Synthesis of a para-quinone macrolactam related to geldanamycin by ring closing metathesis

Model studies conducted with the α,β,γ,δ-unsaturated 3-alkenyl-2,4,5-trimethoxyanilides 11 revealed that a ring closing metathesis (RCM) of these compounds is possible if the ansa chain contains more than 14 atoms. The (Z)-configurated products 12c-e were obtained in good yields (77-87%) and with perfect simple diastereoselectivity. Since the oxidation of the 2,4,5-trimethoxyanilides led predominantly to undesired ortho-quinones such as 15 or to para-azaquinones such as 16 the macrocyclic 2,5-di-iso-propoxy-4-methoxyanilide 22 was prepared. The iso-propyl protecting groups could be selectively cleaved and the intermediate para-hydroquinone oxidized on air to the desired para-quinone 2 (86% yield). The compound shows some key features (macrolactam ring with the same ring size, α,β,γ,δ-unsaturated anilide, para-quinone) of geldanamycin.     

Characterization and pharmacological evaluation of new pyridine analogs

Reaction of 5-ethyl pyridine-2-ethanol 1 and methane sulphonyl chloride gives corresponding sulphonate 2; which on condensation with p-hydroxy benzaldehyde will give 4-[2-(5-ethylpyridin-2-yl)ethoxy]benzaldehyde 3. A series of chalcones 4a–o were prepared from 3 and substituted aromatic acetophenone. Chalcones 4a–o further react with guanidine nitrate to give a series of pyrimidines 5a–o which condense with 3,4-dichlorobenzylchloride to give amide derivatives 6a–o. Newly synthesized compounds have been examined on the basis of spectral analysis. All the compounds were screened against different gram-positive and gram-negative bacteria. Most of these compounds showed better inhibitory activity in comparison with the standard drugs.     

Synthesis and evaluation of a new class of tertiary alcohol based BACE-1 inhibitors

BACE-1 has emerged as one of the best characterized targets for future Alzheimer therapy. In accordance with the successful identification of masked inhibitors of HIV-1 protease, we envisioned that tert-alcohol containing transition-state mimicking structures would also be worthwhile evaluating as BACE-1 inhibitors. Twelve novel inhibitors were prepared via synthetic routes using epoxyalcohol derivates as key intermediates. The best synthesized tert-hydroxy inhibitor exhibited a BACE-1 IC₅₀ value of 0.38 μM.     

Synthesis and biological evaluation of neopeltolide and analogs

The synthesis of neopeltolide analogues that contain variations in the oxazole-containing side chain and in the macrolide core are reported along with the GI(50) values for these compounds against MCF-7, HCT-116, and p53 knockout HCT-116 cell lines. Although biological activity is sensitive to changes in the macrocycle and the side chain, several analogues displayed GI(50) values of <25 nM. Neopeltolide and several of the more potent analogues were significantly less potent against p53 knockout cells, suggesting that p53 plays an auxiliary role in the activity of these compounds.     

Synthesis and evaluation of potent yaku'amide A analogs

Two full-length analogs of the anticancer peptide yaku''amide A (1a) and four partial structures have been synthesized. These analogs were identified by computational studies in which the three E- and Z-ΔIle residues of the natural product were replaced by the more accessible dehydroamino acids ΔVal and ΔEnv. Of the eight possible analogs, modeling showed that the targeted structures 2a and 2b most closely resembled the three-dimensional structure of 1a. Synthesis of 2a and 2b followed a convergent route that was streamlined by the absence of ΔIle in the targets. Screening of the compounds against various cancer cell lines revealed that 2a and 2b mimic the potent anticancer activity of 1a, thereby validating the computational studies.

Simplified full-length analogs of yaku''amide A were designed with the aid of computations and then synthesized. The analog that was predicted to most closely resemble the structure of the natural product mimicked its anticancer activity.     

三芥子酸甘油酯类似物的合成及抑菌活性

以N-(2-溴乙基)邻苯二甲酰亚胺或N-(4-溴丁基)邻苯二甲酰亚胺和硫氢化钠为起始原料,通过取代、肼解、亲核加成等反应合成了10个三芥子酸甘油酯(erucin)类似物,通过核磁共振氢谱、碳谱及质谱对其结构进行了确认。采用比浊法初步测试了其对大肠杆菌、金黄色葡萄球菌、白色葡萄球菌、藤黄八叠球菌、枯草芽孢杆菌、蜡状芽孢杆菌和四联球菌等7种菌的生长抑制活性,测试结果显示,化合物对测试菌种都表现出较好的生长抑制活性,其中苄硫乙基-1-硫代异硫氰酸酯(5e)和苄硫基丁基-1-硫代异硫氰酸酯(5j)活性最高,对大肠杆菌的最低生长抑制浓度仅为7.8μg/m L,对金黄色葡萄球菌的最低生长抑制浓度也仅为15.6μg/m L和31.2μg/m L。     

Synthesis and biochemical evaluation of O-acetyl-ADP-ribose and N-acetyl analogs

Synthetic routes for the preparation of O-acetyl-ADP-ribose and two novel non-hydrolyzable analogs containing an N-acetyl are described and shown to interact with the macro domain of histone protein H2A1.1.     

