Synthesis and evaluation of curcumin analogues as cytotoxic agents

Seventeen curcumin analogues were prepared and evaluated for in vitro and in vivo cytotoxicity against an Ehrlich ascites carcinoma (EAC). In vitro results revealed that compounds 10, 7, and 12 were the most potent analogues against EAC respectively. However, in vivo evaluation of compound 10 proved its capability to normalize the blood picture compared with 5-fluorouracil, a well-known anticancer drug.     

Synthesis and biological evaluation of novel pyrazoline derivatives as anti-inflammatory and antioxidant agents

A series of novel 5-aryl-3-cyclopropyl-4,5-dihydropyrazole derivatives 2a-p were synthesized via cyclization of chalcones 1a-h with thiosemicarbazide or semicarbazide HCl and evaluated as anti-inflammatory/antioxidant agents. The structures were confirmed by elemental analyses and spectral data. The free radical scavenging activity toward superoxide was determined. Their effect on hepatocytes viability and nitric oxide (NO) production in LPS-stimulated macrophages was also determined. The results showed that compounds 2e and 2n demonstrated the highest free-radical scavenging and anti-inflammatory activities, thus can be useful in the prevention of oxidative stress and inflammation-related disorders.     

Synthesis and biological evaluation studies of novel quinazolinone derivatives as antibacterial and anti-inflammatory agents

Some novel 6,8-diiodo-2-methyl-3-substituted-quinazolin-4(3H)-ones bearing sulfonamide derivatives (4–11) were synthesized in good yields and evaluated for their possible antibacterial, anti-inflammatory activities and acute toxicity. The structures of the synthesized compounds were confirmed on the basis of their spectral data and elemental analysis. Their antibacterial activities were evaluated by the agar well diffusion method while their anti-inflammatory activities were evaluated by the carrageenan-induced hind paw edema test. All the tested compounds showed considerable antibacterial activities and high to moderate anti-inflammatory activities that last for 12 h compared to ibuprofen. All the tested compounds showed no toxic symptoms or mortality rates 24 h post-administration at tested anti-inflammatory doses. In addition, LD₅₀ for all tested compounds was higher than that for ibuprofen implying their good safety margin. The obtained results showed that the most active compounds could be useful as a template for future design, modification and investigation to produce more active analogs.     

Synthesis and biological evaluation of pyrazolone analogues as potential anti-inflammatory agents targeting cyclooxygenases and 5-lipoxygenase

New pyrazolone derivatives structurally related to celecoxib and FPL 62064 were synthesized and biologically evaluated for their inhibitory activity against cyclooxygenases (COXs) and 5-lipoxygenase (5-LOX) and their selectivity indices were calculated. The results showed that compounds 3f , 3h , 3l , and 3p have an excellent COX-2 selectivity index. Moreover, they showed potent 5-LOX inhibitory activity relative to celecoxib and zileuton, as positive controls. These promising candidates were further investigated for anti-inflammatory activity using the carrageenan-induced rat paw edema method and ulcerogenic liability. The results showed no ulceration, which implies their gastric safety profile. Moreover, these compounds were evaluated for prostaglandin (PGE2) production in rat serum. Molecular docking in the COX-2 and 5-LOX active sites was performed to rationalize their anti-inflammatory activities. Strong binding interactions and effective docking scores were identified. The results indicated that these derivatives are good leads for dual-acting COX-2/5-LOX inhibitors to be used as potent and safe anti-inflammatory agents.     

那可丁衍生物合成及其作为微管干扰药物的生物学评估(英文)

以2-羟基-3-甲氧基苯甲醛为原料,经13步反应合成了26个那可丁衍生物。以HL-60细胞为靶细胞,采用MTT法进行了初步的体外抗肿瘤活性研究。结果表明,大多数化合物对HL-60细胞株显示出较好的抑制活性和对微管聚合的抑制作用。优选出的化合物31对HL-60细胞株以及微管聚合的抑制活性是那可丁的3倍并诱导HL-60细胞在G2/M期累积,这为那可丁及其衍生物的抗肿瘤活性构效关系的研究打下了基础,值得进一步研究。     

Synthesis and biological evaluation of resveratrol and analogues as apoptosis-inducing agents

