New benzimidazole derivatives: Design,synthesis, docking,and biological evaluation

The aim of this study was to synthesize novel enaminonitrile derivatives starting from 2-aminobenzimidazole and utilize this derivative for the preparation of novel heterocyclic compounds and assess their function for biological activity screening. The key precursor N-(1H-benzo[d]imidazol-2-yl)carbonohydrazonoyl dicyanide (2) was prepared in pyridine by coupling of diazotized 2-aminobenzimidazole (1) with malononitrile. Compound 2 was subjected to react with various secondary amines such as piperidine, morpholine, piperazine, diphenylamine, N-methylglucamine, and diethanolamine in boiling ethanol to give the acrylonitriles (2Z)-2-((1H-benzo[d]imidazol-2-yl)diazenyl)-3-amino-3-(piperidin-1-yl)acrylonitrile (3), (2Z)-2-((1H-benzo[d]imidazol-2-yl)diazenyl)-3-amino-3-morpholinoacrylonitrile (4), (2Z)-2-((1H-benzo[d]imidazol-2-yl)diazenyl)-3-amino-3-(piperazin-1-yl)acrylonitrile (5), (2Z)-2-((1H-benzo[d]imidazol-2-yl)diazenyl)-3-amino-3-(diphenylamino)acrylonitrile (6), (2Z)-2-((1H-benzo[d]imidazol-2-yl)diazenyl)-3-amino-3-(methyl((2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl)amino)acrylonitrile (7), and (2Z)-2-((1H-benzo[d]imidazol-2-yl)diazenyl)-3-amino-3-(bis(2-hydroxyethyl)amino)acrylonitrile (8), respectively. It has been found that the behaviour of nitrile derivative 2 towards hydrazine hydrate to the creation of 4-((1H-benzo[d]imidazol-2-yl)diazenyl)-1H-pyrazole-3,5-diamine (9). The reaction of malononitrile with compound 2 in an ethanolic solution catalyzed with sodium ethoxide afforded 4-amino-1-(1H-benzo[d]imidazol-2-yl)-6-imino-1,6-dihydropyridazine-3,5-dicarbonitrile (11). Moreover, malononitrile reacted with 7 in a boiling ethanolic sodium ethoxide solution to give 2-(5-((1H-benzo[d]imidazol-2-yl)diazenyl)-4-amino-6-(methyl((2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl)amino)pyrimidin-2-yl)acetonitrile (14). Heating 7 in boiling acetic anhydride and pyridine afforded (2R,3R,4R,5S)-6-(((1E)-2-((1-acetyl-1H-benzo[d]imidazol-2-yl)diazenyl)-1-(N-acetylacetamido)-2-cyanovinyl)(methyl)amino)hexane-1,2,3,4,5-pentayl pentaacetate (15). When compound 15 is heated for a long time in refluxing DMF including a catalytic of TEA, cyclization occurs to give the corresponding (2R,3R,4R,5S)-6-((1-acetyl-3-((1-acetyl-1H-benzo[d]imidazol-2-yl)diazenyl)-4-amino-6-oxo-1,6-dihydropyridin-2-yl)(methyl)amino)hexane-1,2,3,4,5-pentayl pentaacetate (16). In addition, triethyl orthoformate was reacted with compound 7 in the presence of acetic anhydride to afford the corresponding ethoxymethyleneamino derivative (2R,3R,4R,5S)-6-(((1E)-2-((1-acetyl-1H-benzo[d]imidazol-2-yl)diazenyl)-2-cyano-1-(((E) ethoxymethylene)amino)vinyl)(methyl)amino)hexane-1,2,3,4,5-pentayl pentaacetate (17). Also, it has been found that heating a mixture of 7 with DMF/DMA in anhydrous xylene yielded compound (1E)-N'-((1E)-2-((1H-benzo[d]imidazol-2-yl)diazenyl)-2-cyano-1-(methyl((2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl)amino)vinyl)-N,N-dimethylformimidamide (18). In addition, compound 7, when reacted with several acid anhydrides, allowed the matching phthalimide derivatives 19–26. The results showed that compound 14 has significantly higher ABTS and antitumor activities than the other compounds. Molecular modelling was also studied for compounds 22 and 24. The viability of four many cell lines—the African green monkey kidney epithelial cells (VERO), human breast adenocarcinoma cell line (MCF-7), human lung fibroblast cell line (WI-38), and human hepatocellular liver carcinoma cell line (HepG2) was examined to determine the antitumor activities of the newly synthesized compounds. Also, it was found that compounds 9, 11, 15, 16, 22, 23, 24 and 25 are strong against HepG2 cell lines, while 16, 22, and 25 are strong against WI-38 cell lines. Moreover, it was also found that compounds 16 and 22 are strong against VERO cell lines. On the other hand, compounds 7, 14, 15, 16, and 22 are strong while the rest of the other compounds are moderate against the MCF-7 cell line. The result of docking showed that compound 24 got stabilized inside the pocket with a very promising binding score of ? 8.12 through hydrogen bonds with Arg184 and Lys179, respectively.     

