Design,Synthesis and Anticancer Profile of New 4-(1H-benzo[d]imidazol-1-yl)pyrimidin-2-amine-Linked Sulfonamide Derivatives with V600EBRAF Inhibitory Effect

A new series of 4-(1H-benzo[d]imidazol-1-yl)pyrimidin-2-amine linked sulfonamide derivatives 12a–n was designed and synthesized according to the structure of well-established V600EBRAF inhibitors. The terminal sulfonamide moiety was linked to the pyrimidine ring via either ethylamine or propylamine bridge. The designed series was tested at fixed concentration (1 µM) against V600EBRAF, finding that 12e, 12i and 12l exhibited the strongest inhibitory activity among all target compounds and 12l had the lowest IC₅₀ of 0.49 µM. They were further screened on NCI 60 cancer cell lines to reveal that 12e showed the most significant growth inhibition against multiple cancer cell lines. Therefore, cell cycle analysis of 12e was conducted to investigate the effect on cell cycle progression. Finally, virtual docking studies was performed to gain insights for the plausible binding modes of vemurafenib, 12i, 12e and 12l.     

Cytotoxicity of Triorganophosphinegold(I) n-Mercaptobenzoates, n = 2, 3 and 4

The results of cytotoxicity trials against a panel of seven human cell lines for a series of triorganophosphinegold(I) 3- and 4-mercaptobenzoates are reported. While the new compounds show moderate to high toxicity, their potencies are inferior to those reported previously for their isomeric 2- mercaptobenzoate derivatives. The results therefore suggest a structure-activity relationship in that the 2-isomeric species are more active, particularly against the non-small cell lung cancer and renal cancer cell lines, results that may indicate some selectivity in their cytotoxic profile.     

Design, synthesis, and in vitro antifungal activity of 1-[(4-substituted-benzyl)methylamino]-2-(2,4-difluorophenyl)-3-(1H-1,2,4-triazol-1-yl)propan-2-ols

As part of our studies focused on the design of 1‐[((hetero)aryl‐ and piperidinylmethyl)amino]‐2‐phenyl‐3‐(1H‐1,2,4‐triazol‐1‐yl)propan‐2‐ols as antifungal agents, we report the development of new extended benzylamine derivatives substituted at the para position by sulfonamide or retrosulfonamide groups linked to alkyl or aryl chains. These molecules have broad‐spectrum antifungal activities not only against Candida spp., including fluconazole‐resistant strains, but also against a filamentous species (A. fumigatus). Concerning fluconazole resistance, selected compounds exhibit the capacity to overcome CDR and ERG11 gene upregulation and to maintain antifungal activity despite a recognized critical CYP51 substitution in C. albicans isolates. Synthesis, investigation of the mechanism of action by sterol analysis in a C. albicans strain, and structure–activity relationships (SARs) are reported.     

Microwave-assisted synthesis and antimicrobial activities of 2-aryl-3-(naphthalene-1 or 2-yl)-1,3-thiazolidin-4-ones

2-aryl-3-(naphthalene-1 or 2-yl)-1, 3-thiazolidin-4-ones 4 and 5 were synthesized in 41%–67% yield by using microwave-assisted one-pot protocol. The structures of the new compounds 4l, 4m, 5c, 5e, 5g, 5h, and 5j–5m were confirmed by IR, NMR, MS, and elemental analysis. The antimicrobial activities of the compounds against Pseudomonas syringae pv. lachrymans (Smith et Bryan) Young, Dye & Wilkie, Botrytis cinerea Pers., and Sphaerotheca fusca Blum. were examined. Some of the compounds showed good antifungical activity against Sphaerotheca fusca Blum.     

Cancer Cell Cytotoxicities of 1-(4-Substitutedbenzoyl)-4-(4-chlorobenzhydryl)piperazine Derivatives

A series of novel 1-(4-substitutedbenzoyl)-4-(4-chlorobenzhydryl)piperazine derivatives 5a-g was designed by a nucleophilic substitution reaction of 1-(4-chlorobenzhydryl)piperazine with various benzoyl chlorides and characterized by elemental analyses, IR and (1)H nuclear magnetic resonance spectra. Cytotoxicity of the compounds was demonstrated on cancer cell lines from liver (HUH7, FOCUS, MAHLAVU, HEPG2, HEP3B), breast (MCF7, BT20, T47D, CAMA-1), colon (HCT-116), gastric (KATO-3) and endometrial (MFE-296) cancer cell lines. Time-dependent cytotoxicity analysis of compound 5a indicated the long-term in situ stability of this compound. All compounds showed significant cell growth inhibitory activity on the selected cancer cell lines.     

