Synthesis and biological evaluation of novel acenaphthene derivatives as potential antitumor agents

Twelve novel acenaphthene derivatives have been synthesized. The structures of all compounds were confirmed by 1H-NMR, MS and elemental analysis. Their antitumor activities were evaluated in six human solid tumor cell lines, namely non-small cell lung cancer (H460), human colon adenocarcinoma (SW480), human breast cancer cell (MDA-MB-468 and SKRB-3), human melanoma cell (A375) and human pancreatic cancer (BxPC-3). Among them, compound 3c shows the best antitumor activity against SKRB-3 cell line, as high as the positive control adriamycin.     

Synthesis of 1,2,3,4-tetrahydroquinazoline derivatives as potential alpha-adrenergic blocking agents

The synthesis of N,N′-bis[6-(1,2,3,4-tetrahydro-3-quinazolidyl)hexyl]cystamine (I) and 3-(6-aminohexyl)-1,2,3,4-tetrahydroquinazoline (II) are described. Compound I is obtained by condensation of o-nitrobenzoyl chloride with 3-(6-aminohexyl)-1,3-thiazolidine (III) followed by dimerization, reduction and formation of tetrahydroquinazoline ring. A similar method was used for preparation of compound II. These compounds and some synthesis intermediates are potential alpha-adrenergic blockers.     

Synthesis and biological evaluation of novel N-methyl-picolinamide-4-thiol derivatives as potential antitumor agents

A novel series of N-methylpicolinamide-4-thiol derivatives were synthesized and evaluated on human cancer cell lines. Among them, compound 6p displayed potent and broad-spectrum anti-proliferative activities in vitro on some human cancer cell lines, even better than sorafenib. The advanced kinase inhibitory assays showed that compound 6p could selectively inhibit Aurora-B kinase. The biological results were rationalized by the molecular docking study, which indicated the stable interactions of 6p with the Aurora-B kinase.     

Synthesis and pharmacological evaluation of 1-isopropyl-1,2,3,4-tetrahydroisoquinoline derivatives as novel antihypertensive agents

A series of 1-isopropyl-1,2,3,4-tetrahydroisoquinoline derivatives were synthesized and their bradycardic activities were evaluated in isolated guinea pig right atria. Structure-activity relationship studies revealed that the introduction of an appropriate substituent and its position on the 1,2,3,4-tetrahydroisoquinoline ring are essential for potent in vitro activity. Furthermore, the tether between the piperidyl moiety and the terminal aromatic ring is important for potent antihypertensive activity. Oral administration of 6-fluoro-1-isopropyl-2-{[1-(2-phenylethyl)piperidin-4-yl]carbonyl}-1,2,3,4-tetrahydroisoquinoline (3b) to spontaneously hypertensive rats (SHR) elicited antihypertensive effects without inducing reflex tachycardia, which is often caused by traditional L-type Ca2? channel blockers.     

氯硝柳胺衍生物的合成及抗肿瘤活性研究

以氯硝柳胺为起始原料,经醚化、亲核取代反应得到目标化合物,采用MTT法考察所合成化合物对人类乳腺癌细胞(MDA-MB-231)和人类胰腺癌细胞(ASPC-1)的体外抗肿瘤活性。合成了5个氯硝柳胺衍生物,其结构均经IR、1H-NMR、13C-NMR和MS确证。初步的体外抗肿瘤活性结果显示目标化合物9b和9c的抗肿瘤活性强于阳性对照药,其中化合物9b的活性对所测两种肿瘤株的抑制活性均强于阳性对照药,展现出较强的应用前景。     

Synthesis of 5-substituted 6-methoxy-1,2,3,4-tetrahydro-β-carbolin-1-ones

The nitration and bromination of 6-methoxy-1,2,3,4-tetrahydro--carbolin-1-one were studied. 5-Nitro and 5-bromo derivatives were obtained. 5-Acetyl-1,2,3,4-tetrahydrocarbolin-1-one oxime was obtained, and its Beckmann rearrangement was studied. The use of lithium aluminum hydride leads to reduction of the 5-acetyl group to give an alcohol group, whereas reduction of the acetyl group to an ethyl group occurs in the case of reduction with a palladium catalyst. Saponification of 5-substituted carbolin-1-ones with alcoholic alkali makes it possible to obtain 4-substituted tryptamines with a carbonyl group in the 2 position. The structures of the compounds were established by means of the PMR and mass spectra.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 1, pp. 80–85, January, 1979.     