Synthesis,structure elucidation and plants growth promoting effects of novel quinolinyl chalcones

The readily synthesized 3-(4-Hydroxy-1-methyl-1,2-dihydro-2-oxoquinolin-3-yl)-1-phenyl-1H-pyrazole-4-carbaldehyd (5) and 3-(2-Oxo-2H-chromen-3-yl)-1-phenyl-1H-pyrazole-4-carbaldehyde (6) were utilized as a convenient starting precursor materials for synthesis of novel enone system 4-hydroxy-1-methyl-3-(4-(2H-2-oxo-chromen-3-yl)prop-2-enoyl)-1-phenyl-1H-pyrazol-4-yl)quinolin-2(1H)-one (7) and4-hydroxy-1-methyl-3-(2E)-3-(3-(2-oxo-2H-chromen-3-yl)-1-phenyl-1H-pyrazol-4-yl)acryloyl)quinolin-2(1H)-one (8). Simple homonuclear NOE experiment (NOESY 1D) method was performed for structure elucidation of the novel quinolinyl chalcones. The synthesized compounds have been estimated for their effect of growth on some selective crop of plants (Hibiscus, Mint and Basil).     

Quinoline-pyrimidine hybrid compounds from 3-acetyl-4-hydroxy-1-methylquinolin-2(1H)-one: Study on synthesis,cytotoxicity, ADMET and molecular docking

Some novel 2-amino-6-aryl-4-(4′-hydroxy-N-methylquinolin-2′-on-3′-yl)pyrimidines have been synthesized from α,β-unsaturated ketones of 3-acetyl-4-hydroxy-N-methylquinolin-2-one by reaction of corresponding α,β-unsaturated ketones with guanidine hydrochloride. The purity and structure of the obtained products have been confirmed by thin layer chromatography, IR, ¹H NMR, ¹³C NMR, HSQC, HMBC and MS spectra. All the synthesized of 3-(2-amino-6-arylpyrimidin-4-yl)-4-hydroxy-1-methylquinolin-2(1H)-ones 6a-i were screened for their in vitro cytotoxic activity against human hepatocellular carcinoma HepG2 and squamous cell carcinoma KB cancer lines. Compounds 6b and 6e had the best activity in the series, with IC₅₀ values equal to 1.33 μM. Compounds 6a-g exhibited weak or insignificant activity with liver cancer cell lines HepG2, while compounds 6a and 6g had more powerful activity in this sequence, with IC₅₀ values equal to 47.99 and 89.38 μM, respectively. ADMET properties showed that compounds 6b, 6e, and 6f possessed the drug-likeness behavior. Cross-docking results indicated that two hydrogen bonding interactions in the binding pocket, as potential ligand binding hot-spot residues for compounds 6b and 6e, may be one of the mechanisms of action responsible for the higher cytotoxic effect on HepG2 and KB cells.     

Synthesis and antineoplastic properties of (1H-1,2,3-triazol-1-yl)furazans

A method of 3-amino-4-[5-aryl(heteroaryl)-1H-1,2,3-triazol-1-yl)]furazan synthesis was optimized. Condensation of these compounds with 2,5-dimethoxytetrahydrofuran resulted in a series of previously unknown 4-[5-aryl(heteroaryl)-1H-1,2,3-triazol-1-yl)]-3-(pyrrol-1-yl)furazans. All target compounds were evaluated for both antimitotic microtubule destabilizing effect in a phenotypic sea urchin embryo assay and cytotoxicity in a panel of 60 human cancer cell lines. Pyrrolyl derivatives of triazolylfurazans were determined as antiproliferative compounds. The most potent microtubule targeting compounds 7a and 7e are of interest for further trials as antineoplastic agents.     