Resveratrol 1 (3,4',5-trihydroxy-trans-stilbene), a phytoalexin present in grapes and other food products, has recently been suggested as a potential cancer chemopreventive agent based on its striking inhibitory effects on cellular events associated with cancer initiation, promotion, and progression. This triphenolic stilbene has also displayed in vitro growth inhibition in a number of human cancer cell lines. In this context, a series of cis- and trans-stilbene-based resveratrols were prepared with the aim of discovering new lead compounds with clinical potential. All the synthesized compounds were tested in vitro for cell growth inhibition and the ability to induce apoptosis in HL60 promyelocytic leukemia cells. The tested trans-stilbene derivatives were less potent than their corresponding cis isomers, except for trans-resveratrol, whose cis isomer was less active. The best results were obtained with compounds 11b and 7b, the cis-3,5-dimethoxy derivatives of rhapontigenin 10a (3,5,3'-trihydroxy-4'methoxy-trans-stilbene) and its 3'-amino derivative 10b, respectively, which showed apoptotic activity at nanomolar concentrations. The corresponding trans isomers 12b and 8b were less active both as antiproliferative and as apoptosis-inducing agents. Of interest, 11b and 7b were active toward resistant HL60R cells and their activity was higher than that of several classic chemotherapeutic agents. The flow cytometry assay showed that at 50 nM compounds 7b or 11b were able to recruit almost all cells in the apoptotic sub-G(0)-G(1) peek, thus suggesting that the main mechanism of cytotoxicity of these compounds could be the activation of apoptosis. These data indicate unambiguously that structural alteration of the stilbene motif of resveratrol can be extremely effective in producing potent apoptosis-inducing agents.     

Antitumor agents. 254. Synthesis and biological evaluation of novel neo-tanshinlactone analogues as potent anti-breast cancer agents

In our previous study, neo-tanshinlactone (1) showed potent and selective anti-breast cancer activity. To explore the SAR of 1, nine analogues (15-18, 24-28) were designed and synthesized. Together with 1 and tamoxifen (TAM), all newly synthesized compounds and some intermediates were evaluated for in vitro anticancer activity against several human tumor cell lines. Compounds without a ring D did not show promising activity, while compounds with a methylated furan ring D showed better activity than those with unsubstituted furan or hydroxy-dihydrofuran rings. Among all newly synthesized compounds, compound 15 with an ethyl group at the 4-position showed the best activity and selectivity with ED50 values of 0.45 and 0.18 microg/mL against MCF-7 and ZR-75-1 (ER+) and 13.5 and 10.0 microg/mL against MDA MB-231 and HS 587-1 (ER-), respectively. Furthermore, 15 also showed potent activity against SK-BR-3 (ER-, HER2+) with an ED50 value of 0.10 microg/mL. Our preliminary SAR studies showed that a methylated furan ring D and the C-4 substituent in ring A are critical for anti-breast cancer activity. Further development of 1 and 15 as anti-breast cancer drug candidates is warranted.     

Synthesis,biological evaluation of certain pyrazolo[3,4-d]pyrimidines as novel anti-inflammatory and analgesic agents

In the present study, a series of pyrazolo[3,4-d]pyrimidin-4(5H)-ones linked at 5-position to thiazoline or thiazolidinone ring systems through imino linkage (5–8) was designed and synthesized. The compounds were assessed for their anti-inflammatory activity and analgesic in vivo. Also, their ability to inhibit ovine COX-1/COX-2 isozymes was evaluated using in vitro cyclooxygenase (COX) inhibition assay. The newly synthesized compounds 7, 8d, and 8e showed potent anti-inflammatory and analgesic activity. Moreover, compound 7 displayed preferential COX-2 inhibitory potency (IC₅₀ = 0.53 µM and COX-2 selectivity index = 10.07) which is more potent than the standard drug meloxicam. Interestingly, the tested compounds showed excellent gastrointestinal safety profile and were well tolerated by experimental animals with high safety margins than the reference drug meloxicam.     

Synthesis and biological evaluation of new curcumin derivatives as antioxidant and antitumor agents

Twenty-four new compounds were prepared, taking curcumin as a lead, in order to explore their antioxidant and antitumor properties. The capacities of these derivatives to scavenge the 2,2′-azinobis(3-ethylbenzothiazoline-6-sulfonic acid) radical cation (ABTS^.+), and to protect human red blood cells (RBCs) from oxidative haemolysis were investigated. In addition, the percentage viability of different cell lines (Hep G2, WI38, VERO and MCF-7) was tested. The result of the antitumor testing was generally in accordance with those of the antioxidant assays. Compounds which bear o-methoxy substitution to the 4-hydroxy function in the phenyl ring (7g, 5g and 3g) exhibited significantly higher ABTS^.+-scavenging, antihaemolysis, and antitumor activities than other derivatives. In addition, molecular modelling studies were carried out for biologically active and inactive compounds, to study the structure–activity relationship, with the aim to elucidate which portions of the molecules are critical for the antioxidant and antitumor activity.     

