA), a natural product from the lapacho tree in South America, is a potential chemotherapeutic agent that exhibit a wide variety of pharmacological effects such as anti-virus, anti-parasitic, anti-cancer, and anti-inflammatory activities. In order to discover novel anti-inflammatory agents, we have synthesized a series of β-LAPA derivatives for evaluation. Among them, 4-(4-methoxyphenoxy)naphthalene-1,2-dione (6b) was found to be able to inhibit NO and TNF-α released in LPS-induced Raw 264.7 cells. Inhibition of iNOS and COX-2 was also observed in compound 6b treated cells. Mechanism studies indicated that 6b exhibited anti-inflammatory properties by suppressing the release of pro-inflammatory factors through down-regulating NF-κB activation. In addition, it suppressed NF-κB translocation by inhibiting the phosphorylation of p38 kinase. Our results also indicate that the inhibitory effect of 6b on LPS-stimulated inflammatory mediator production in Raw 264.7 cell is associated with the suppression of the NF-κB and MAPK signaling pathways. A low cytotoxicity (IC₅₀ = 31.70 μM) and the potent anti-inflammatory activity exhibited by compound 6b make this compound a potential lead for developing new anti-inflammatory agents. Further structural optimization of compound 6b is on-going.     

Synthesis and cytotoxicity evaluation of A-ring derivatives of cycloartanone

Sixteen derivatives, eight of which are new compounds, were prepared from cycloartenone (1) and cycloartanone (2), and the cytotoxic activity of 14 of these compounds, together with 1 and 2, was evaluated against a panel of four cell lines. Compound 1 was obtained from the epiphyte plant Tillandsia tenuifolia collected at Salta, Argentina. Due to chemoselectivity and regioselectivity problems observed in the reactions of compound 1, this substance was hydrogenated to compound 2. The attempted transformations were focused on ring A of the cited triterpenes with the aim to verify previous structure-activity relationships obtained from related compounds. The cytotoxicity results of the derivatives showed that only the diosphenol 13 displayed significant activity against all the tested cell lines. These results show that an oxidized side chain, for example an ether bridge between the side chain and ring D, is necessary for the cytotoxic activity of cycloartane derivatives.     

Synthesis and biological evaluation of cyanoguanidine derivatives of loratadine

Cyanoguanidine derivatives of loratadine (3a–i) were synthesized and screened for antitumor and anti-inflammatory activity. The most promising compound 3c (R = n-C₈H₁₇) possessed at least twofold higher in vitro cytotoxicity than 5-fluorouracil against mammary (MCF-7 and MDA-MB 231) as well as colon (HT-29) carcinoma cells. The mode of action, however, is so far unclear. The participation of the COX-1/2 enzymes on the cytotoxicity, however, is very unlikely. Nevertheless all compounds showed stronger in vivo anti-inflammatory activity than ibuprofen in the xylene-induced ear swelling assay in mice.     

Sapelenins G–J,acyclic triterpenoids with strong anti-inflammatory activities from the bark of the Cameroonian medicinal plant Entandrophragma cylindricum

Four acyclic triterpene derivatives named sapelenins G–J (1–4), along with eight known compounds, sapelenins A–D, ekeberin D2 (5), (+)-catechin and epicatechin, and anderolide G, were isolated from the stem bark of the Cameroonian medicinal plant, Entandrophragma cylindricum Sprague, on the basis of bioassay-guided fractionation. Their structures were determined by means of high-resolution mass spectrometry and NMR spectroscopic data, as well as by comparison with the literature values of their analogs. The absolute configurations of the compounds (1–4) were assigned by the modified Mosher’s method in conjunction with NOESY experiments and chemical modifications. The anti-inflammatory activities of the sapelenins were evaluated by assessing their ability to suppress or inhibit the secretion of cytokine interleukin-17 (IL-17) by human peripheral blood mononuclear cells (PBMC) stimulated with phytohemagglutinin (PHA). The cytotoxicity of these compounds on PMBCs was further assessed for correctly interpreting their anti-inflammatory responses. The tested compounds demonstrated moderate to significant anti-inflammatory activities by suppressing the secretion of IL-17 by PHA-stimulated human PBMCs. One of them, sapelenin G (1), showed high potency in suppressing the secretion of IL-17 by PBMCs comparable to reference cyclosporine A, without causing any cytotoxic effects (negligible), and deserves further considerations towards developing an effective anti-inflammatory drug.     