Marine bacterial inhibitors from the sponge-derived fungus Aspergillus sp.

Chromatographic separation of a crude extract obtained from the fungus Aspergillus sp., isolated from the Mediterranean sponge Tethya aurantium, yielded a new tryptophan derived alkaloid, 3-((1-hydroxy-3-(2-methylbut-3-en-2-yl)-2-oxoindolin-3-yl)methyl)-1-methyl-3,4-dihydrobenzo[e][1,4]diazepine-2,5-dione (1), and a new meroterpenoid, austalide R (2), together with three known compounds (3–5). The structures of the new compounds were unambiguously elucidated on the basis of extensive one and two-dimensional NMR (¹H, ¹³C, COSY, HMBC, and ROESY) and mass spectral analysis. Interestingly, the compounds exhibited antibacterial activity when tested against a panel of marine bacteria, with 1 selectively inhibiting Vibrio species and 2 showing a broad spectrum of activity. In contrast, no significant activity was observed against terrestrial bacterial strains and the murine cancer cell line L5178Y.     

Design,synthesis, cytotoxicity and 3D-QSAR analysis of new 3,6-disubstituted-1,2,4,5-tetrazine derivatives as potential antitumor agents

We synthesized two new series of 3-substituted-6-(2,5-dimethylpyrazol-1-yl)-1,2,4,5-tetrazines and analysed them for a potential role as antitumor agents. Twenty-two compounds were obtained, and four molecular structures were determined by X-ray diffraction analysis. Using flow cytometry and MTT assay, potential action on cell toxicity was determined for each of the compounds for four cancer cell lines. The potency and selectivity demonstrated by these compounds are dependent on the cancer cell line, where the following compounds were found the most promising agents against certain cell lines: compounds 1i and 1j for HL-60 cells, 1a and 1b on HCT116 cells, 1f on Hela cells and 2h on H1975 cells. The action exerted by these compounds is comparable to the well-known cancer treatment drug etoposide and higher than vatalanib. To arrive at the structural requirements for activity on each cell line, a SAR and 3D-QSAR analysis was carried out. From the 3D-QSAR models, steric and electronic features were identified in the aromatic centres, and were key components for cytotoxic activity on HL-60 cell lines. The cytometry results suggest that some tetrazine derivatives induce apoptosis on HCT116 cells.     

Synthesis and biological evaluation of indole-2-carbohydrazides and thiazolidinyl-indole-2-carboxamides as potent tubulin polymerization inhibitors

A new series of N’-(substituted phenyl)-5-chloro/iodo-3-phenyl-1H-indole-2-carbohydrazide (5, 6) and N-[2-(substituted phenyl)-4-oxo-1,3-thiazolidin-3-yl]-5-iodo/chloro-3-phenyl-1H-indole-2-carboxamide (7, 8) derivatives were synthesized and evaluated for their anticancer properties. Compounds 5a and 6b, selected as prototypes by the National Cancer Institute for screening against the full panel of 60 human tumor cell lines at a minimum of five concentrations at 10-fold dilutions, demonstrated remarkable antiproliferative activity against leukemia, non-small cell lung cancer, colon cancer, central nervous system (CNS) cancer, melanoma, ovarian cancer, renal cancer, and breast cancer (MCF-7) cell lines with GI₅₀ values < 0.4 μM. A subset of the compounds was then tested for their potential to inhibit tubulin polymerization. Compounds 6f and 6g showed significant cytotoxicity at the nM level on MCF-7 cells and exhibited significant inhibitory activity on tubulin assembly and colchicine binding at about the same level as combretastatin A-4. Finally, docking calculations were performed to identify the binding mode of these compounds. Group 5 and 6 compounds interacted with the colchicine binding site through hydrophobic interactions similar to those of colchicine. These compounds with antiproliferative activity at high nanomolar concentration can serve as scaffolds for the design of novel microtubule targeting agents.     