Synthesis and evaluation of a series of novel imidazolidinone analogues of 6-aminoflavone as anticancer and anti-inflammatory agents

The flavone moiety is a potential pharmacophore known for its diverse range of pharmacological activities. Aminoflavones have recently been the subject of considerable attention as lead molecules in several cancer research projects. Imidazolidinone heterocycles represent another biologically active scaffold with known cytotoxic properties. In an attempt to provide synergistic cytotoxic activity, these two moieties have been combined, and the resulting novel analogues evaluated for their anticancer and anti-inflammatory activities. The results revealed that the cytotoxicities of these compounds were fivefold greater than those of aminoflavone. DNA histograms obtained from cell cycle analysis in the presence of these compounds were apoptotic in their nature. Furthermore, the in vivo screening of these compounds using Ehrlich’s ascites tumour model showed an increase in life span, whereas an in vivo anti-inflammatory study resulted in the enhancement of the anti-inflammatory potential. The results therefore supported the hypothesis that there is a relationship between inflammation and cancer.     

Synthesis of curcumin analogues as potential antioxidant, cancer chemopreventive agents

New series of 3, 5-bis(substituted benzylidene)-4-piperidones, 2, 7-bis(substituted benzylidene)cycloheptanones, 1, 5-bis(substituted phenyl)-1, 4-pentadien-3-ones, 1, 7-bis(substituted phenyl)-1, 6-heptadien-3, 5-diones, 1, 1-bis(substituted cinnamoyl)-cyclopentanes, and 1, 1-bis(substituted cinnamoyl)cyclohexanes have been synthesized and tested for their antioxidant activity. Among the tested compounds, compounds II(4), II(9) II(10), II(11), V(1), and V(4) exhibited higher free radical scavenger activity with % inhibition values of 90.71, 91.24, 96.91, 94.26, 99.23, and 99.85%, respectively. Moreover, compound V(1) is the safest member toward peripheral multinuclear neutrophils (PMNs) with a % viability value of 91%. Detailed synthesis, spectroscopic, and biological data are reported.     

Synthesis,in vitro and in vivo biological evaluation of novel lappaconitine derivatives as potential anti-inflammatory agents

Lappaconitine (LA), a natural compound with a novel C18-diterpenoid alkaloid skeleton, displayed extensive biological profile. Recent research on LA is focused mainly on its anti-tumor and analgesic effects, and therefore we aimed to investigate its anti-inflammatory potential. A series of novel LA derivatives with various substituents on the 20-N position was designed and synthesized. In the initial screening of LA derivatives against NO production, all the target compounds, except compound E2, exhibited excellent inhibitory ability relative to that of LA. Particularly, compound A4 exhibited the most potent inhibition with IC₅₀ of 12.91 μmol/L. The elementary structure–activity relationships (SARs) of NO inhibitory activity indicated that replacement of the benzene ring with an electron donating group could improve the anti-inflammatory efficacy. Furthermore, compound A4 shows an anti-inflammatory mechanism by inhibiting NO, PGE2, and TNF-α generation via the suppression of NF-κB and MAPK signaling pathways. Notably, compound A4 could exert a significant therapeutic effect on LPS-induced acute lung injury (ALI) in vivo. Based on the above research, we further investigated the preliminary pharmacokinetic property of A4 in rats. Therefore, compound A4 could be a promising candidate for the development of anti-inflammatory agents in the future.     

Synthesis and biological evaluation of new quinoxaline derivatives as antioxidant and anti-inflammatory agents

We report the synthesis, anti-inflammatory, and antioxidant activities of novel quinoxaline and quinoxaline 1,4-di-N-oxide derivatives. Microwave-assisted methods have been used to optimize reaction times and to improve yields. The tested compounds presented important scavenging activities and promising in vitro inhibition of soybean lipoxygenase (LOX). Two of the best LOX inhibitors (compounds 7b and 8f) were evaluated as in vivo anti-inflammatory agents using the carrageenin-induced edema model. One of them (compound 7b) showed important in vivo anti-inflammatory effect (41%) similar to that of indomethacin (47%) used as the reference drug.     

Synthesis and biological testing of novel analogues of sydnone as potential antibacterial agents

Several series of 3-phenylsydnone derivatives conjugated to well-known moieties with antibacterial activity were synthesized via several routes. These derivatives include 3-cyano-2-oxopyridine, 2-amino-3-cyanopyridine, 2-arylidene-1-ethylidenehydrazine and 2-aroyl-1-ethylidenehydrazine moieties. Thus, the key intermediate 3-(4-acetylphenyl)sydnone (3) was allowed to react with the appropriate aldehyde, ethyl cyanoacetate or malononitrile in presence of excess ammonium acetate in two steps (method 1) or through a one-pot reaction technique (methods 2 and 3) to give the corresponding sydnone derivatives 5 and 6, respectively. Moreover, condensation of compound 3 with hydrazine hydrate followed by the reaction with the appropriate aldehyde, mono- and dicarboxylic acid hydrazide yielded the corresponding sydnone derivatives 8, 9 and 10, respectively. Most of the synthesized compounds were screened for their in vitro antibacterial activity against various pathogenic organisms of both Gram-positive and Gram-negative bacteria. The minimum inhibitory concentrations (MICs) were determined using agar dilution method.     