Darstellung von 1-Cyan-4-dimethylamino-3-(pyrid-4-yl)-buta-1,3-dien-1-carbonsäure-Derivaten und ihre Cyclisierung zu 3-substituierten 2-Amino-5-(pyrid-4-yl)-pyridinen sowie den entsprechenden 1-Oxiden

Synthesis of 1-Cyano-4-dimethylamino-3-(4-pyridinyl)-1,3-butadiene-1-carboxylic Acid Derivatives and Their Cyclisation to 3-Substituted 2-Amino-5-(4-pyridinyl)-pyridines Including the Corresponding 1-Oxides The vinylogous amidinium salt 1 is transformed to 1-cyano-4-dimethylamino-3-(4-pyridinyl)-1,3-butadiene-1-carboxylic acid derivatives 3a - f by reaction with the cyanoacetic acid compounds 2a - f in the presence of bases. Treatment of the 3a - f with ammonia and hydroxylamine yields the 2-amino-5-(4-pyridinyl)-pyridine-3-carboxylic acid derivatives 5a - f and the corresponding 1-oxides 6a - f , respectively. The products 5d , e are also prepared via the 6d , e by reduction with phosphorus trichloride.     

1-(2-Hydroxy-5-methylphenyl)-3-phenyl-1,3-propanedione Induces G1 Cell Cycle Arrest and Autophagy in HeLa Cervical Cancer Cells

The natural agent, 1-(2-hydroxy-5-methylphenyl)-3-phenyl-1,3-propanedione (HMDB), has been reported to have growth inhibitory effects on several human cancer cells. However, the role of HMDB in cervical cancer remains unclear. Herein, we found that HMDB dose- and time-dependently inhibited growth of HeLa cervical cancer cells, accompanied with G1 cell cycle arrest. HMDB decreased protein expression of cyclins D1/D3/E and cyclin-dependent kinases (CDKs) 2/4/6 and reciprocally increased mRNA and protein levels of CDK inhibitors (p15, p16, p21, and p27), thereby leading to the accumulation of hypophosphorylated retinoblastoma (Rb) protein. HMDB also triggered the accumulation of acidic vesicles and formation of microtubule-associated protein-light chain 3 (LC3), followed by increased expression of LC3 and Beclin-1 and decreased expression of p62, suggesting that HMDB triggered autophagy in HeLa cells. Meanwhile, suppression of the expression of survivin and Bcl-2 implied that HMDB-induced autophagy is tightly linked to apoptosis. Exploring the action mechanism, HMDB induced autophagy via the modulation of AMP-activated protein kinase (AMPK) and mTOR signaling pathway rather than the class III phosphatidylinositol 3-kinase pathway. These results suggest that HMDB inhibits HeLa cell growth by eliciting a G1 arrest through modulation of G1 cell cycle regulators and by concomitantly inducing autophagy through the mediation of AMPK-mTOR and Akt-mTOR pathways, and may be a promising antitumor agent against cervical cancer.     

Synthesis and characterization of coumarin thiazole derivative 2-(2-amino-1,3-thiazol-4-yl)-3H-benzo[f]chromen-3-one with anti-microbial activity and its potential application in antimicrobial polyurethane coating

Coumarin, thiazole and their respective derivative products are some of the oldest and most commonly known class of nitrogen and sulphur containing compounds. In recent years there has been considerable interest in this coumarin–thiazole derivatives, which have been reported to exhibit significant biological activity and are widely used as pharmaceuticals. They are capable of imparting anti-microbial activity properties when incorporated into polymers and polymer composites. In this research, coumarin–thiazole derivative 2-(2-amino-1,3-thiazol-4-yl)-3H benzo[f]chromen-3-one (compound III), was prepared and its structure was confirmed by means of its spectra data. It was also screened for its anti-microbial activity against eight different micro-organisms when physically incorporated into a polyurethane varnish formula. Experimental coatings were manufactured on a laboratory scale and applied by means of a brush on both glass and steel panels. The results of the biological activity indicated that the polyurethane varnishes containing the 2-(2-amino-1,3-thiazol-4-yl)-3H-benzo[f]chromen-3-one (compound III) derivative, exhibit a very good antimicrobial effect. The molecular modeling study revealed that it is biologically safe, it is active and it fulfills Lipinski's rule of five. The physical and mechanical resistances of the polyurethane varnish formulations were also studied to evaluate any drawbacks associated with the addition of the derivative. The studies indicate that the physical incorporation of compound III actually enhances slightly both the physical and mechanical properties.     