Synthesis of 1-aryl-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indoles (1,2,3,4-tetrahydro-β-carbolines) under high pressures

The reactions of aromatic aldehydes with tryptamine (1) in solvents of different polarity were studied. The yields of carbolines in the chosen media decrease with an increase in the donating properties of the aryl substituent, but they markedly increase at a high pressure (5 kbar), especially for compounds with electron-donating aryl groups. The phase transition of dioxane at 5 kbar also sharply increases the yields of the target products.     

Novel pyrazolo[3,4-d]pyrimidine derivatives as potential antitumor agents: exploratory synthesis, preliminary structure-activity relationships, and in vitro biological evaluation

In a cell-based screen of novel anticancer agents, the hit compound 1a which bears a pyrazolo[3,4-d]pyrimidine scaffold exhibited high inhibitory activity against a panel of four different types of tumor cell lines. In particular, the IC?? for A549 cells was 2.24 μM, compared with an IC?? of 9.20 μM for doxorubicin, the positive control. Four synthetic routes of the key intermediate 3 of 1a were explored and 1a was prepared via route D on the gram scale for further research. Two analogs of 1a were synthesized and their preliminary structure-activity relationships were studied. Flow cytometric analysis revealed that compound 1a could significantly induce apoptosis in A549 cells in vitro at low micromolar concentrations. These results suggest that the target compound 1a and its analogs with the pyrazolo[3,4-d]pyrimidine scaffold might potentially constitute a novel class of anticancer agents, which requires further studies.     

A general method for the asymmetric synthesis of both enantiomers of 1-substituted 1,2,3,4-tetrahydro-β-carbolines employing pyroglutamic acid derivatives as chiral auxiliaries

9-(S)-Pyroglutaminyl-β-carbolines were allowed to react with a nucleophile (allyltributyltin or a silyl enol ether) in the presence of 2,2,2-trichloroethyl chloroformate to give 1,2-addition products in good yields and high diastereoselectivity. The chiral auxiliary at N-9 was readily removed by a mild hydrolysis. The same chiral source afforded both enantiomers by simply altering a protecting group of the amide nitrogen. That is, (S)-pyroglutaminyl groups which had an N-alkyl group afforded the (S) isomer, whereas the ones having an N-acyl group produced the (R) isomer of the addition products.     

Synthesis of 1,3,5-cis,cis-triaminocyclohexane N-pyridyl derivatives as potential antitumor agents

Iron deprivation has been previously proven to be a promising strategy in treating tumor cells. A series of cis,cis-1,3,5-triaminocyclohexane N-pyridyl derivatives as iron-depleting antitumor agents were prepared. Cytotoxic activity of these derivatives was evaluated in the HeLa cancer cell line. Among the tested derivatives, N-ethyl-N,N',N"-tris(2-pyridylmethyl)-cis,cis-1,3,5-triaminocyclohexane (17) exhibited potent cytotoxicity against this cancer cell line. On the basis of the structure of 17, a bifunctional iron chelator 24 was designed and prepared. Bifunctional agent 24 possessing a maleimide linker that is functional for conjugation to thiolated monoclonal antibodies is a promising lead compound for development of antitumor conjugates for antibody-targeted therapies.     

Synthesis and biological evaluation of new pyrrolopyrazinone compounds as potential antitumor agents

A series of pyrrolo[1,2-a]pyrazinone compounds(5a-9f) were synthesized,and their cytotoxic activity against SKOV-3,A549.HeLa cells in vitro were evaluated by the MTT method.Some of the compounds showed potential antitumor activity against three tumor cell lines.Among them,compounds 9c and 9d showed the most potent cytotoxic activity.The preliminary mechanism of action was discussed.     

Microwave-assisted synthesis of some novel fluorinated pyrazolo[3,4-d]pyrimidine derivatives containing 1,3,4-thiadiazole as potential antitumor agents

A facile microwave-assisted procedure for synthesis of novel fluorinated pyrazolo[3, 4-d]pyrimidine derivatives containing 1, 3, 4-thiadiazole is described. This protocol presented such advantages as short reaction time, high yields, simple purification and environmentally benign procedures. Their antitumor activities were evaluated against HL-60 by an MTT assay. The preliminary results indicated that some title compounds exhibit more potent antitumor inhibitory activity than doxorubicin (DOX).     

