Synthesis and in vitro biological evaluation of farnesylthiosalicylic acid derivatives as anti-tumor carcinoma agents

Novel farnesylthiosahcylic acid(FTA) derivatives 5a-m with different substituted 1,3,4-thiadiazoles were synthesized. Compounds 5b,5c,5e and 5f displayed anti-tumor activities superior to FTA in most cancer cells tested.Furthermore,5e induced tumor cell apoptosis,which was accompanied by lower Bcl-2 expression,but with higher Bax and caspase 3 expression activities in cancer cells.     

Synthesis and in vitro biological evaluation of nitric oxide-releasing derivatives of hydroxylcinnamic acids as anti-tumor agents

Novel furoxan-based nitric oxide-releasing derivatives 6a-p of hydroxylcinnamic acids were synthesized by coupling the carboxyl group of hydroxylcinnamic acids with furoxan through various alkylol amines. Compounds 6a, e-i and m-p displayed more potent anti-tumor activities superior to control 5-fluorouracil (5-FU) in most cancer cells tested. Furthermore, 6f could selectively inhibit tumor cells, but not non-tumor cell proliferation. This inhibition was attributed to high levels of NO released in cancer cells and potentially synergistic effect of NO donor moieties and the bioactivity of hydroxylcinnamic acids.     

Synthesis and biological evaluation of novel farnesylthiosalicylic acid/salicylic acid hybrids as potential anti-tumor agents

A series of FTS/salicylic acid hybrids was designed and synthesized and their in vitro antitumor activities were evaluated.It was found that the anti-proliferation activities of hybrids were better than that of FTS.Compound 10 a displayed the strongest antitumor activities with IC_(50) values of 5.72-9.76 μmol/L and selectively inhibited tumor cell proliferation.In addition,10 a induced tumor cell apoptosis in a dosedependent manner by up-regulating the expression of Bax and caspase-3 and down-regulating Bcl-2.Our findings suggest that these novel hybrids may hold a great promise as therapeutic agents for the intervention of human cancers.     

Synthesis and biological evaluation of novel phenothiazine derivatives as non-peptide arginine vasopressin V2 receptor antagonists

A series of novel phenothiazine derivatives was synthesized and tested for arginine vasopressin receptor antagonist activity. They were synthesized as novel arginine vasopressin receptor antagonists from phenothiazine as a scaffold via successive acylation, reduction and acylation reactions. Their structures were characterized by 1HNMR, 13CNMRandHRMS, and biological activitywas evaluated by in vitro and in vivo studies. The in vitro binding assay indicated that several compounds are potent selective V2 receptor antagonists. Compounds with promising binding affinity to V2 receptors were selected to conduct the in vivo diuretic studies on Sprague-Dawley rats. Among them, 1n, 1r, 1t and 1v exhibited excellent diuretic activity, especially 1r and 1v. Therefore, 1r and 1v are potent novelAVP V2receptor antagonist candidates.     

Design,synthesis and biological evaluation of novel non-azole derivatives as potential antifungal agents

A series of 3-substituted quinazolinones, 2-substituted quinoxalines and 2-substituted benzopyrans were synthesized and evaluated for their antifungal activity in vitro. The new compounds revealed excellent in vitro antifungal activity with broad spectrum. The structure-activity relationships (SARs) of the derivatives were analyzed. Compound 9A2 exhibits better antifungal activity against 5 tested fungi in vitro than fluconazole, especially against Trichophyton rubrum and Microsporum gypseum. This study provides a series of novel lead compounds for the development of non-azole antifungal agents.     