Synthesis of Novel Acyl Derivatives of 3-(4,5,6,7-Tetrabromo-1H-benzimidazol-1-yl)propan-1-ols—Intracellular TBBi-Based CK2 Inhibitors with Proapoptotic Properties

Protein kinase CK2 has been considered as an attractive drug target for anti-cancer therapy. The synthesis of N-hydroxypropyl TBBi and 2MeTBBi derivatives as well as their respective esters was carried out by using chemoenzymatic methods. Concomitantly with kinetic studies toward recombinant CK2, the influence of the obtained compounds on the viability of two human breast carcinoma cell lines (MCF-7 and MDA-MB-231) was evaluated using MTT assay. Additionally, an intracellular inhibition of CK2 as well as an induction of apoptosis in the examined cells after the treatment with the most active compounds were studied by Western blot analysis, phase-contrast microscopy and flow cytometry method. The results of the MTT test revealed potent cytotoxic activities for most of the newly synthesized compounds (EC₅₀ 4.90 to 32.77 µM), corresponding to their solubility in biological media. We concluded that derivatives with the methyl group decrease the viability of both cell lines more efficiently than their non-methylated analogs. Furthermore, inhibition of CK2 in breast cancer cells treated with the tested compounds at the concentrations equal to their EC₅₀ values correlates well with their lipophilicity since derivatives with higher values of logP are more potent intracellular inhibitors of CK2 with better proapoptotic properties than their parental hydroxyl compounds.     

N-[4-(间甲基苯甲酰基哌嗪)乙酰基]-N-甲基-3-(1-萘氧基)-3-(2-噻吩基)-丙胺的合成

以N-甲基-3-(1-萘氧基)-3-(2-噻吩基)-丙胺(Duloxetine)为原料,合成了标题化合物.中间体和产物的结构经 ~1HNMR、IR和质谱表征.     

Anodic oxidation of 3-amino-5-(pyrid-4-yl)-1, 2-dihydropyrid-2-one (amrinone)

The anodic behavior of the cardiotonic drug 3-amino-5-(pyrid-4-yl)-1,2-dihydropyrid-2-one 1 and of 6 compounds with similar structure was investigated at platinum and vitreous carbon electrodes in acetonitrile and in aqueous medium. Caused by the 3-amino group 1 is oxidized at a relatively small oxidation potential in an irreversible two-electron process. Depending on the addition of a strong base or a strong acid the oxidation potential vs. SCE in acetonitrile is −0.08 V (anion), +0.66 V (neutral compound), +0.93 V (monocation) or +1.15 V (dication). In H₂O a strong decrease of the oxidation potential with increasing pH was found as a reason for the sensitivity of 1 against oxygen in alkaline solution. The anodic oxidation of 3-dimethylamino-5-(pyrid-4-yl)-1, 2-dihydro-pyrid-2-one 3 in 0.1 m H₂SO₄ leads to 5-(pyrid-4-yl)-piperidine-2,3,6-trione 9a or 5-(pyrid-4-yl)-piperidine-2,3,4-trione 9b , which is also the oxidation product of 1 at small concentration. At high concentration of 1 coupling reactions at the 3-amino-group lead to dimeric products, which could not be identified.     

