Design, synthesis and biological evaluation of novel quinazoline derivatives as potential anti-cancer agents

Twenty-two quinazoline derivatives have been synthesised and examined for their anti-tumour activity against three tumour cell lines, namely human breast cancer cell line (MCF-7), human cervical cancer cell line (HeLa) and human hepatoma cell line (HepG2). Twelve of the tested compounds have shown promising anti-tumour activity with an IC(50) range of 5.0-9.7 μg/mL. Regarding the spectrum of activity, five compounds exhibited interesting anti-proliferative properties against the three tested cell lines comparable to the reference drug (dasatinib).     

Design,synthesis and biological evaluation of novel quinazoline derivatives as potential anti-cancer agents

Twenty-two quinazoline derivatives have been synthesised and examined for their anti-tumour activity against three tumour cell lines, namely human breast cancer cell line (MCF-7), human cervical cancer cell line (HeLa) and human hepatoma cell line (HepG2). Twelve of the tested compounds have shown promising anti-tumour activity with an IC₅₀ range of 5.0–9.7 µg/mL. Regarding the spectrum of activity, five compounds exhibited interesting anti-proliferative properties against the three tested cell lines comparable to the reference drug (dasatinib).     

Design, synthesis and evaluation of novel sulfonyl pyrrolidine derivatives as matrix metalloproteinase inhibitors

A series of novel sulfonyl pyrrolidine derivatives were designed, synthesized and assayed for their inhibitory activities on matrix metalloproteinase 2 (MMP-2) and aminopeptidase N (AP-N). The results showed that these pyrrolidine derivatives exhibited highly selective inhibition against MMP-2 as compared with AP-N. Compounds 6a-d were more potent MMP-2 inhibitors than the positive control LY52. The structure-activity relationships were also briefly discussed.     

Design,synthesis and evaluation of carbazole derivatives as potential antimicrobial agents

Five series of novel carbazole derivatives containing an aminoguanidine, dihydrotriazine, thiosemicarbazide, semicarbazide or isonicotinic moiety were designed, synthesised and evaluated for their antimicrobial activities. Most of the compounds exhibited potent inhibitory activities towards different bacterial strains (including one multidrug-resistant clinical isolate) and one fungal strain with minimum inhibitory concentrations (MICs) between 0.5 and 16 µg/ml. Compounds 8f and 9d showed the most potent inhibitory activities (MICs of 0.5–2 µg/ml). Furthermore, compounds 8b, 8d, 8f, 8k, 9b and 9e with antimicrobial activities were not cytotoxic to human gastric cancer cell lines (SGC-7901 and AGS) or a normal human liver cell line (L-02). Structure–activity relationship analyses and docking studies implicated the dihydrotriazine group in increasing the antimicrobial potency and reducing the toxicity of the carbazole compounds. In vitro enzyme activity assays suggested that compound 8f binding to dihydrofolate reductase might account for the antimicrobial effect.     

Design,synthesis and evaluation of novel 4-dimethylamine flavonoid derivatives as potential multi-functional anti-Alzheimer agents

A series of 4-dimethylamine flavonoid derivatives 5a–5r were designed, synthesized and evaluated as potential multi-functional anti-Alzheimer agents. The results showed that most of the synthesized compounds exhibited high acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory activity at the micromolar range (IC₅₀, 1.83–33.20 μM for AChE and 0.82–11.45 μM for BChE). A Lineweaver–Burk plot indicated a mixed-type inhibition for compound 5j with AChE, and molecular modeling study showed that 5j targeted both the catalytic active site (CAS) and the peripheral anionic site (PAS) of AChE. Besides, the derivatives showed potent self-induced Aβ aggregation inhibitory activity at 20 μM with percentage from 25% to 48%. In addition, some compounds (5j–5q) showed potent oxygen radical absorbance capacity (ORAC) ranging from 1.5- to 2.6-fold of the Trolox value. These compounds should be further investigated as multi-potent agents for the treatment of Alzheimer’s disease.     