Design, synthesis and in vitro antitumor evaluation of novel diaryl urea derivatives bearing sulfonamide moiety

A novel series of diaryl urea derivatives bearing sulfonamide moiety have been designed and synthesized.Their in vitro antitumor effect against human cancer cell lines MX-1,A375,HepG2,Ketr3 and HT-29 was screened and evaluated by the standard MTT assay with sorafenib as the positive control.Some of the compounds showed significant inhibitory activity against multiple cell lines compared to sorafenib.In particular,2,6-dimethyl-4-{6-[3-(4-chloro-3-(trifluoromethyl)phenyl)urea]naphthalen-2-yl}sulfonyl morpholine(10d)was found to be the most potent against A375,HepG2 and Ketr3 with IC50values of 0.65–0.97mol/L,which were 5–20-fold more potent than sorafenib.Compound 10d emerged as a valuable lead for further optimization.     

Chemical-epigenetic method to enhance the chemodiversity of the marine algicolous fungus, Aspergillus terreus OUCMDZ-2739

Four new meroterpenoids identified as (R)-4-((2,2-dimethylchroman-6-yl)methyl)-3-(4-hydroxyphenyl)-5-methoxyfuran-2(5H)-one (1), 1-(2,2-dimethylchroman-6-yl)-3-(4-hydroxyphenyl)propan-2-one (2), (R,E)-3-(2,2-dimethylchroman-6-yl)-4-hydroxy-5-((2-(2-hydroxypropan-2-yl)-2,3-dihydrobenzofuran-5-yl)methylene)furan-2(5H)-one (3), methyl (R)-2-(2-(2-hydroxypropan-2-yl)-2,3-dihydrobenzofuran-5-yl) acetate (4), along with nine known compounds (5–13) were isolated from a chemical-epigenetic culture of Aspergillus terreus OUCMDZ-2739 with 10 μM trichostatin A (TSA). Under the same condition without TSA, A. terreus OUCMDZ-2739 produced different compounds (14–20), supporting that the chemical-epigenetic modification of fungi could enrich the chemodiversity of the fungal products. The cytotoxicity was observed for compound 8 against K562 cell, 9 against MCF-7 and K562 cells and 12 against MCF-7 cell with IC₅₀ values of 9.5, 10.1, 13.0 and 8.5 μM, respectively. Compounds 3, 8 and 17 exhibited stronger α-glucosidase inhibition than 1-deoxynojirimycin and acarbose (positive controls) with IC₅₀ values of 24.8, 1.2, 61.6, 191.7 and 555.1 μM, respectively. The enzyme kinetics study further indicated that compound 8 was an anticompetitive inhibitor with K_i value of 1.42 μM.     

A convenient ultrasound-promoted synthesis of some new thiazole derivatives bearing a coumarin nucleus and their cytotoxic activity

Successful implementation of ultrasound irradiation for the rapid synthesis of a novel series of 3-[1-(4-substituted-5-(aryldiazenyl)thiazol-2-yl)hydrazono)ethyl]-2H-chromen-2-ones 5a-h, via reactions of 2-(1-(2-oxo-2H-chromen-3-yl)ethylidene) thiosemicarbazide (2) and the hydrazonoyl halides 3(4), was demonstrated. Also, a new series of 5-arylidene-2-(2-(1-(2-oxo-2H-chromen-3-yl)ethylidene)hydrazinyl)thiazol-4(5H)-ones 10a-d were synthesized from reaction of 2 with chloroacetic acid and different aldehydes. Moreover, reaction of 2-cyano-N'-(1-(2-oxo-2H-chromen-3-yl)ethylidene)-acetohydrazide (12) with substituted benzaldehydes gave the respective arylidene derivatives 13a-c under the conditions employed. The structures of the synthesized compounds were assigned based on elemental analyses and spectral data. Also, the cytototoxic activities of the thiazole derivative 5a was evaluated against HaCaT cells (human keratinocytes). It was found that compound 5a possess potent cytotoxic activity.     

