Synthesis and cytostatic evaluation of some 2-(5-substituted-2-oxoindolin-3-ylidene)-N-substituted hydrazine carbothioamide

Various substituted 2-(5-substituted-2-oxoindolin-3-ylidene)-N-substituted hydrazine carbothioamide 4a–g and 2-(5-substituted-1-(4-substituted benzyl)-2-oxoindolin-3-ylidene)-N-substituted hydrazine carbothioamide 5a–k were synthesized. The compounds were evaluated for their cytostatic activity against human Molt4/C8 and CEM T-lymphocytes as well as murine L1210 leukemia cells. Several of these compounds were endowed with low micromolar 50%-inhibitory concentration (IC₅₀) values, and some were virtually equally potent as melphalan. The most potent inhibitors against the murine leukemia cells were also most inhibitory against human T-lymphocyte tumor cells. 2-(5-fluoro-1-(4-fluorobenzyl)-2-oxoindolin-3-ylidene)-N-p-tolylhydrazine carbothioamide (5b) emerged as the most potent cytostatic compound among the tested compounds. The encouraging cytostatic data provide an adequate rationale for further modification of these molecular scaffolds.     

Synthesis and anti-HIV activity of 4-[(1,2-dihydro-2-oxo-3H-indol-3-ylidene) amino]-N(4,6-dimethyl-2-pyrimidinyl)-benzene sulfonamide and its derivatives

4-[(1,2-Dihydro-2-oxo-3H-indol-3-ylidene) amino]-N(4,6-dimethyl-2-pyrimidinyl)-benzene sulphonamide and its derivatives were synthesized by reaction of isatin and its derivatives with sulphadimidine. Their chemical structures have been confirmed by IR, ¹H NMR data and elemental analysis. Investigation of anti-HIV activity of compounds were tested against replication of HIV-1 (IIIB) and HIV-2 (ROD) strains in acutely infected MT-4 cells and the activity compared with standard azidothymidine. Among the compounds tested, 4-[(1,2-dihydro-2 oxo-3H-indol-3-ylidene)amino]-N(4,6-dimethyl-2-pyrimidinyl)-benzene sulphonamide and its N-acetyl derivative were the most active compounds.     

Synthesis and Antitumor Activity of Some New 2-Chloroethylnitrosoureas

The synthesis of a series of N-(2-chloroethyl)-N′-(9H-xanthen-9-yl)-N-nitrosoureas and N-(2-chloroethyl)-N′-(9H-thioxanthen-9-yl)-N-nitrosoureas is described. The title compounds were evaluated against NSCLCN6 L16 bronchial epidermoid carcinoma in vitro and some of them were found to be active. N-(2-chloroethyl)-N′-(2-methoxy-9H-xanthen-9-yl)-N-nitrosourea ( 8e ) was active against leukemia P388 tumor system in mice.     

含有替加氟的卵磷脂类似物设计、合成及抗癌活性

目的合成含有替加氟的以卵磷脂类似物作载体的缀合物,并测定其生物活性。方法将替加氟转化为羟烷基衍生物,六乙基亚磷酰三胺作磷酰化试剂,与羟烷基替加氟、1-十六烷基甘油及硫作用,经一锅法合成得到环甘油硫代磷脂羟烷基替加氟缀合物,通过三乙胺对环甘油硫代磷脂替加氟缀合物开环得到标题产物。结果得到新化合物9个(2a～c,3a～c,4a～c),其结构经IR,NMR和元素分析确证。结论体外活性测定表明,化合物4a对人体膀胱癌细胞的抑制效果比替加氟好。     

Synthesis characterization and biological evaluation of some alkoxyphthalimide derivatives of 3-(4-substituted phenyl)-6,6-diphenyl-3,3a-dihydro-2H-imidazo[2,1-b]pyrazolo[3,4-d][1,3]thiazol-7(6H)-one