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.     

Design, synthesis and biological evaluation of novel compounds with conjugated structure as anti-tumor agents

A series of hydroxamic acids with conjugated structure was designed and synthesized to explore the possible HDAC subtype selectivity by testing these compounds against recombinant human HDAC1 and HDAC4. The most selective compound resulted 5a, with a SI of 11.9. The enzymatic inhibitory activity of these conjugated compounds was relatively weak; however, some of these compounds showed significant effect in inducing apoptosis. Moreover, the anti-proliferative activity in cancer cells resulted quite promising, especially in the HCT119 cell line.     

Design, synthesis and biological evaluation of novel chalcone derivatives as antitubulin agents

A series of novel chalcone derivatives have been designed and synthesized, and their biological activities were also evaluated as potential inhibitors of tubulin. These compounds were assayed for growth-inhibitory activity against MCF-7 and A549 cell lines in vitro. Compound 3d showed the most potent antiproliferative activity against MCF-7 and A549 cell lines with IC(50) values of 0.03 and 0.95 μg/mL and exhibited the most potent tubulin inhibitory activity with IC(50) of 1.42 μg/mL. Docking simulation was performed to insert compound 3d into the crystal structure of tubulin at colchicines binding site to determine the probable binding model. Based on the preliminary results, compound 3d with potent inhibitory activity in tumor growth may be a potential anticancer agent.     

Design,synthesis and evaluation of novel levoglucosenone derivatives as promising anticancer agents

A series of levoglucosenone-derived 1,2,3-triazoles and isoxazoles featuring a flexible spacer between the heteroaromatic and anhydropyranose cores have been designed and synthesized following an hetero Michael // 1,3-dipolar cycloaddition path. The use of a design of experiments approach allowed the optimization of the oxa-Michael reaction with propargyl alcohol as nucleophile, a key step for the synthesis of the target compounds. All of the compounds were tested for their anticancer activity on MDA-MB-231 cells, featuring mutant p53. The results highlighted the importance of the introduction of the flexible spacer as well as the higher activity of oxa-Michael isoxazole-derivatives. The most prominent compounds also showed anti-proliferative activities against lung and colon cancer cell lines. The compounds showed enhanced cytotoxic effects in the presence of mutant p53, determined both by endogenous mutant p53 knock down (R280K) and by reintroducing p53 R280K in cells lacking p53 expression.     

Design,synthesis and biological evaluation of novel thiazole-naphthalene derivatives as potential anticancer agents and tubulin polymerisation inhibitors

A novel series of thiazole-naphthalene derivatives as tubulin polymerisation inhibitors were designed, synthesised, and evaluated for the anti-proliferative activities. The majority of the tested compounds exhibited moderate to potent antiproliferative activity on the MCF-7 and A549 cancer cell lines. Among them, compound 5b was found to be the most active compound with IC₅₀ values of 0.48 ± 0.03 and 0.97 ± 0.13 μM. Moreover, mechanistic studies revealed that 5b significantly inhibited tubulin polymerisation with an IC₅₀ value of 3.3 µM, as compared to the standard drug colchicine (IC₅₀ = 9.1 μM). Further cellular mechanism studies elucidated that 5b arrested the cell cycle at G2/M phase and induced apoptosis in MCF-7 cancer cells. Molecular modelling study indicated that 5b binds well to the colchicine binding site of tubulin. In summary, these results suggest that 5b represents a promising tubulin polymerisation inhibitor worthy of further investigation as potential anticancer agents.     

Ligustrazine derivatives. Part 3: Design,synthesis and evaluation of novel acylpiperazinyl derivatives as potential cerebrocardiac vascular agents

A series of novel acylpiperazinyl Ligustrazine derivatives was designed, synthesized, and their protective effects on damaged ECV-304 cells and antiplatelet aggregation activities were evaluated. The results showed that compound E33 displayed most potential protective effects on the ECV-304 cells damaged by hydrogen peroxide, and compound E1 was found to be the most active antiplatelet aggregation agent. Structure–activity relationships were briefly discussed.     