Design,synthesis and docking studies of new hydrazinyl-thiazole derivatives as anticancer and antimicrobial agents

Increase in the number of infections caused by pathogenic microbes in cancer patients has prompted the searcher to invest in the development of agents having dual anticancer and antimicrobial properties. The present study is concerned with synthesis and screening for anticancer and antimicrobial activity of a series of 5-hydrazinyl-2-(2-(1-(thien-2-yl)ethylidene)hydrazinyl)thiazole derivatives. The structure elucidation of the synthesized hydrazinyl thiazole derivatives was illustrated by spectroscopic and elemental analysis. All the newly synthesized compounds 5a-p were evaluated for in-vitro cytotoxic activity against breast carcinoma (MCF-7 cell line), hepatocellular carcinoma (HePG-2) and colorectal cancer (HCT-116) cell lines using MTT assay method. Compounds 5 g, 5h showed broad spectrum activity against three cancer cell lines with IC₅₀ ranged from 3.81 to 11.34 µM in compared to the reference drug Roscovitine (IC₅₀ = 9.32 to 13.82 µM), while compounds 5 l and 5 m were found to be more selective against HePG-2 and HCT-116 cell line (IC₅₀ = 9.29 and 8.93 µM respectively) and compound 5j was more selective against HePG-2 and MCF-7 cell lines (IC₅₀ = 6.73 and 10.87 µM respectively). The inhibitory activity of the most promising compounds was tested against the EGFR and ARO enzymes and were further tested for apoptosis and Annexin V/PI staining. The results of enzyme-based tests revealed that the tested compound 5j has a dual inhibitory effect on the EGFR and ARO enzymes with IC₅₀ = 82.8 and 98.6 nM respectively in compared to the reference drugs Erlotinib and Letrozole (IC₅₀ = 62.4 and 79 nM respectively). Furthermore, the majority of the tested hydrazinyl thiazole derivatives exhibited significant antimicrobial activity against the used pathogenic microbes species. Compounds 4b, 5h, 5j and 5 m exerted a good antibacterial and antifungal activity against all tested pathogenic microbes. Therefore, it was concluded that compounds 5 h, 5j and 5 m proved to possess dual anticancer and antimicrobial agent and may serves as a useful lead compounds in search for further modification or derivatization to give more potent and selective agents.     

Four new ginkgolic acids from Ginkgo biloba

Four new compounds, 2-hydroxy-6-(12′-hydroxyheptadec-13′(E)-en-1-yl)benzoic acid (1), 2-hydroxy-6-(13′-hydroxyheptadec-11′(E)-en-1-yl)benzoic acid (2), 2-hydroxy-6-(10′-hydroxypentadec-11′(E)-en-1-yl)benzoic acid (3), and 2-hydroxy-6-(11′-hydroxypentadec-9′(E)-en-1-yl)benzoic acid (4) were isolated from the leaves of Ginkgo biloba and the structures of new ginkgolic acids were deduced on the basis of spectroscopic methods and chemical means. Compounds 1 and 2, and 3 and 4 examined as an inseparable mixture of hydroxyl and double bond positional isomers, were ultimately defined by total synthesis. Compounds 1–4 showed moderate lipid droplets accumulation inhibitory activity on mouse pre-adipocyte cell line, MC3T3-G2/PA6.     

Design, synthesis, and cytotoxicity of 4-sulfonamide substituted benzamidobenzimidazolones and an acyl benzimidazolone

4-Sulfonamide substituted benzamidobenzimidazolones were designed and docked into the active site model of CDK2, using an oxindole inhibitor as the template. Compounds 6a-6i were then prepared from the reaction of the sulfonyl chloride 1 with different amines to give the corresponding acids (2a-2i), which were converted to their corresponding acyl chlorides (3a-3i). Reaction of 3a-3i with o-nitrophenylhydrazine afforded the respective nitro derivatives (4a-4i). The nitro groups were then reduced to give the corresponding amines (5a-5i), which, upon reaction with ethyl chloroformate, the target compounds (6a-6i) were produced. Target benzimidazolone derivatives (9a-9e) were also prepared from the reaction of isopropenyl benzimidazolone (8) with different sulfonyl or acyl chlorides. The target compounds were then tested by a modified 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay against the cancer cell lines, Hep G2, HT-29, CL1-5 and AGS. Despite similar binding properties of the flexible benzamidobenzimidazolones and rigid cytotoxic oxindole inhibitors at the active site of CDK2, biological screening results indicated that benzamidobenzimidazolones did not exhibit significant cell growth inhibition in vitro. Their analogue, 3-acyl benzimidazolone (12), however, revealed cytotoxicity similar to that of the reference oxindole inhibitor.     