A series of 2-N-ethoxyphthalimido 3-(4-substitutedphenyl)-6,6-diphenyl-3,3a-dihydro-2H-imidazo[2,1-b]pyrazolo[3,4-d][1,3]thiazol-7(6H)-one(7a–e) and 4-(4-substituted phenyl)-2-(N-ethoxyphthalimido amino)-7,7-diphenylimidazo[2′,1′:2,3][1,3]thiazolo[4,5-d] pyrimidin-8(7H)-one (9a–e) have been designed and synthesized starting from thiohydentoin (1). The structure of all synthesized compounds has been established by IR, ¹H NMR, ¹³C NMR and mass studies. These compounds have been screened for antimicrobial activities in order to evaluate the possibility of the derivatives to be used as potential chemotherapeutic agents.     

Synthesis and Authentication of Iodoazidophenpyramine,a Photoaffinity Reporter Ligand Previously used for Histamine H1-Receptor Labelling

The synthesis is described of aminophenpyramine ( 7 ) (N-{5-[2-(4-aminophenyl)ethananmido]pentanyl}-N′-(4-methoxybenzyl)-N-methyl-N′-(2-pyridinyl)-1,2-ethandiamine), its monoiodo- and diiodo-derivatives ( 8 and 9 ), and iodoazidophenpyramine ( 1 ). The last compound is synthesised by two different routes to confirm the identity of the [¹²⁵I]iodinated ligand previously made only in solution and used for characterisation of the histamine H₁-receptor protein. The procedures employ the novel intermediates 4-amino-3-iodo-phenylacetic acid ( 11 ) and 4-azido-3-iodo-phenylacetic acid ( 13 ). They have general applicability to the synthesis of non-radioactive iodinated photoaffinity receptor ligands which may be required for chemical authentication of the corresponding radiolabelled compounds.     

Zur Amino- und Amidomethylierung von N,N-Dimethylanilin und Abkömmlingen

Amino- and Amidomethylation of N,N-Dimethylaniline and Related Derivatives The reaction of N,N-dimethylaniline (4) with N-methylenemorpholinium chloride (10g) affords 2,4-bis(morpholinomethyl)-N,N-dimethylaniline (11g) via 4-(morpholinomethyl)-N,N-dimethylaniline (9g) as an intermediate. From 4-(dimethylaminomethyl)- or 4-(pyrrolidinomethyl)-N,N-dimethylaniline ( 9a and 9e ) and all dialkyl(methylene)iminium chlorides 10 so far used the quaternary salts 12 are formed, rather than the products 11 , which are aminomethylated twice at the aromatic nucleus. N-Chloromethylbenzamide (13a) or N-chloromethyl-N-methylbenzamide (13b) are shown to undergo reaction with N,N-dimethylaniline to form a mixture of the monoamidomethylation products 14 and 15 substituted in o- and p-position, resp., in addition to o,p-disubstituted compounds of type 16 . Upon treatment of 13a and 13b with the phenylogous aminal 9a instead of ring substitution amidoalkylation to quaternary salts of type 17 takes place.     

Biokinetic investigation of the photodynamic activity of new photosensitizers

Results of an in vivo biokinetic investigation of the photodynamic activity of a series of new photosensitizers including a tetraazachlorin derivative (2,3,3α,21α-tetrahydro-2-methyl-3α,8,13,18-tetraphenyl-5,10,15,20-tetraaza-1H,22H,24H-pyrrolo[3, 4-b]porphine), two difluoroboryl-substituted complexes of 3,3′-diphenylazadiisoindolylmethene {N,N-difluoroboryl-N-[3-(4-t-butylphenyl)-2H-isoindol-1-yl)]-N-[3-(4-t-butylphenyl)-1H-isoindol-1-yliden]amine and N,N-difluoroboryl-1-[3-(4-methoxyphenyl)-2H-isoindol-1-yl)]-N-[3-(4-methoxyphenyl)-1H-isoindol-1-yliden]amine}, and a sulfanyl-substituted phthalocyanine [1,8,15,22-tetrakis(t-butylsulfanyl)-29H, 31H-phthalocyanine] are reported. These compounds exhibit pronounced photodynamic activity in mice bearing solid Ehrlich ascites carcinoma and sarcoma S-37 upon intravenous injection as micellar suspensions in aqueous solutions (4%) of Cremophor EL and Proxanol 268. Acomparison of the tumor growth rate and the time of attaining a critical tumor volume in the test and control groups shows evidence for high photodynamic activity of the new photosensitizers.     