Synthesis and biological evaluation of novel pyrazole carboxamide with diarylamine-modified scaffold as potent antifungal agents

Twenty-seven novel pyrazole carboxamides with diarylamine-modified scaffold were designed, synthesized and characterized in detail via ¹H NMR, ¹³C NMR, IR and ESI-HRMS. Preliminary bioassays showed that some of the target compounds exhibited good antifungal activity against Rhizoctonia solani, Rhizoctonia cerealis and Sclerotinia sclerotiorum. Among them, compound 9c-7 exhibited the highest antifungal activities against R. solani, R. cerealis and S. sclerotiorum in vitro with IC₅₀ values of 0.013, 1.608 and 1.874 μg/mL, respectively. Notably, compound 9c-7 still presented the highest fungicidal activities against R. solani in vivo with an IC₅₀ value of 22.21 μg/mL. Molecular docking simulation results reveal that compound 9c-7 binds well to the hydrophobic pockets of the receptor protein succinate dehydrogenase. This study suggests that compound 9c-7 could act as a potential fungicide to be used for further optimization.     

Synthesis and biological evaluation of new ligustrazine derivatives as anti-tumor agents

To discover new anti-cancer agents with multi-effect and low toxicity, a series of ligustrazine derivatives were synthesized using several effective anti-tumor ingredients of Shiquandabu Wan as starting materials. Our idea was enlightened by the "combination principle" in drug discovery. The ligustrazine derivatives' anti-tumor activities were evaluated on the HCT-8, Bel-7402, BGC-823, A-549 and A2780 human cancer cell lines. In addition the angiogenesis activities were valued by the chick chorioallantoic membrane (CAM) assay. 1,7-bis(4-(3,5,6-Trimethylpyrazin-2-yl)-3-methoxyphenyl)-1,6-heptadiene-3,5-dione (4) and 3 α,12 α-dihydroxy-5β-dholanic acid-3,5,6-trimethylpyrazin-2-methyl ester (5) not only displayed antiproliferative activities on these cancer cells, but also dramatically suppressed normal angiogenesis in CAM. The LD?? value of the compound 5 exceeded 3.0 g/kg by oral administration in mice.     

Design,synthesis and in vitro biological evaluation of novel 4-methoxy-5-hydroxycanthin-6-one derivatives as potential anti-tumor agents

Abstract

Canthin-6-one analogue, 4-methoxy-5-hydroxycanthin-6-one (CAN1) was isolated from Picrasma quassioides (D.Don) Benn., and a series of derivatives containing the CAN1 framework were designed, synthesized, and evaluated for anti-proliferative activity against two human cancer cell lines, HepG2 and HCT116. Among these compounds, the most representative compound d exhibited better anti-proliferative activities in vitro compared with the positive control Fluorouracil (5-FU), with IC₅₀ values of 5.05?μM (HepG2) and 6.65?μM (HCT116), respectively. Compound d triggered more significant HepG2 cell apoptosis than 5-FU did in a dose-dependent manner. Furthermore, western blot assay indicated that d could enhance the expression of p65 while promoting pro-apoptotic proteins and suppressing the anti-apoptotic proteins in a dose-dependent manner. All these results demonstrated that d might be a potential agent for cancer therapy deserving further exploring.     

Synthesis and biological evaluation of 4-thiazolidinone derivatives as antitubercular and antimicrobial agents

New series of N-[2-{2-(substitutedphenyl)-4-oxo-5-(substitutedbenzylidene)-1,3-thiazolidine}-iminoethyl]-2-amino-5-nitrothiazole, 5(a–m) have been synthesized from 2-amino-5-nitrothiazole as a starting material by conventional as well as microwave methods. All the synthesized compounds 4(a–m) were screened for their antibacterial and antifungal activities against some selected bacteria and fungi and antitubercular activity screened against Mycobacterium tuberculosis. The structure of all the synthesized compounds were confirmed by chemical and spectral analyses such as IR, ¹H NMR, ¹³C NMR and FAB-Mass.     

Synthesis and cytotoxic activity of novel 2, 6-disubstituted-4-mor- pholinothieno[3, 2-d]pyrimidines as potent anti-tumor agents

正A series of 2,6-disubstituted-4-morpholinothieno[3,2-d]pyrimidine derivatives were synthesized and their cytotoxic activity against H460,HT-29,MDA-MB-231,U87MG and H1975 cancer cell lines were evaluated in vitro.Most of the target compounds exhibited moderate to excellent activity to the tested cell lines.The most promising compound 23(0.84μmol/L,0.23μmol/L, 2.52μmol/L,1.80μmol/L) was 1.0,2.9,29.3 and 4.3 times more active than GDC-0941(0.87μmol/L,0.66μmol/L,73.8μmol/L, 7.77μmol/L) against H460,HT-29,MDA-MB-231 and U87MG cell lines,respectively.     