Design,synthesis and biological evaluation of novel desloratadine derivatives with anti-inflammatory and H1 antagonize activities

To improve the anti-inflammatory activity of desloratadine, we designed and synthesized a series of novel desloratadine derivatives. All compounds were evaluated for their anti-inflammatory and H₁ antagonistic activities. Among them, compound 2c showed the strongest H₁ antagonistic and anti-inflammatory activity. It also exhibited promising pharmacokinetic profiles and low toxicity. All these results suggest that compound 2c as a novel anti-allergic agent is worthy of further investigation.     

Identification and structure activity relationship of novel flavone derivatives that inhibit the production of nitric oxide and PGE2 in LPS-induced RAW 264.7 cells

In an effort to identify novel anti-inflammatory compounds, a series of flavone derivatives were synthesized and biologically evaluated for their inhibitory effects on the production of nitric oxide (NO) and prostaglandin E₂ (PGE₂), representative pro-inflammatory mediators, in LPS-induced RAW 264.7 cells. Their structure-activity relationship was also investigated. In particular, we found that compound 3g displayed more potent inhibitory activities on PGE₂ production, similar inhibitory activities on NO production and less weak cytotoxicity than luteolin, a natural flavone known as a potent anti-inflammatory agent.     

Isolation,structural elucidation,and insights into the anti-inflammatory effects of triterpene saponins from the leaves of Stauntonia hexaphylla

Using various chromatographic techniques, 23 triterpene saponins (1–23) were isolated from an ethanol extract of Stauntonia hexaphylla, including two new compounds (12 and 15). Their chemical structures were established by comprehensive spectroscopic methods such as 1D- and 2D-NMR, and HR-ESI-MS, and chemical reactions. The anti-inflammatory activities of the isolated saponins were determined using the nitric oxide (NO) assay. Compound 13 exhibited the greatest inhibitory effect (IC₅₀?=?0.59?μM). In addition to NO, compound 13 suppressed the secretion of PGE₂, IL-1β, and IL-6, but not TNF-α, and inhibited the protein expression of iNOS and COX-2 in LPS-activated RAW264.7 cells. The chemical derivatives of the isolated compounds were studied using structure–activity relationships. The results suggested that compound 13 isolated from S. hexaphylla might be useful for treating inflammation. This is the first comprehensive study of saponins from the leaves of S. hexaphylla based on anti-inflammatory extract screening guidelines.     

Synthesis and antitumor activity of biotinylated camptothecin derivatives as potent cytotoxic agents

A series of biotinylated camptothecin derivatives were designed and synthesized. The key to the synthesis was achieved by employing an esterification reaction and click chemistry. All of the new derivatives were tested for cytotoxicity against five human tumor cell lines, including HL-60, SMMC-7721, A-549, MCF-7, and SW480 with IC₅₀ values ranging from 0.13 to 21.53?μM. Most of the derivatives exhibited potent cytotoxicity, especially compound 17 (IC₅₀?=?0.13–3.31?μM) and compound 18 (IC₅₀?=?0.23–1.48?μM), which exhibited the highest potencies. The structure-activity relationships (SARs) of the biotinylated camptothecin derivatives were discussed for exploring novel anticancer agents.     

Antioxidant activities of 5-hydroxyoxindole and its 3-hydroxy-3-phenacyl derivatives: The suppression of lipid peroxidation and intracellular oxidative stress

The antioxidant activities of 5-hydroxyoxindole (1) and newly synthesized 3,5-dihydroxy-3-phenacyl-2-oxindole derivatives against rat liver microsome/tert-butylhydroperoxide system-induced lipid peroxidation and hydrogen peroxide-induced intracellular oxidative stress were investigated. Compound 1 and its derivatives showed significant suppression of lipid peroxidation and an intracellular oxidative stress. The effects of the more lipophilic derivatives tended to be greater than that of the original compound 1. The cytotoxicity of all of the oxindole derivatives on human promyelocytic leukemia HL60 cells was lower than that of 2,6-di(tert-butyl)-4-hydroxytoluene (BHT), a widely used phenolic antioxidant. These results show that compound 1 and its 3-substituted derivatives could be good lead candidates for future novel antioxidant therapeutics.     