Synthesis and biological evaluation of novel podophyllotoxin analogs as antitumor agents

A series of 4β N-indole-substituted podophyllotoxin derivatives were synthesized. Nine target compounds were evaluated against human cancer cell lines (HeLa, K562, and K562/A02) using MTT assay including three imine derivatives 8, 9, and 10in vitro. The result showed that the three compounds had higher antitumor activity than their reduced forms. Among them, compounds 8, 9, 11, and 16 were superior to the positive control VP-16.     

Synthesis and biological evaluation of novel phenylcarbazoles as potential anticancer agents

We here report the synthesis and biological evaluation of new phenylcarbazole derivatives designed as potential anticancer agents. Indole and hydroxyindole were used to generate three scaffolds that were successively exploited to introduce various substituents on the maleimide moiety. The synthesis includes a final intramolecular key Heck-type reaction, which was carried out with a triflate derivative or with a bromophenyl derivative. Each step was optimized and the complete chemical strategy is detailed. Several compounds showed a marked cytotoxicity against CEM human leukemia cells with IC(50) values in the 10-100 nM range. Precise structure-activity relationships were delineated. Cell cycle analysis, topoisomerase I inhibition, and interaction with DNA were evaluated, and inhibition of CDK activity was also investigated. Although binding of the drugs to DNA likely contributes to the cytotoxic action, the exact molecular targets of these molecules remain undiscovered. The efficient chemical routes reported here for the design of highly cytotoxic compounds provide novel opportunities to identify antitumor agents in the phenylcarbazole series.     

Synthesis and biological evaluation of novel naphthocarbazoles as potential anticancer agents

We report the efficient synthesis involving palladium-catalyzed reactions and biological evaluation of new naphthocarbazoles designed as potential anticancer agents. The use of 5- and 6-benzyloxyindoles generated three substitution sites which were successively exploited to introduce several hydrophilic side chains. The cytotoxicity of the newly designed compounds was evaluated on three cell lines. Several compounds showed a marked cytotoxicity with IC(50) values in the sub-micromolar range. This is the case for the 3-hydroxy-naphthopyrrolocarbazoledione 37, bearing a dimethylaminoethyl side chain, which is extremely cytotoxic to L1210 and DU145 cells (IC(50): 36 nM, 108 nM) and induces an accumulation of L1210 cells in the G2+M phases of the cell cycle. Some of the most cytotoxic compounds were tested for inhibition of CDK-5, GSK-3 and topoisomerase I, and their interaction with DNA was also evaluated. Interaction with DNA was detected, suggesting that nucleic acids represent a privileged target for these molecules.     

Synthesis and biological evaluation of novel benzoquinones as potential antimicrobial agents

New series of 2,5-dihydroxyphenyl-1,3-thiazoles 4a–l was synthesized by reacting 2,5-dihydroxyphenacyl bromide with various 4-aryl thiosemicarbazones 3a–l that on oxidation with ferric chloride yielded the corresponding N ¹-substituted benzylidene-N ²-[3-aryl-4-(1,4-benzoquinon-2-yl)-1,3-thiazol-2-ylidene]hydrazines 5a–l. They were evaluated for antibacterial activity against Staphylococcus aureus and Bacillus subtilis as Gram-positive bacteria, Escherichia coli and Pseudomonas aeruginosa as Gram-negative bacteria. They were also evaluated for their in vitro antifungal potential against Candida albicans. Almost all tested compounds were found to possess variable degrees of antimicrobial activity. The obtained data revealed that compounds 4b–h and 5e, 5f and 5l exhibited promising antimicrobial activity against the tested organisms of which compound 4b proved to be the most active.     

Microwave-mediated synthesis of triazolothiadiazoles as anti-inflammatory,analgesic, and anti-oxidant agents

Efficient approach to the synthesis of a series of triazolothiadiazole analogs of ibuprofen has been carried out using microwave energy. Thus a series of 1,2,4-triazolo[3,4-b]-thiadiazoles 5 were synthesized starting from 4-amino-3-[1-(4-isobutylphenyl)ethyl]-5-mercapto-1,2,4-triazole 3 and different aromatic acids using phosphorous oxychloride as cyclizing agent by microwave and conventional method. Microwave irradiation reduces both time and reaction endeavors along with reduced amount of phosphorous oxychloride. In addition, preliminary results of the biological evaluation of these compounds are also reported and they found to exhibit significant antioxidant, anti-inflammatory, and analgesic activities with reduced ulcerogenicity.