1-[2-(2,4-二氯苯基)-4-酰氧基甲基-1,3-二氧戊环-2-基]甲基-1H-1,2,4-三氮唑的合成及生物活性

2, 4 二氯苯乙酮经溴化得ω 溴 2, 4 二氯苯乙酮,该化合物与丙三醇反应并脱水得 2 (2, 4 二氯苯基 ) 2 溴甲基 4 羟甲基 1, 3 二氧戊环,再在常温下与苯甲酰氯反应合成 2 (2, 4 二氯苯基) 2 溴甲基 4 苯甲酰氧基甲基 1, 3 二氧戊环,然后在 130℃与 1H 1, 2, 4 三唑钠反应 36h,所得产物经水解得 1 [2 (2, 4 二氯苯基 ) 4 羟甲基 1, 3 二氧戊环 2 基]甲基 1H 1, 2, 4 三氮唑,再在室温以吡啶作缚酸剂,与甲磺酰氯反应 20h,合成 1 [2 (2, 4 二氯苯基) 4 甲磺酰氧基甲基 1, 3 二氧戊环 2 基]甲基 1H 1, 2, 4 三氮唑,最后与各类羧酸的钾盐反应,合成了 10种 1 [2 (2, 4 二氯苯基 ) 4 酰氧基甲基 1, 3 二氧戊环 2 基 ]甲基 1H 1, 2, 4 三氮唑类化合物。产物的结构经GC MS、IR证实。对目标产物进行了杀菌活性测定,结果表明,各化合物均具有不同程度的生物活性,其中: 1 [2 (2, 4 二氯苯基) 4 (α 甲基苯乙酰氧基)甲基 1, 3 二氧戊环 2 基]甲基 1H 1, 2, 4 三氮唑对水稻稻瘟病菌和油菜菌核病菌的抑制率,分别达到 92 1%与 95 6%,对小麦赤霉病菌和瓜类灰霉病菌的抑制率达到 80%以上;1 [2 (2, 4 二氯苯基) 4 对氟苯甲酰氧基甲基 1, 3 二氧戊环 2 基 ]甲基 1H 1, 2, 4 三氮唑对水稻稻瘟病菌和油菜菌核病菌的抑制率分别为 9     

Design, synthesis, and biological evaluation of 1-[(biarylmethyl)methylamino]-2-(2,4-difluorophenyl)-3-(1H-1,2,4-triazol-1-yl)propan-2-ols as potent antifungal agents: new insights into structure-activity relationships

We recently reported the design and synthesis of azole antifungal agents with a focus on modifications to the side chain appended to the propanol group. Herein we have identified a series of new 1-[(biarylmethyl)methylamino] derivatives with broad-spectrum antifungal activities against the most prevalent human pathogenic fungi (Candida spp. and Aspergillus fumigatus). Compounds containing a flexible benzylamine moiety were clearly shown to yield the best antifungal activities, without the need for a hydrogen-bond acceptor substituent directly attached to the para position. We were also able to determine that selected compounds are able to overcome gene overexpression and point mutations that lead to reduced susceptibility or resistance against current treatments, such as fluconazole. As the minor differences observed with small structural modifications cannot be explain with only a three-dimensional model of CYP51, adequate physicochemical parameters must be evaluated in terms of antifungal potency, bioavailability, and toxicity. Therefore, structure-activity relationship studies such as these reveal new insights for the development of future antifungal therapies.     

One-Pot Three-Component Synthesis of Novel Diethyl((2-oxo-1,2-dihydroquinolin-3-yl)(arylamino)methyl)phosphonate as Potential Anticancer Agents

With the aim of discovering new anticancer agents, we have designed and synthesized novel α-aminophosphonate derivatives containing a 2-oxoquinoline structure using a convenient one-pot three-component method. The newly synthesized compounds were evaluated for antitumor activities against the A549 (human lung adenocarcinoma cell), HeLa (human cervical carcinoma cell), MCF-7 (human breast cancer cell), and U2OS (human osteosarcoma cell) cancer cell lines in vitro, employing a standard 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) assay. The results of pharmacological screening indicated that many compounds exhibited moderate to high levels of antitumor activities against the tested cancer cell lines and that most compounds showed more potent inhibitory activities comparable to 5-fluorouracil (5-FU) which was used as a positive control. The mechanism of representative compound 4u (diethyl((2-oxo-1,2-dihydroquinolin-3-yl)(phenyl-amino)methyl)phosphonate) indicated that the compound mainly arrested HeLa cells in S and G2 stages and was accompanied by apoptosis in HeLa cells. This action was confirmed by acridine orange/ethidium bromide staining, Hoechst 33342 staining, and flow cytometry.     

New 3-Aryl-2-(2-thienyl)acrylonitriles with High Activity Against Hepatoma Cells

New 2-(thien-2-yl)-acrylonitriles with putative kinase inhibitory activity were prepared and tested for their antineoplastic efficacy in hepatoma models. Four out of the 14 derivatives were shown to inhibit hepatoma cell proliferation at (sub-)micromolar concentrations with IC₅₀ values below that of the clinically relevant multikinase inhibitor sorafenib, which served as a reference. Colony formation assays as well as primary in vivo examinations of hepatoma tumors grown on the chorioallantoic membrane of fertilized chicken eggs (CAM assay) confirmed the excellent antineoplastic efficacy of the new derivatives. Their mode of action included an induction of apoptotic capsase-3 activity, while no contribution of unspecific cytotoxic effects was observed in LDH-release measurements. Kinase profiling of cancer relevant protein kinases identified the two 3-aryl-2-(thien-2-yl)acrylonitrile derivatives 1b and 1c as (multi-)kinase inhibitors with a preferential activity against the VEGFR-2 tyrosine kinase. Additional bioinformatic analysis of the VEGFR-2 binding modes by docking and molecular dynamics calculations supported the experimental findings and indicated that the hydroxy group of 1c might be crucial for its distinct inhibitory potency against VEGFR-2. Forthcoming studies will further unveil the underlying mode of action of the promising new derivatives as well as their suitability as an urgently needed novel approach in HCC treatment.     