Synthesis and biological evaluation of andrographolide derivatives as potent anti-HIV agents

A series of Andro derivatives were described and evaluated for their anti-HIV activity in vitro.Compound 10 and 16b,of which TI were>10,had some anti-HTV-l activity in vitro.Therein,compound 10 which was the best potent compound,could serve as a new lead for further development of anti-AIDS agents.     

Synthesis and biological evaluation of novel furozan-based nitric oxide-releasing derivatives of oridonin as potential anti-tumor agents

To search for novel nitric oxide (NO) releasing anti-tumor agents, a series of novel furoxan/oridonin hybrids were designed and synthesized. Firstly, the nitrate/nitrite levels in the cell lysates were tested by a Griess assay and the results showed that these furoxan-based NO-releasing derivatives could produce high levels of NO in vitro. Then the anti-proliferative activity of these hybrids against four human cancer cell lines was also determined, among which, 9 h exhibited the most potential anti-tumor activity with IC?? values of 1.82 μM against K562, 1.81 μM against MGC-803 and 0.86 μM against Bel-7402, respectively. Preliminary structure-activity relationship was concluded based on the experimental data obtained. These results suggested that NO-donor/natural product hybrids may provide a promising approach for the discovery of novel anti-tumor agents.     

Synthesis and cytotoxic activity of novel curcumin analogues

Five novel curcumin analogues bearing different substituents at 4-position of phenyl group were synthesized. Their structures were confirmed by NMR and HRMS spectrum. Their cytotoxic activities against six tumor cell lines were tested by the standard MTT assay in vitro. The results indicated that four analogues （1A-1C, 1E） with solubilizing moieties showed selective potent cytotoxicity against HepG2, HeLa and CT26 cell lines, and analogue 1A and 1C exhibited more potent cytotoxicity than curcumin against CT26 cell line. It was suggested that introduction of appropriate substituents to 4-position of phenyl group might be a potential option for structural modification of curcumin.     

Synthesis,cytotoxicity, apoptosis and molecular docking studies of novel phenylbutyrate derivatives as potential anticancer agents

Phenylbutyrate (PB), a small aromatic fatty acid, has been known as an interesting compound with the ability of anti-proliferation and cell growth inhibition in cancer cells. In the present study, a series of PB derivatives were synthesized by Passerini multicomponent reaction and their cytotoxic activities against various human cancer cell lines including A549 (non-small cell lung cancer), MDA-MB-231 (breast cancer), and SW1116 (colon cancer) were evaluated. The results revealed that B9, displayed significantly higher in vitro cytotoxicity with IC₅₀ of 6.65, 8.44 and 24.71 μM, against A549, MDA-MB-231 and, SW1116, respectively, in comparison to PB. The effects of these compounds on the proliferation of MCF-10A as non-tumoral breast cell line, showed good selectivity of the compounds between tumorigenic and non-tumorigenic cell lines. Moreover, B9 has indicated apoptosis-inducing activities to MDA-MB-231 cancer cell line in a dose-dependent manner. The molecular docking studies of the synthesized compounds on pyruvate dehydrogenase kinase 2 (PDK2; PDB ID: 2BU8) and histone deacetylase complex (HDAC; PDB ID: 1C3R), as the main targets of PB were applied to predict the binding sites and binding orientation of the compounds to these targets.     

Synthesis and biological evaluation of novel thalidomide analogues as potential anticancer drugs

In search of novel anticancer agents, a series of thalidomide analogs （6a-j） were designed and synthesized. Cytotoxicity of these compounds against human hepatoma cells （HepG2） was evaluated by MTT method. Compounds 6d, 6h and 6i showed significant cytotoxic activities comparable to or stronger than control 5-fluorouracil.     