Synthesis and biological evaluation of novel indoleamide derivatives as antioxidative and antitumor agents

Novel indole amide derivatives C1-C10 were successfully synthesized and characterized by ¹H NMR, ¹³C NMR, IR, MS, and elemental analysis, and their molecular formulas were C₁₄H₁₀N₆O, C₁₃H₁₀N₄O, C₁₆H₁₃N₃O₂, C₁₉H₁₄N₂O₂, C₁₆H₁₁N₃OS, C₁₅H₁₃N₃O, C₁₂H₉N₅O, C₁₆H₁₀ClN₃OS, C₁₅H₁₇N₃O₂, and C₁₃H₁₄N₂O₃, respectively. The primary biological activities of these compounds were evaluated in vitro by the DPPH assay, H₂O₂-induced oxidative stress injury assay, and cytotoxicity assay. The results indicated that compounds C1, C2, C4, C7, and C9 exhibited DPPH·scavenging ability, while C3, C4, C5, and C8 showed potent growth-inhibitory activities against various human tumor cells, including MDA-MB-231, Hela, A549, and HT29. Interestingly, compound C4 showed potent scavenging effects on the DPPH radical and possessed protective effect on H₂O₂-induced oxidative stress injury in human neuroblastoma SH-SY5Y cells at low concentrations; however, C4 exhibited significant toxicity against four human tumor cells at a higher concentration in all treatments, and the range of IC₅₀ value was 7.91 to 13.35 μM.     

Tricyclic heteroaromatic systems. 1,2,3,4-tetrahydropyrazolo[4,3-c][l]benzazepin-1-ones as potential antitumor agents

The synthesis of 1,2,3,4-tetrahydropyrazolo[4,3-c][1]benzazepin-1-ones 1 and that of its 10-methyl derivative 2 is reported. The preparation of the latter from 3-(2-aminobenzyl)3-pyrazolin-5-one and triethyl ortho-formate gave as the main product a derivative of the new tricyclic ring system, pyrazolo[1,5-c][1,3]benzo-diazepine. The structures of the new compounds synthesized were assigned by means of a ¹³C nmr study.     

Synthesis and biological evaluation of piperidyl benzimidazole carboxamide derivatives as potent PARP-1 inhibitors and antitumor agents

We have synthesized a series of compounds based on a piperidyl benzimidazole carboxamide structure,and tested their PARP-1 inhibitory activity,as well as cellular inhibitory activity.Some of them show great potency as PARP-1 inhibitors and antitumor activity,which are valuable for further research.In addition,the predicted ADME properties and proposed binding mode with PARP-1 of the compounds were obtained via computational simulation.     

Novel benzothiazole, benzimidazole and benzoxazole derivatives as potential antitumor agents: synthesis and preliminary in vitro biological evaluation

In a previous hit-to-lead research program targeting anticancer agents, two promising lead compounds, 1a and 1b, were found. However, the poor solubility of 1a and 1b made difficult further in vivo studies. To solve this problem, a lead optimization was conducted through introducing N-methyl-piperazine groups at the 2-position and 6-position. To our delight, the optimized analogue 1d showed comparable antiproliferative activity in vitro with better solubility, compared with 1a. Based on this result, the replacement of the benzothiazole scaffold with benzimidazole and benzoxazole moieties afforded 1f and 1g, whose activities were fundamentally retained. In the preliminary in vitro biological evaluation, the immunofluorescence staining of HCT116 cells indicated that 1d, 1f and 1g led to cytosolic vacuolization which was not induced by 1a at low micromolecular concentrations. These results suggest that these optimized compounds might potentially constitute a novel class of anticancer agents, which merit further studies.     

Synthesis of 3-substituted 7-(3,3-dimethyl-1-triazeno)-10-methylphenothiazines as potential antitumor agents

A series of 3-substituted (chloro, bromo, fluoro or methyl) 7-(3,3-dimethyl-1-triazeno)-10-methylphenothiazines were synthesized as potential antitumor agents. Treatment of p-substituted anilines with ammonium thiocyanate in the presence of bromine gave 6-substituted 2-aminobenzthiazoles which, after methylation with methyl iodide were hydrolyzed in 50% potassium hydroxide to give 5-substituted 2-methylaminothiophenols in moderate yield. Condensation of methylaminothiophenols with 3,4-dichloronitrobenzene in ethanol under an atomsphere of nitrogen gave adducts which were cyclized in dimethylformamide under the catalysis of copper and cuprous iodide to give 3-substituted 7-nitro-10-methylphenothiazines. The nitro group was reduced to the amino function with stannous chloride. Diazotization of the amines followed by coupling with dimethylamine gave the corresponding triazenes.     

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.