Synthesis and antitumor activity of 10-arylcamptothecin derivatives

A series of 10-arylcamptothecin derivatives was designed and synthesized. The key step of the synthesis was achieved by employing Suzuki cross-coupling chemistry. All of the new derivatives were tested for cytotoxicity against three human tumor cell lines, BEL-7402, A549, and HL-60; most of the derivatives exhibited potent cytotoxicity. The stability study showed that compound 30 was more stable than its lead compound 10-hydroxycamptothecin under the physiological condition. Mechanistic study demonstrated that compound 30 and its hydrochloride 31 had a pharmacological profile similar with camptothecin.     

Design,synthesis and biological evaluation of 1,4-dihydroxyanthraquinone derivatives as anticancer agents

The novel hydroxyanthraquinone derivatives containing nitrogen-mustard and thiophene group were designed to covalently bind to topoisomerase II, and their structures were confirmed by nuclear magnetic resonance and high resolution mass spectrometer technologies in this article. The in vitro cytotoxicity against different cancer cell lines and one normal liver cell line (L02) was evaluated by MTT assay. Compound A1 was the most potent anti-proliferative agent against the human liver cancer HepG-2 cells (IC₅₀?=?12.5?μM), and there is no obvious growth inhibitory effect on normal liver tissue L02 cells. The good cytotoxicity and selectivity of compound A1 suggest that it could be a promising lead for further optimization. The mechanisms of action about compound A1 and A4 were further investigated through analysis of cell apoptosis. Confocal microscopy tracks the location of compound A1 in the cell, which could enter the cytoplasm and nucleus, and induce severe deformation of the nucleus. The docking study demonstrated that A1 could interact with the catalytic active site in topoisomerase II.     

Synthesis and mechanistic studies of novel spin-labeled combretastatin derivatives as potential antineoplastic agents

Two series (14a–d and 21a–h) of novel spin-labeled combretastatin derivatives were synthesized and evaluated for cytotoxicity against four tumor cell lines (K562, SGC-7901, Hela and HepG-2). Simultaneously, a representative compound 21a was selected to investigate the antitumor mechanisms of these synthetic compounds. The results indicated that some of the compounds showed significant cytotoxicity against four tumor cell lines in vitro and were more active than etoposide, a clinically available anticancer drug. Among the newly synthesized compounds, 21a, 21b and 21c displayed the greatest cytotoxicity against three tested tumor cell lines (HEPG-2, BGC-832 and Hela), with IC₅₀ values ranging from 0.15 to 1.05 μM, compared with values of 0.014–0.403 μM for 3-amino-deoxycombretastatin A-4 (3). In addition, the mechanistic analysis revealed that compound 21a effectively interfered with tubulin dynamics to prevent mitosis in cancer cells, leading to cell cycle arrest and, eventually, dose dependent apoptosis.     

Design and synthesis of 1,3-benzothiazinone derivatives as potential anti-inflammatory agents

A series of 1,3-benzothiazinone derivatives were designed and synthesized for pharmacological assessments. Among the synthesized 19 compounds, some compounds showed high activities on inhibiting LPS-induced nitrite oxide and TNF-α production, down-regulating COX-2 and increasing IL-10 production in RAW264.7 cells. All the compounds had no obvious cytotoxicity in in vitro assay. LD₅₀ value of compound 25 was greater than 2000 mg/kg, which was safer than meloxicam. Compound 25 significantly inhibited phosphorylation of NF-κB and STAT3 in LPS-induced RAW264.7 cells. Inhibition of synthesized compounds on COX activity was weaker than meloxicam. Compound 25 displayed lower gastrointestinal toxicity than meloxicam. Besides, compound 25 decreased the swelling in carrageenan-induced paw edema models of inflammation and reduced PGE₂ level significantly. In summary, 1,3-benzothiazinone derivatives are unique scaffolds with anti-inflammatory activity and low toxicity.     