Synthesis and biological evaluation of aziridine-containing analogs of phytosphingosine

Six new aziridine-containing analogs of phytosphingosine designed as constrained anhydrophytosphingosine were synthesized. The synthetic route developed also afforded an access to an original bicyclic analog of the natural anhydrophytosphingosine jaspine B. All these new compounds were evaluated for their capacities to affect melanoma cell viability.     

Synthesis and evaluation of simplified functionalized bongkrekic acid analogs

Bongkrekic acid (BKA) is a strong inhibitor of adenine nucleotide translocase (ANT), inducing inhibition of adenosine triphosphate synthesis. We designed and synthesized simplified benzene-ring-containing BKA analogs. The key reaction is the one-pot double Sonogashira reaction, which forms the main skeleton. The analogs were efficiently synthesized in 8–10 longest linear sequence steps. This synthetic method can be applied for the preparation of other analogs having different combinations of carbon chain lengths. Furthermore, the allyloxy group on the benzene ring can be easily replaced by other functional groups. Our preliminary biological evaluation based on mitochondrial inhibitory effects revealed the high potency of the analogs bearing the same carbon chain length as that of BKA. In particular, the prefunctionalized analogs are potential ANT inhibitors.     

Synthesis and antibacterial evaluation of diaminomaleonitrile-based azo-Schiff bases and 8,9-dihydro-7H-purine-6-carboxamides

Research on Chemical Intermediates - Some new DAMN-based Schiff base 6a–6g were synthesized via a condensation reaction of the corresponding azo dyes with...     

Synthesis and biological evaluation of substituted indazolyl amide derivatives as S-adenosyl-L-homocysteine hydrolase inhibitors

A series of novel amide derivatives bearing an indazole moiety were synthesized and evaluated for their in vitro S-adenosyl-L-homocysteine hydrolase (SAHase) inhibitory activity. Among these compounds, 8b, 8m, 8r and 8w showed better or similar inhibitory effects compared to the positive control aristeromycin. These results provide a novel lead for the discovery of more potent non-adenosine analogs as SAHase inhibitors.     

Synthesis and characterization of N-alkyl 1,3-diamino-4,6-diamidobenzenes

A new preparation of N-substituted 1,3-diamino-4,6-diamidobenzenes has been achieved. This synthesis affords the first N-alkylamino derivatives for which a fine-tuning of the NR¹R² substituents should modify the reactivity of the amine functions.     

Synthesis and biological evaluation of peptidyl organotrifluoroborates and their corresponding boron analogs

Six peptidyl organotrifluoroborates and their corresponding boronate esters and/or boronic acid analogs were designed and synthesized. Their anti-proliferative activity against hepatocellular carcinoma cells (HepG2) and human metastatic breast cancer cells (MDA-MB231) were evaluated by use of an MTT assay. Potassium {4-[(3S,6S,9S)-3,6-dibenzyl-9-isopropyl-4,7,10-trioxo-11-oxa-2,5,8-triazadodecyl]phenyl}trifluoroborate (B6) was potent (IC₅₀ = 29.9 μM) against MDA-MB231, and {4-[(3S,6S,9S)-6-benzyl-3-((benzyloxy)methyl)-9-isopropyl-4,7,10-trioxo-11-oxa-2,5,8-triazadodecyl]phenyl}boronic acid (B9) and Potassium {4-[(3S,6S,9S)-6-benzyl-3-((benzyloxy)methyl)-9-isopropyl-4,7,10-trioxo-11-oxa-2,5,8-triazadodecyl]phenyl}trifluoroborate (B10) had broad anti-proliferative activity against HepG2 (IC₅₀ = 24.7 and 21.8 μM, respectively) and MDA-MB231 (IC₅₀ = 24.5 and 18.9 μM, respectively).     