Synthesis and evaluation of antiproliferative activity of substituted N-(9-oxo-9H-xanthen-4-yl)benzenesulfonamides

Several novel N-(9-oxo-9H-xanthen-4-yl)benzenesulfonamide derivatives were prepared as potential antiproliferative agents. The in vitro antiproliferative activity of the synthesized compounds was investigated against a panel of tumor cell lines including breast cancer cell lines (MDA-MB-231, T-47D) and neuroblastoma cell line (SK-N-MC) using MTT colorimetric assay. Etoposide, a well-known anticancer drug, was used as a positive standard drug. Among synthesized compounds, 4-methoxy-N-(9-oxo-9H-xanthen-4-yl)benzenesulfonamide (5i) showed the highest antiproliferative activity against MDA-MB-231, T-47D, and SK-N-MC cells. Furthermore, pentafluoro derivatives 5a and 6a exhibited higher antiproliferative activity than doxorubicin against human leukemia cell line (CCRF-CEM) and breast adenocarcinoma (MDA-MB-468) cells. Structure–activity relationship studies revealed that xanthone benzenesulfonamide hybrid compounds can be used for the development of new lead anticancer agents.     

Synthèse des 2-hydroxy-7-〚benzimidazol-2-yl〛-méthyl-5-méthylpyrazolo〚1,5-a〛pyrimidines à partir de la 4-hydroxy-6-méthylpyran-2-one

Condensation of 3-amino-5-hydroxypyrazole 1 with triacetic acid lactone 2 in refluxed alcohols afforded 2-hydroxy-5,7-dimethylpyrazolo〚1,5-a〛pyrimidine 3 beside to 7-alkoxycarbonylmethyl-2-hydroxy-5- methylpyrazolo〚1,5-a〛pyrimidine 4. Action of hydrazine on compounds 4 yielded 7-hydrazinocarbonylmethyl-2-hydroxy-5-methylpyrazolo〚1,5-a〛pyrimidine 5. Condensation of o-phenylenediamines 6 with hydrazide 5 to melting reactants afforded 2-hydroxy-7-〚benzimidazol-2-yl〛methyl-5-methylpyrazolo〚1,5-a〛pyrimidines 7. Structures of the obtained products have been assigned by means of spectroscopic measurements.     

Identification and synthesis of volatiles released by the myxobacterium Chondromyces crocatus

Cultures of the myxobacterium Chondromyces crocatus on agar plates were analysed by closed-loop-stripping analysis or solid phase micro extraction. The odour profiles consist mainly of pyrazines, sesquiterpenoids and some aromatic compounds, summing up to more than 50 components. Several new pyrazines as 2-(1-hydroxy-1-methylethyl)-3-methoxypyrazine (9), 2-(1-hydroxy-1-methylpropyl)-3-methoxypyrazine (10), and 2-(1-hydroxy-2-methylpropyl)-3-methoxypyrazine (11) were identified besides several known pyrazines. A major pyrazine occurring in most samples was 2,5-bis-(1-methylethyl)pyrazine (3). While the well known sesquiterpenoid geosmin (1) was present in low amounts, the related compound (1(10)E,5E)-germacradien-11-ol (21) was identified in most samples in larger quantities. Other prominent sesquiterpenoids not reported before from microorganisms were (6S,10S)-6,10-dimethylbicyclo[4.4.0]dec-1-en-3-one (16), which was accompanied by smaller amounts of several derivatives. The biosynthesis of these compounds is discussed in relation to the recently proposed biosynthetic pathways to 1 and 21.     

