Synthesis and antibacterial activity of 1-(2-fluorovinyl)-7-substituted-4-quinolone-3-carboxylic acid derivatives, conformationally restricted analogues of fleroxacin

The novel 1-(2-fluorovinyl)-4-quinolone-3-carboxylic acid derivatives Z-15a-c, E-15a-c, Z-16a-c, and E-16a-c, conformationally restricted analogues of fleroxacin (5), were synthesized, and their in vitro antibacterial activity was evaluated. A dehydrosulfenylation of a 2-fluoro-2-[(4-methoxyphenyl)sulfinyl]ethyl group was employed as a key step for the construction of a 2-fluorovinyl group at the N-1 position. It appeared evident that the Z-isomers Z-15a-c and Z-16a-c exhibited 2- to 32-fold more potent in vitro antibacterial activity than the corresponding E-isomers E-15a-c and E-16a-c. Furthermore, since Z-15b showed in vitro antibacterial activity and DNA gyrase inhibition comparable to that of 5, it was hypothesized that the conformation of Z-15b would be equivalent to the active conformer of 5. The results revealed that the antibacterial Z-1-(2-fluorovinyl)quinolone derivatives carry the novel N-1 substituent of the fluoroquinolones.     

Antibacterial and antifungal agents. VI. Pirfloxacin and related compounds: synthetic and microbiological studies

A new route to pirfloxacin, a fluorinated pyrrylquinolone with high broad-spectrum antibacterial activities, is described starting from 7-amino-1-ethyl-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid and 2,5-dimethoxytetrahydrofuran. When the reaction with the latter compound was carried out using the ethyl ester of the above acid the related pyrryl ester formed, which on alkaline hydrolysis gave pirfloxacin. The synthesis and antibacterial activities of the 1-allyl analogue of pirfloxacin and of 7-[2-(1-pyrrolidinomethyl)-1-pyrryl]-1-ethyl-1, 4-dihydro-4-oxoquinoline-3-carboxylic acid and its 6-fluoroderivative are also reported.     

Stereoselective total synthesis of (+)-licochalcone E

The synthesis of (+)-licochalcone E (1) was accomplished for the first time in 13 steps from aryl bromide (6) with 8% overall yield. Palladium-catalyzed Negishi-Reformatsky coupling reaction of compound 6 with ethyl 2-(tributylstannyl)acetate provided the aryl acetic ester (5), which was converted to aryl acetamide (4) via mixed anhydride formation. Chiral auxiliarymediated methylation of the (S)-4-benzyl-2-oxazolidinone-derived aryl acetamide (4) provided the key asymmetric benzylic methyl group in compound 1.     

Bisbenzothieno[3,2-b: 2',3'-e]pyridines

Heating potassium 3-aminobenzo[b]thiophene-2-carboxylate (1) with ethyl propiolate or ethyl 3-ethoxyacrylate in acetic acid yielded the ethyl 2-(6,12-Dihydro-bis[1]benzothieno[3,2-b:2',3'-e]pyridin-6-yl)acetate (3) as main product and 1,4-dihydro-[1]benzothieno[3,2-b]-4-pyridone (2) as by-product. The dihydropyridine (DHP) 3 was dehydrogenated with ammonium cerium nitrate (CAN) to give the pyridine (Py) 4. The half wave potential E(1/2) = 1.64 V showed that 3 was much more stable against oxidizing agents than the reference compound nifedipine with E(1/2) = 1.15 V. Alkaline saponification of the acetic acid ester 4 did not yield the corresponding acetic acid, because decarboxylation took place to form the methylpyridine 5.     