Synthesis and biological evaluation of novel triazole derivatives as antifungal agents

A series of 1-(benzylamino)-2-(2,4-difluorophenyl)-3-(1H-1,2,4-triazol-l-yl)propan-2-ols compounds were synthesized and evaluated for their antifungal activities in vitro.The results showed that compounds 6A and 6B exhibited good antifungal activity.Compound 6A8 showed the strongest antifungal activity,which was significantly higher than that of the lead compounds and positive-control drugs Fluconazole and Itraconazole.In particular,the antifungal activity of compound 6A8 against Candida albicans and Candida krusei(MIC80 both at 0.00097μg/mL) was 515 and 64 times that of Fluconazole,respectively.The structure-activity relationships of the synthesized compounds were discussed,and the docking model of the target compounds with fungal lanosterol 14α-demethylase (CYP51) was analyzed.     

2-巯基苯并咪唑衍生物的设计、合成及抗肿瘤活性研究

为了从苯并咪唑类衍生物中寻找新的活性化合物,以溴乙酸作为起始原料,设计合成了17个2-巯基苯并咪唑衍生物4a～4q。采用噻唑蓝(MTT)法测试了目标化合物对人宫颈癌细胞(He La)、人乳腺癌细胞(MCF-7)、人肝癌细胞(HepG2)、人非小细胞肺癌细胞(A549)的增殖抑制活性。结果显示,大部分化合物具有较好的抗肿瘤活性,其中,((1H-苯并[d]咪唑-2-基)硫基)-1-(4-二苯甲基哌嗪-1-基)乙烷-1-酮(4l)对HepG2细胞的抑制活性最好,IC_(50)值为12. 62±0. 78μmol/L,接近于对照药品吉非替尼(9. 72±0. 38μmol/L)。此外,利用分子对接方法对目标化合物的构效关系进行了讨论。     

Synthesis and biological evaluation of indole-3-carboxamide derivatives as antioxidant agents

A novel series of indole-3-carboxamide derivatives (6a-6l) have been designed, synthesized and evaluated for their antioxidant activity against human neuroblastoma SH-SY5Y cell line using H2O₂ radical scavenging assay. Biological activity evaluation showed that compounds 6a, 6f and 6i exhibited significant in vitro activities, which could have the potential to be developed for novel antioxidants.     

Synthesis and biological evaluation of dihydrotriazine derivatives as potential antibacterial agents

A series of 1,4-dihydro-1,3,5-triazine derivatives were designed and synthesized and their antibacterial and antifungal activities were evaluated. Most of the synthesized compounds showed potent inhibition of several Gram-positive bacterial strains(including multidrug-resistant clinical isolates) and Gramnegative bacterial strains, with minimum inhibitory concentrations(MICs) in the range of 2.1–181.2 mmol/L. Compounds 7a and 7c presented the most potent inhibitory activities against Grampositive bacteria(e.g., Staphylococcus aureus 4220), Gram-negative bacteria(e.g., Escherichia coli 1924),and the fungus Candida albicans 7535, with MICs of 2.1 or 4.1 mmol/L. Especially, compound 7a was the most potent, with an MIC of 2.1 mmol/L against four multidrug-resistant, Gram-positive bacterial strains.The cytotoxic activity of the compound 7a, 7c and 7f was assessed in HepG2 cells, and the results suggest that 1,4-dihydro-1,3,5-triazine derivatives bearing a 6-benzyloxynaphthalen moiety are interesting scaffolds for the development of novel antibacterial agents.     

Synthesis and biological evaluation of indole-3-carboxamide derivatives as antioxidant agents

Oxidative stress results in various pathologies and as consequence antioxidant agents have attracted uninterrupted attention. In this paper, a novel series of indole-3-carboxamide derivatives (6a–6l) were designed and synthesized based on the melatonin structure as novel antioxidants. All of them were evaluated for the antioxidant activities in vitro against human neuroblastoma SH-SY5Y cell line using H₂O₂ radical scavenging assay. The target compounds 6a, 6f and 6i indicated better activities than the positive control, ascorbic acid, and 6a exhibited the best antioxidant activity. In addition, the structure-activity relationships of the target compounds were also preliminarily summarized based on the obtained experimental data.