Sesquiterpenoid with new skeleton from Chloranthus henryi

Dayejijiol (1), a novel sesquiterpene with a new carbon skeleton, and a novel labdane-type diterpenoid (13S)-13-hydroxy-19-methoxy-5αH-8(17), 14-labdadien (3), together with three known compounds chloranthalactone A (4), shizukanolide (5), shizukolidol (6) were isolated from Chloranthus henryi Hemsl. Their structures were established by a combination of 1D and 2D NMR spectroscopic techniques. Compounds 1 and 5 exhibited anti-tumor activities against Hela and K562 human tumor cell lines.     

The synthesis of cypridina etioluciferamine and the proof of structure of cypridina luciferin

An unambiguous synthesis of Cypridina etioluciferamine was accomplished in order to prove the structure of this important bioluminescent natural product. Several 2-aminopyrazine 1-oxides were synthesized in order to establish a spectroscopic method for determining the placement of substituents on the pyrazine nucleus of Cypridina etioluciferamine. Titanium tetrachloride was used to improve the yields of these compounds; for example, the yield of 2-amino-3-methyl-5-phenylpyrazine 1-oxide (19) from reaction of phenylglyoxal 1-oxime and α-aminopropionitrile was raised from 3% to 51% by the use of titanium tetrachloride. The pyrazine ring proton is found at τ 1·37 (DMSO-d₆). The isomeric 2-amino-3-methyl-6-phenylpyrazine 1-oxide (22) was similarly prepared and its pyrazine ring proton is found at τ 2·18. This large difference (0·81 ppm) in chemical shift was used to determine whether a 2-aminopyrazine 1-oxide was 5- or 6- substituted. Prepared in an analogous fashion were 2-amino-5-(indol-3-yl)-3-methylpyrazine 1-oxide (23) and 2-amino-5-(indol-3-yl)-3-(3-phthalimidopropyl)pyrazine 1-oxide (16). The structures of these compounds were verified by NMR spectroscopy. By treatment with Raney nickel and hydrogen gas, then 100% hydrazine hydrate, 16 was converted to 2-amino-3-(3-aminopropyl)-5-indol-3-ylpyrazine (5), isolated as the dihydrochloride. This compound, with the indole moiety definitely placed at C-5, is identical with Cypridina etioluciferamine dihydrochloride (IR, UV, TLC). These results show that the structures of Cypridina etioluciferamine and luciferin are correct as published.     

Iodine-catalyzed three-component one-pot synthesis of novel 1,8-dioxo-decahydroacridines derivatives bearing benzene sulfonamide moiety

An efficient synthetic method for 1,8-dioxo-decahydroacridines derivatives bearing the biologically active sulfonamide moiety is described. Aromatic aldehyde reacted with 5,5-dimethyl-1,3-cyclohexanedione and sulfanilamide, with molecular iodine as catalyst, to give 1,8-dioxo-decahydroacridines derivatives in high to excellent yield. The structures of these compounds were established on the basis of elemental (C, H and N) and spectral analysis (¹H NMR, ¹³C NMR, MS and FTIR). All the compounds were tested for their cytotoxic activity in vitro against three human tumor cell lines: human mammary cancer cells (MCF-7), human cervical carcinoma cells (Hela), and human lung cancer cells (A549) by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Most of them showed moderate to potent cytotoxic activity against the tested cell lines. Among them, the most active compound 4e exhibited more efficient activity (10.92 μM) against MCF-7 cells than cisplatin (11.06 μM).     

Synthesis of 5-substituted-3-[(2′S,3′S)-3′-hydroxy-2′-hydroxymethyltetrahydrofuran-3′-yl]-1,2,4-oxadiazoles and their epimers

5-Phenyl-3-[(2′R,3′S)-3′-hydroxy-2′-dimethoxymethyltetrahydrofuran-3′-yl]-1,2,4-oxadiazole 10a and its epimer 11a, 5-methyl-3-[(2′R,3′S)-3′-hydroxy-2′-dimethoxymethyltetrahydrofuran-3′-yl]-1,2,4-oxadiazole 10b and its epimer 11b were synthesized from cyanohydrin benzoates 8a, 9a and cyanohydrin acetates 8b, 9b, respectively, by treatment with hydroxylamine in methanol via intramolecular transacylation and subsequent cyclization of the corresponding amidoximes. Hydrolysis and reduction of the dimethoxymethyl groups in the above compounds gave the desired compounds 12a, 13a, 12b and 13b.