Synthesis and antiproliferative evaluation of glucosylated pyrazole analogs of K252c

Pyrazole analogs of the staurosporine aglycon K252c were recently described as potent inhibitors of the three Pim protein kinase isoforms. To evaluate the impact of the introduction of a sugar moiety on the biological activities of this heterocyclic scaffold, four new glucosylated pyrazole analogs of K252c were synthesized. Their biological evaluation demonstrated that most active compounds 11 and 19 substituted by a β-d-glucosyl moiety at N12 or N13 positions exhibited antiproliferative activities toward HCT116 cells.     

Synthesis and biological evaluation of SGLT2 inhibitors: gem-difluoromethylenated Dapagliflozin analogs

Dapagliflozin is currently the most advanced SGLT2 inhibitor, which has been used in Phase III clinical trials for treatment of diabetes. Here we describe the design and synthesis of Dapagliflozin analogs modified with gem-difluoromethylene group. Their biological evaluation of in vitro inhibitory activity against human SGLT2 showed that some of the analogs with CF₂ at C-4 are better SGLT2 inhibitors compared with Dapagliflozin.     

Synthesis and biological evaluation of novel tert-azido or tert-amino substituted penciclovir analogs

tert-Azido or amino substituted penciclovir analogs, 1-3 were synthesized for the purpose of improving the efficacy and bioavailability of penciclovir and searching for novel antiviral agents. Among several methods attempted to insert an azido group into the alpha,beta-unsaturated ester 6, only Bronsted acid-catalysed 1,4-conjugate addition conditions (NaN3, 75% acetic acid, 80 degrees C) gave the desired tert-azido product 7. The synthesized final penciclovir analogs 1-3 were evaluated in vitro against several viruses such as HIV-1, HSV-1 and 2, poliovirus, VZV, and VSV. Compound 2 only showed weak antiviral activity against HSV-1 without cytotoxicity. Although the synthesized compounds did not exhibit an excellent antiviral activity, the successful method used in introducing the tert-azido group is expected to be generally utilized for the synthesis of nucleoside analogs with a tert-azido substituent.     

Synthesis and Spectroscopic Study of Coumarin Derivatives

Five new coumarin amide derivatives were synthesized with coupling reagent,the structures of which were characterized by IR,1H NMR,13C NMR,MS and element analysis.Their spectral properties were studied in dichloromethane,in N,N-dimethylformamide(DMF) and in solid state.Solvent polarity has less influence on the UV-Vis maximum absorption at about 430 nm.The maximum emission wavelengths change from 464 nm to 474 nm in dichloromethane,from 476 nm to 482 nm in DMF and from 521 nm to 548 nm in solid state,respec...     

三羟甲基十一烷的合成与表征

三羟甲基烷烃是用于醇酸树脂、聚氨酯树脂、表面活性剂、合成润滑油等的原料[1-3].三羟甲基十一烷(化学结构见图1)作为三羟甲基烷烃中直碳链最长的一员,不仅具有亲水性(分子中含三个亲水基),而且具有疏水性(含一个长直碳链亲油基),因此可用作表面活性剂.不仅如此,与同样用作乳化剂的一般高级脂肪醇(如十六烷醇)相比,可以在化妆品用的乳液中加入三羟甲基十一烷作乳化剂,以降低乳液的黏度,防止乳液中由于大量加入高级脂肪醇而导致产品黏度过高以至不能在皮肤上被充分涂抹开的状况发生[4].为制备智能芳香缓释型聚氨酯微胶囊壳材[5],需要设计聚氨酯的分子结构中含有能与相变石腊和油溶性香料有良好相容性的疏水链(三羟甲基十一烷与六亚甲基二异氰酸酯的加成物).因此,本文合成并表征了三羟甲基十一烷.     

Concise and Efficient Synthesis of Cinepazide

An efficient synthesis of cinepazide has been carried out in four steps with an overall yield of 51%. The synthesis was started from a commercially available 3,4,5-tri-methoxy benzaldehyde. All the reactions were very clean and the isolation of products was also very easy.     

Synthesis and biological evaluation of analogs of altohyrtin C (spongistatin 2)

Several structural analogs that contain only part of the altohyrtin structure have been prepared and compared with synthetic altohyrtin C (2) for in vitro cytotoxicity against human colon (HCT116) and ovarian (A2780) cell lines. Whereas altohyrtin C was found to be exceedingly potent against these lines (IC₅₀=0.0003 μM), analogs 3-5 were >27,000-fold less potent (IC₅₀>8 μM). Analogs 6 and 7 also demonstrated weak cytotoxicity with IC₅₀ values for the HCT116 and A2780 cells of 4.8 μM and 2.4 μM, respectively, for 6.