1-[2-(2,4-二氯苯基)-4-烃氧基甲基-1,3-二氧戊环-2-基]甲基-1H-1,2,4-三氮唑类化合物的合成及杀菌活性研究

2,4-二氯苯乙酮经溴化得ω-溴-2,4-二氯苯乙酮,该化合物与丙三醇在对甲基苯磺酸催化下脱水,得2-(2,4-二氯苯基)-2-溴甲基-4-羟甲基-1,3-二氧戊环,该中间体与苯甲酰氯在常温下反应,合成了2-(2,4-二氯苯基)-2-溴甲基-4-苯甲酰氧基甲基-1,3-二氧戊环,然后与三氮唑钠盐在130℃反应36 h,之后在碱性条件下水解,获得1-[2-(2,4-二氯苯基)-4-羟甲基-1,3-二氧戊环-2-基]甲基-1H-1,2,4-三氮唑,再以吡啶为缚酸剂继续与甲磺酰氯反应,合成了1-[2-(2,4-二氯苯基)-4-甲磺酰氧基甲基-1,3-二氧戊环-2-基]甲基-1H-1,2,4-三氮唑,最后在碱性条件下,与12个不同结构的酚缩合成标题化合物1-[2-(2,4-二氯苯基)-4-烃氧基甲基-1,3-二氧戊环-2-基]甲基-1H-1,2,4-三氮唑。标题化合物的结构用GC-MS、FTIR进行了表证。生物活性实验结果表明,12个标题化合物对水稻稻瘟病菌的抑菌率均在88.0%以上,其中,1-[2-(2,4-二氯苯基)-4-间甲基苯氧基甲基-1,3-二氧戊环-2-基]甲基-1H-1,2,4-三氮唑达100%。1-[2-(2,4-二氯苯基)-4-苯氧基甲基-1,3-二氧戊环-2-基]甲基-1H-1,2,4-三氮唑和1-[2-(2,4-二氯苯基)-4-对硝基苯氧基甲基-1,3-二氧戊环-2-基]甲基-1H-1,2,4-三氮唑对油菜菌核病菌的抑菌率分别为100%和97.8%;1-[2-(2,4-二氯苯基)-4-间甲基苯氧基甲基-1,3-二氧戊环-2-基]甲基-1H-1,2,4-三氮唑对小麦赤霉病菌的抑制活性为91.2%。     

螺螨酯类似物AC-101的合成与杀螨活性

为寻求高活性的杀螨剂,通过对螺螨酯进行结构改造,合成了新杀螨活性化合物3-(2,4-二氯苯基)-2-氧-1-氧杂螺[4.5]癸-3-烯-4-基-丁基-1-磺酸酯(试验代号:AC-101;暂命名:螺螨丁酯),并开发了24%悬浮剂(SC)和24%可分散油悬浮剂(OD)制剂。室内生物活性测试显示:在1 mg/L质量浓度下,螺螨丁酯对朱砂叶螨螨卵的防效达95%。田间药效试验显示:24%螺螨丁酯SC和OD药后14 d对山楂叶螨的最高防效分别为95.7%和96.2%,药后21 d对山楂叶螨的防效在73.6%以上。螺螨丁酯具有杀螨活性高、速效性好和持效期长的特点,有一定的应用开发价值。     

Pd(O) Promoted Transformation of 1,1-Dialkoxycarbonyl-2-(1,3-butadienyl)cyclopropanes into 2-Ethenyl-3-cyclopentenes

1,3-Butadienylcyclopropanes activated by two electron-withdrawing groups ( 1 ) smoothly rearrange to vinylcyclopentene derivatives in the presence of a Pd(O) catalyst under mild conditions. For example, dimethyl 1,3-butadienylcyclopropane-1,1-dicarboxylate 1a reacts with 3 mol% Pd(PPh₃)₄ in DMSO at 25–60 °C for 30 min to provide dimethyl 2-ethenyl-3-cyclopentene-1,1-dicarboxylate 2a in 87% yield. Other data show that the new method is useful in the synthesis of cyclopentene derivatives including dolichodial and iridodiol.