瑞戈非尼的合成工艺优化

本研究对抗肿瘤药瑞戈非尼(1)的合成工艺进行优化。4-氯吡啶-2-甲酸甲酯(3)与甲胺反应得4-氯-N-甲基吡啶-2-甲酰胺(4)。以四丁基溴化铵为催化剂,4与4-氨基-3-氟苯酚(5)在二(口恶)烷中反应得4-(4-氨基-3-氟苯氧基)-N-甲基吡啶-2-甲酰胺(6)。三光气与4-氯-3-三氟甲基苯胺(7)在甲苯和吡啶中反应得4-氯-3-(三氟甲基)苯异氰酸酯(8)。6与8在乙酸乙酯中缩合得瑞戈非尼无水物(2),2在氯化氢的乙酸乙酯溶液作用下成盐酸盐,再在丙酮/水中加入碳酸氢钠转化为1,纯度99.8%。优化后的工艺反应条件温和,操作简单,总收率65%(以3计),较适合工业生产。     

(2E,6E)-3,7-二甲基-8-羟基-2,6-辛二烯-1-醇乙酸酯的合成

目的合成(2E,6E)-3,7-二甲基-8-羟基-2,6-辛二烯-1-醇乙酸酯。方法以香叶醇为起始原料,经酯化、加成-消除、取代、氧化、重排反应制得目标化合物。结果各步中间体结构经核磁共振谱确证,最终目标产物结构经红外光谱和核磁共振谱确证,总收率为49.7%。结论通过实验探索出一条新的合成(2E,6E)-3,7-二甲基-8-羟基-2,6-辛二烯-1-醇乙酸酯的路线。     

烯丙基作为保护基团合成对烯丙基苯酚

用对溴苯酚为原料,与烯丙基溴反应以保护酚羟基;经格氏反应用烯丙基取代溴;然后去除烯丙基保护基,得到对烯丙基苯酚,总收率6％。     

Bioactive epoxides and hydroperoxides derived from naturally monoterpene geranyl acetate

Geranyl acetate (1) was oxidized thermally and photochemically using (mcpba, H₂O₂) respectively to obtain (E)-5-(3, 3-dimethyloxiran-2-yl)-3-methylpent-2-enyl acetate (2) and 3-(2-(3, 3-dimethyloxiran-2-yl) ethyl)-3-methyloxiran-2-yl) methyl acetate (3). On the other hand, photooxygenation of 1 with tetraphenyl porphin (TPP) as a photo sensitizer gave corresponding acitic acid 2,6-bis-hydroperoxy-7-methyl-3-methylene-oct-7-enyl-ester (4), acitic acid 7-hydroperoxy-3,7-dimethyl-octa-2,5-dienyl ester (5) and Acitic acid 3-hydroperoxy-7-methyl-3,7-dimethyl-octa-1,6-dienyl ester (6). Antifungal studies were carried out on geranyl acetate and its derivatives. Studies on the antifungal activity especially Microsporum gypsum, Trichophyton vercossum and Candida tropicalis showed that geranyl acetate, its epoxide and hydroperoxide derivatives have good antifungal action.     

Isomerization of (Z,Z) to (E,E)1-bromo-2,5-bis-(3-hydroxycarbonyl-4-hydroxy)styrylbenzene in strong base: probes for amyloid plaques in the brain.