Design,synthesis and evaluation of novel HDAC inhibitors as potential antitumor agents

Phenyl imidazolidin-2-one was introduced as the linker for novel HDAC inhibitors. A focused library of 20 compounds was designed and synthesized, among which eight compounds showed equivalent or higher potencies against HDAC1 as compared to vorinostat. In vitro antitumor activity assays in HCT-116, PC-3 and HL-60 cancer cells revealed six compounds with potent antitumor activities, and compound 1o showed 6- to 9-fold higher potencies compared to vorinostat. In an HCT-116 nude mice xenograft model, compound 1o displayed significant antitumor activity in both continuous and intermittent dosing schedules.     

Design, synthesis, and activity of caffeoyl pyrrolidine derivatives as potential gelatinase inhibitors

The synthesis and biological evaluation of caffonyl pyrrolidine derivatives as MMPs inhibitors are reported in this paper. Inhibiting activities of synthesized compounds on gelatinase (MMP-2 and -9) were tested by using succinylated gelatin as substrate. Structure-activity relationship results from these tested compounds demonstrated that longer and more flexible side chain linked to the pyrrolidine ring at C(4) produced higher activity at gelatinase. Furthermore, aromatic heterocycle and sulfamide in the same position could enhance the activities. Compounds with free phenol hydroxyl group showed higher activity compared to methylated derivatives (or counterparts), which confirms the importance of phenol hydroxyl functionality in the interaction with gelatinase. The anti-metastasis model of mice bearing H(22) tumor cell was used to evaluate their in vivo inhibiting activities. All tested compounds were orally administered at a dose of 50 or 100mg/kg, 6days/week for two weeks. The test results demonstrated that most of these inhibitors showed significant anti-cancer activities (inhibitory rate>35%) and were devoid of toxic effects. Compound 29 showed the highest inhibitory rate at 69.25%, indicating that it might be a promising lead compound.     

Design, synthesis, and evaluation of novel 6-chloro-/fluorochromone derivatives as potential topoisomerase inhibitor anticancer agents

6-Chloro-2-pyrrolidino-/morpholino-/piperidino-/N-methylpiperazino-3-formyl-chromones (13-16) and 6-fluoro-2,7-di-morpholino-/piperidino-/N-methylpiperazino-3-formylchromones (17-19) have been synthesized as potential topoisomerase inhibitor anticancer agents, and evaluated, in vitro, against Ehrlich ascites carcinoma (EAC) cells, and also in vivo on EAC bearing mice. The compounds displayed promising anticancer activity under these test systems and shall serve as useful 'leads' for further design.     

Design,synthesis and biological evaluation of chrysin long-chain derivatives as potential anticancer agents

A series of long-chain derivatives of chrysin (compounds 3–22) were synthesized to evaluate for their antiproliferative activities against the human liver cancer cell line HT-29 and EGFR inhibitory activity. Among the compounds tested, compounds hexadecyl 2-(5-hydroxy-4-oxo-2-phenyl-4H-chromen-7-yloxy)acetate (10) and N-hexadecyl 2-(5-hydroxy-4-oxo-2-phenyl-4H-chromen-7-yloxy)acetamide (20) displayed potent EGFR inhibitory activity with IC₅₀ values of 0.048 μM and 0.035 μM), comparable to the positive control erlotinib. Docking simulation of compounds 10 and 20 was carried out to illustrate the binding mode of the molecular into the EGFR active site, and the result suggested that compound 10 and 20 can bind the EGFR kinase well. Thus, compounds 10 and 20 with potent EGFR inhibitory activity would be potential anticancer agents.     