Discovery,synthesis and molecular corroborations of medicinally important novel pyrazoles; drug efficacy determinations through in silico,in vitro and cytotoxicity validations

As the global need for drugs getting increases, the necessity of novel and effective drugs are the need of the day. Pyrazoles are one of the active molecules in novel drug discovery. The present study deals about the synthesis of precursors 4-(4-fluorophenyl)-6-isopropyl-2-(methylsulfonyl) pyrimidine-5-carbohydrazides (3a-m) from methyl-4-(4-fluorophenyl)-6-isopropyl-2-(methyl sulfonyl) pyrimidine-5-carboxylate (2) by treating with substituted acetophenone. Further, Vilsmeier-Haack reaction of compounds 3a-m at 70 °C for 8–10 hrs gave novel pyrazole carbaldehyde derivatives (4a-m) in good yield. Biological properties like antioxidant, anti-breast cancer and anti-inflammatory of newly synthesized compounds (4a-m) were determined. The enzymes Cyclooxygenase-2 and Phosphoinositide-3-Kinase are most responsible for the corresponding diseases such as inflammation and breast cancer respectively. In order to examine the interaction between these two enzymes and our synthesized compounds 4a-m, molecular docking study was carried out. From the results, few compounds of 4a-m were found to have anti-inflammatory properties by showing excellent COX-2 inhibition and HRBC membrane stabilization properties. ADMET prediction results were also valuable to screen the most effective pyrazole derivatives to establish them as future COX-2 inhibitors or anti-inflammatory drugs.     

Synthesis,antiproliferative and apoptosis induction potential activities of novel bis(indolyl)hydrazide-hydrazone derivatives

In recent years, indole-indazolyl hydrazide-hydrazone derivatives with strong cell growth inhibition and apoptosis induction characteristics are being strongly screened for their cancer chemo-preventive potential. In the present study, N-methyl and N,N-dimethyl bis(indolyl)hydrazide-hydrazone analog derivatives were designed, synthesized and allowed to evaluate for their anti-proliferative and apoptosis induction potential against cervical (HeLa), breast (MCF-7 and MDA-MB-231) and lung (A549) cancer cell lines relative to normal HEK293 cells. The MTT assay in conjunction with mitochondrial potential assays and the trypan blue dye exclusion were employed to ascertain the effects of the derivatives on the cancer cells. Further, mechanistic studies were conducted on compound 14a to understand the biochemical mechanisms and functional interactions with various signaling pathways triggered in HeLa and MCF-7 cells. Compound 14a induced apoptosis via caspase independent pathway through the participation of mitogen-activated protein kinases (MAPK) such as extracellular signal related kinase (ERK) and p38 as well as p53 pathways. It originates the activation of pro-apoptotic proteins such as Bak and Mcl-1s and also strongly induced the generation of reactive oxygen species. In downstream signaling pathway, activated p53 protein interacted with MAPK pathways, including SAPK/c-Jun N-terminal protein kinase (JNK), p38 and ERK kinases resulting in apoptotic cell death. The involvement of MAPK cascades such as p38, ERK and p38 on compound 14a induced apoptotic cell death was evidenced by the fact that the inclusion of specific inhibitors of p38, ERK1/2 and JNK MAPK (SB2035809, PD98059 and SP600125) prevented the compound 14a towards induced apoptosis. The results clearly showed that MAP kinase cascades were crucial for apoptotic response in compound 14a induced cellular killing and were dependent on p53 activity. Based on the results, compound 14a was identified as a promising candidate for cancer therapeutics and these findings furnish a basis for further in vivo experiments on anti-proliferative activity.     

Phenylpropanoids and triterpenoids from Tripterygium regelii and their anti-inflammatory activities

Two new compounds named cleroserroside C (1), schisphenlignan O (2), as well as twenty-one known compounds (3–23) were isolated from the roots of Tripterygium regelii. The structures of the new compounds were determined by 1D and ²D NMR spectra and HR-ESI-MS data. The known compounds were determined by comparing the ¹D NMR data in the literature. All compounds were evaluated for anti-inflammatory activity using the LPS-induced RAW264.7 inflammatory cell model, and the results showed that compounds 1, 8-11, 15-16, and 20-21 had good anti-inflammatory activity (IC₅₀ < 20 μM). The cytotoxicity of all compounds was tested by CCK-8 assay, using RAW264.7 cells. The results showed that all compounds had no cytotoxicity to RAW264.7 in the range of 0 ~ 200 μM.