Synthesis, antiplatelet aggregation activity, and molecular modeling study of novel substituted-piperazine analogues

Abstract  

New carbamoylpyridine and carbamoylpiperidine analogues containing nipecotic acid scaffold were designed, synthesized, and evaluated for their platelet aggregation inhibitory activity. Molecular modeling investigation was performed and the impact of lipophilicity on activity was also discussed. Structure activity relationship among this series was obtained. N ¹-[1-(4-bromobenzyl)-3-piperidino-carbonyl]-N ⁴-(2-chlorophenyl)-piperazine hydrobromide (20), and 1,4-bis-[3-[N ⁴-(2-chlorophenyl)-N ¹-(piperazino-carbonyl)]-piperidin-1-yl-methyl]-benzene dibromide (30) are the most active antiplatelet aggregating compounds in this study, both at concentration of 0.06 μM.     

5-Lipoxygenase inhibitors

Ether containing compounds are claimed as inhibitors of 5-lipoxygenase (5-LO), useful in treating allergic and inflammatory diseases. Data are given for 11 compounds in an in vitro assay of inhibition of calcium ionophore-induced LTB₄ biosynthesis in human whole blood. In US5268379 (101] the syntheses of 22 compounds are described as examples, and the structure of an additional 24 compounds are described in a table. Two particularly preferred and specifically claimed compounds are 4-methoxy-4-[3-(1,2-dihydro-1-methyl-2-oxoquinolin-6-yl)methoxy)-trans-prop-1-enyi]tetra hydropyran (1) and 3-(4-methoxytetrahydropyran-4-yl)-N-[(1,2-dihydro-1-methyl-2-oxoquinolin-6-yl)met hyll-trans-propenyl amide (2).     

Synthesis of N-(2-chloroethyl)-N-nitrosocarbamoyl derivatives of biologically active polypeptide hormone fragments

N-(2-chloroethyl)-N-nitrosocarbamoyl derivatives of α-melanotropin and gastrin fragments were synthesized by the acylation of the peptides with active esters of N-(2-chloroethyl)-N-nitrosocarbamic acid. These compounds are supposed to be antitumor agents of low toxicity and increased selectivity.     

A new cerebroside from Uvaria tonkinensis var. subglabra

A new cerebroside, subglain A (1), together with five known compounds (2–6) have been isolated from the stems of Uvaria tonkinensis var. subglabra. The structure of 1 has been determined to be 1-O-β-D-glucopyranosyl-(2S,3S,4R,8Z,2′R)-2-[N-(2′-hydroxytetracosanyl)-N-(1″,2″-dihydroxyethyl)-amide]-8-tetradecene-1,3,4-triol by spectroscopic evidence. The known compounds were identified as schisandriside (2), erythritol (3), β-D-glucopyranose (4), kaempferol-3,7-O-α-L-dirhamnoside (5), and (+)-lyoniresinol (6).     

Diffusion of homologous N-alkyl-N-[2-(2,2-diphenyl-2-hydroxyacetyloxy)ethyl]-N,N-dimethyl-ammonium bromides through lipid membranes (author's transl)

Diffusion of Homologous N-Alkyl-N-[2-(2,2.diphenyl-2-hydroxyacetyloxy)ethyl]-N,N-dimethyl. ammonium Bromides through Lipid Membranes The diffusion of homologous N-Alkyl-N-[2-(2,2-diphenyl-2-hydroxyacetyloxy)ethyl]-N,N-dimethylammonium bromides through porous filters of cellulose nitrate soaked with n-octanol is studied. With hydrophilic compounds the diffusion through the lipid membranes is rate determining and thus a function of the membrane/water partition coefficient. The diffusion of lipophilic compounds however is independent of the partition coefficient, the rate-determining step is the diffusion through the stationary water layers. These results are consistent with the diffusion kinetics of the same compounds in the three-phase model water/n-octanol/water.     