Design,synthesis and biological evaluation of azithromycin glycosyl derivatives as potential antibacterial agents

A series of 11,12-cyclic carbonate azithromycin-4″-O-carbamoyl glycosyl derivatives were designed, synthesized, and evaluated as antibacterial agents to search for target compounds with excellent activity. The results of preliminary antibacterial tests against eight strains in vitro revealed that all of the title compounds exhibited improved activities with broad spectrum compared with the parent compound. The glycosylated side chains may be the pharmacophores responsible for the improved activity.     

Design,synthesis and biological evaluation of aryl pyrimidine derivatives as potential leishmanicidal agents

A series of substituted aryl pyrimidine derivatives was synthesized and evaluated in vitro for their antileishmanial potential against intracellular amastigotes of Leishmania donovani using reporter gene luciferase assay. Among all, 8 compounds showed promising IC₅₀ values ranging from 0.5 to 12.9 μM. Selectivity indices (S.I.) of all these compounds are far better than reference drugs, sodium stibogluconate (SSG) and miltefosine. On the basis of good S.I., compounds were further screened for their in vivo antileishmanial activity against L. donovani/hamster model. Compounds 2d, 4a and 4b have shown significant inhibition of parasitic multiplication that is 88.4%, 78.1% and 78.2%, respectively at a daily dose of 50 mg/kg × 5 days, when administered intraperitoneally. Compound 2d is most promising one, which may provide a new lead that could be exploited as a new antileishmanial agent.     

Design, synthesis, and biological evaluation of chalcone oxime derivatives as potential immunosuppressive agents

A series of deoxybenzoin oximes were recently reported as potent immunosuppressive agents by our group. In order to continue the original research for potential immunosuppressive agents with high efficacy and low toxicity, we synthesized a series of new chalcone oximes and evaluated them for their cytotoxicities and immunosuppressive activities. Among the synthesized compounds, chalcone oximes 25 and 27 exhibited lower cytotoxicities and higher inhibitory activities on anti-CD3/anti-CD28 co-stimulated lymph node cells than other compounds. Specially, compound 27 displayed 200-fold lower cytotoxicity (CC(50)=2174.39 μM) than cyclosporin A (CC(50)=10.10 μM) and showed SI value (SI=176.69) close to cyclosporin A (SI=154.13). Besides, the preliminary mechanism of inhibition effect of compounds 25 and 27 was also detected by flow cytometry, and the compounds exerted immunosuppressive activities via inducing the apoptosis of activated lymph node cells in a dose dependent manner. Also, the deep mechanism of apoptosis was detected by Western blot analysis.     

Design,synthesis, and biological evaluation of biotinylated colchicine derivatives as potential antitumor agents

Chemical drug design based on the biochemical characteristics of cancer cells has become an important strategy for discovering new anti-tumour drugs to improve tumour targeting effects and reduce off-target toxicities. Colchicine is one of the most prominent and historically microtubule-targeting drugs, but its clinical applications are hindered by notorious adverse effects. In this study, we presented a novel tumour-specific conjugate 9 that consists of deacetylcolchicine (Deac), biotin, and a cleavable disulphide linker. 9 was found to exhibit potent anti-tumour activity and exerted higher selectivity between tumour and nontarget cells than Deac. The targeting moiety biotin might enhance the transport capability and selectivity of 9 to tumour cells via biotin receptor-mediated endocytosis. The tubulin polymerisation activity of 9 (with DTT) was close to the parent drug Deac. These preliminary results suggested that 9 is a high potency and reduced toxicity antitumor agent and worthy of further investigation.     

Design, synthesis, and evaluation of novel kazusamycin A derivatives as potent antitumor agents

Novel kazusamycin A derivatives were designed in the viewpoint of decrease of reactivity at the alpha,beta-unsaturated delta-lactone moiety against Michael-type addition. Although 25-30 steps were required for the synthesis of each compound, their syntheses were achieved. Cytotoxicity against HPAC cell line was evaluated, and two of them exhibited comparable potency to kazusamycin A. Hepatic toxicity of these designed compounds was much lower than that of kazusamycin A.