An Exploration of the Structure-activity Relationships of 4−Aminoquinolines: Novel Antimalarials with Activity In-vivo

The structure-activity relationships of bisquinolines, a potentially important group of novel antimalarial drugs, were studied. The high-temperature (180?250°C) synthesis of 4?aminoquinolines, including bisquinolines, by nucleophilic displacement was both fast and efficient. Several bisquinolines including (±)-trans-N¹,N²-bis(7?trifluoroquin-olin-4?yl)cyclohexane-1,2?diamine and 1R,2R-(-)-, 1S,2S-(+)-, (±)-trans- and cis-N¹,N²-bis(7?chloroquin-olin-4?yl)cyclohexane-1,2?diamine exhibited potent activity against Plasmodium berghei in mice; (±)-trans-N¹,N²-bis(7?chloroquinolin-4?yl)cyclohexane-1,2?diamine was orally active. Our results indicate that these compounds conform to a putative receptor for quinoline antimalarials. In addition, a 7?haloquinoline linked by a heterocyclic bridge, at the 4?position, to another heterocycle (such as an acridine at the 9?position) maximally occupies the active site of our postulated target.     

Dithiocarbamates of Improved Efficacy for the Mobilization of Retained Cadmium from Renal and Hepatic Deposits

Abstract: The preparation and properties of two novel cadmium-mobilizing dithiocarbamates namely, sodium N-(4-methylbenzyl)-and sodium N-(4-methoxybenzyl)-4-O-(β-D-galactopyranosyl)-D-glucamine-N-carbodithioates derived from α-lactose and substituted benzylamines are described. These compounds are more effective than previously prepared compounds of this type for the mobilization of cadmium from its aged deposits in both the liver and the kidneys. An examination of the structural features of the more effective compounds for the mobilization of cadmium from its aged deposits reveals that the combination of a high molecular weight with a suitable amphipathic structure in which the polar and non-polar groups are in an appropriate balance are key features. A histopathological evaluation of the animals from which cadmium is removed by these compounds indicates no variations from the normal for the kidney and no evidence of hepatic damage resulting from the removal of the cadnium. On the basis of the trends observed in cadmium mobilizing efficacy, there are grounds for suspecting that agents which are significantly more effective than any prepared so far, should also be accessible.     

罗氟司特中3,5-二氯-4-氨基吡啶引入两个杂质的合成研究

目的 设计并合成罗氟司特中3,5-二氯-4-氨基吡啶引入的两个杂质3-(环丙甲氧基)-N-(3-氯-5-溴-4-吡啶基)-4-(二氟甲氧基)苯甲酰胺和3-(环丙甲氧基)-N-(3-氯-4-吡啶基)-4-(二氟甲氧基)苯甲酰胺。方法 以4-二氟甲氧基-3-羟基苯甲醛为起始原料经过亲核取代、氧化、酰氯化和酰胺化合成了目标化合物。结果 合成了目标化合物,并利用¹H-NMR、¹³C-NMR和MS确证了结构;HPLC归一化法测得样品质量分数分别为98.8%、99.8%。并证明这两个杂质存在于罗氟司特中。结论 这两种杂质的合成为罗氟司特中杂质的研究提供了依据。     

Phenolic and Terpenoid Constituents from the Sri Lankan Medicinal Plant Osbeckia aspera.

Abstract

A crude aqueous acetone extract of Osbeckia aspera. Blume (Melastomataceae), a plant from Sri Lanka used traditionally to treat liver disease, was fractionated by column and preparative paper chromatography, and the fractions were analyzed by high-performance liquid chromatography (HPLC) using diode array and mass spectrometric detection. Phenolic acids (gallic, protocatechuic, and ellagic acid), flavonol glycosides [quercetin 3-O.-β-galactopyranoside, quercetin 3-O.-β-glucopyranoside, kaempferol 3-O.-β-glucopyranoside, and kaempferol 3-O.-(6″-O.-p.-coumaroyl-β-glucopyranoside) (tiliroside)] and flavonol aglycones (quercetin and kaempferol) were identified by comparison of their retention times, UV and MS spectra with those of authentic standards. Five compounds from a methanol extract were identified by NMR spectroscopy as the flavonol glycosides, quercetin 3-O.-(3″-O.-acetyl-β-galactopyranoside) and kaempferol 3-O.-[2″,6″-di-O.-(E.,E.)-p.-coumaroyl-β-glucopyranoside], and the norsesquiterpenoids 6,9-dihydroxy-4,7-megastig-madien-3-one, 9-hydroxy-4,7-megastigmadien-3-one and 9-hydroxy-4-megastigmen-3-one. A crude water extract, 50% acetone extract and fractions from this extract, a 100% methanol extract, and three of the phenolic acids in the fractions were tested for in vitro. hepatoprotective activity against bromobenzene and 2,6-dimethyl-N.-acetyl p.-quinoneimine toxicity to HepG2 liver-derived cells. The crude water extract showed protective activity against both liver toxins, whereas the fractions and compounds were more protective against 2,6-dimethyl-N.-acetyl p.-quinoneimine than bromobenzene. Of the three phenolic acids present in the extracts that were tested, gallic and protocatechuic acids were more active at protecting the liver cells from the two toxic compounds than ellagic acid.     

4-甲氧羰基芬太尼非芳基类似物的合成及镇痛作用

报道了某些4-N-苯基或4-N-苯基与1-β苯基同时被某些非芳香基团替代的4-甲氧羰基芬太尼衍生物的合成及其镇痛活性。结果表明,4-N-苯基和1-β-苯基被某些适宜非芳香基团替代可保持强效镇痛活性。分子中不含苯(或芳)基的化合物4和6的镇痛活性分别是吗啡活性的695倍和818倍。讨论了结构与镇痛活性之间的关系。     

An efficient and practical EPC synthesis of β-amino acids from L-asparagine

The synthesis of enantiomerically pure β-arnino acids (1a-c) via an O-activated equivalent of β-homoserine is discussed. The chiral synthon 2 was planned to be represented by (S)-3-N,N-dibenzylamino-4-mesyloxybutanoic acid methyl ester (3) or by (S)-3-N,N-dibenzylamino-4-mesyloxybutanenitrile (6). Both intermediates should be approached from L-aspartic acid 4 or L-asparagine 5 through selective reduction of the α-carboxyl group. It turned out that only nitrile 6 was suitable for the envisioned β-amino acid synthesis, since alcohol 14 - the synthetic precursor of 3 - was unstable towards intramolecular nucleophilic attack to accomplish the chiral building block 15. Reaction of mesylate 6 with different ‘Gilman cuprates’ afforded the 3-N,N-dibenzylamino nitrile derivatives 22a-c, which could be readily deprotected to give the target compounds 1a-c in 23-36% overall yield from asparagine. In contrast Me₂Cu(CN)Li₂ as an example for higher order ‘Lipshutz cuprates’ did not afford the desired substitution product 22a. The optical integrity of the synthesis was established by coupling of the methyl ester 24 with chiral 1-phenylethyl isocyanate followed by appropriate NMR studies of carbamate 25.     

海岛轮环藤碱-N-氧化物的制备和结构

Oxidation of insularine (Ⅰ) with m-chloroperbenzoic acid yielded four insularine-N-oxides. Two of them are identical in every respect with our insularine-2β-N-oxide (Ⅱ) and insularine-2'β-N-oxide (Ⅲ), two rare examples of naturally occurring head-to-tail bisbenzyliso-quinoline N-oxides newly isolated from Cyclea sutchnenensis, which confirmed the structures of the two novel natural N-oxides. The other two are new. compounds and their structures have been established as insularine-2'α-N-oxide (Ⅳ) and insularine-2β-2'β-N, N-dioxide (Ⅴ), on the basis of spectral data (UV, IR. ¹HNMR, NOEDS AND MS) analysis.