In developing probes for detecting beta-amyloid (Abeta) plaques in the brain of Alzheimer's disease (AD), we have synthesized 1-bromo-2,5-bis-(3-hydroxycarbonyl-4-hydroxy)styrylbenzene (5, BSB). Due to the presence of two double bonds, formation of four different isomers is possible. Four isomers, E,E-5, E,Z-5, Z,E-5, and Z,Z-5, were prepared. Surprisingly, all showed strong fluorescent labeling of Abeta plaques in the brain of postmortem brain sections of patients with confirmed AD. In vitro binding assay also showed that all four isomers of BSB (E,E-5, E,Z-5, Z,E-5, and Z,Z-5) displayed a similar high binding affinity inhibiting the binding of [(125)I]E,E-6, 1-iodo-2,5-bis-(3-hydroxycarbonyl-4-methoxy)styrylbenzene (IMSB) to Abeta(1-40) aggregates. The inhibition constants (K(i)) of E,E-5, E,Z-5, Z,E-5, and Z,Z-5 were 0.11 +/- 0.01, 0.19 +/- 0.03, 0.27 +/- 0.06, and 0.13 +/- 0.02 nM, respectively. Due to the fact that geometric stability of these styrylbenzenes is unknown, and the conversion of Z,Z-5 to E,E-5 may occur automatically in the binding or labeling assaying conditions, we have investigated the kinetics of conversion of Z,Z-5 to E,E-5 by NMR in D(2)O/NaOD at elevated temperatures (70, 95, and 115 degrees C). The activation energy was determined to be 14.15 kcal/mol. The results strongly suggest that the isomeric conversion at room temperature in aqueous buffer solution is unlikely. All of the styrylbenzene isomers clearly showed potential as useful tools for studying Abeta aggregates in the brain. The data suggest that, despite the rigidity of this series of styrylbenzenes, the binding sites on Abeta aggregates may have certain flexibility and the binding pockets could be adaptable for binding to other smaller ligands. Such information could be exploited to develop new ligands for detecting amyloid plaques in AD.     

Acetoxy-substituted 1,1,2-triphenylbut-1-enes with antiestrogenic and mammary tumor inhibiting properties

1,1,2-Triphenylbut-1-enes (E- and Z-10-12), which are substituted with one p- and one m-acetoxy group in two different aromatic rings, were synthesized. The E and Z isomers were isolated, and their identity was established by 1H NMR spectroscopy. A study of the structure-activity relationship was carried out with regard to estradiol receptor affinity in vitro, estrogenic and antiestrogenic properties (mouse), inhibition of the hormone-dependent human MCF7 breast cancer cell line in vitro, and the hormone-dependent MXT mammary tumor of the mouse in vivo. Among the tested compounds, (E)- and (Z)-1-(3-acetoxyphenyl)-1-(4-acetoxyphenyl)-2-phenylbut-1-enes+ ++ (E-10 and Z-10) and (Z)-1-(3-acetoxyphenyl)-1-phenyl-2-(4-acetoxyphenyl)-but-1-ene (Z-12) proved to be partial antiestrogens, which lead to an inhibition of the MCF7 cell line. They exert a growth-inhibiting activity on the hormone-dependent MXT mammary carcinoma of the mouse. In the case of E-10 and Z-10, this effect is only slightly weaker than that of 1,1-bis(4-acetoxyphenyl)-2-phenylbut-1-ene (13) and tamoxifen. Under the applied experimental conditions, there were no significant changes of uterine weight as an indicator of estrogenic side effects.     

硫酸二乙酯作乙基化剂制备-7氯-1-乙基-6-氟1,4-二氢-4-氧喹啉-3-羧酸的工艺改进

本文采用硫酸二乙酯与7-氯-6-氟-4-羟基喹啉-3-羧酸乙酯反应,然后用氢氧化钠液水解得7-氯-1-乙基-6-氟-1,4-二氢-4-氧喹啉-3-羧酸。其总收率为80％,此法降低了原料成本,简化了工艺,适合工业生产。     

Metabolism of citral, an alpha,beta-unsaturated aldehyde, in male F344 rats

Citral is a naturally occurring aliphatic aldehyde of the terpene series and is an isomeric mixture of geranial and neral. It is the main component (approximately 80%) of lemongrass oil, which is found in all citrus fruits and used extensively in the food, cosmetic, and detergent industries. In this study, urinary metabolites of citral in male F344 rats were characterized and identified by comparison with synthetic standards of known stereochemistry. Stereospecific oxidation of citral at the C-8 methyl was investigated, as was the hydrolytic sensitivity of biliary and urinary metabolites. For metabolite identification, urine was collected over dry ice for 24 hr after a single po 500 mg/kg dose of [14C]citral. Elimination in urine was rapid, with approximately 50% of the dose excreted within 24 hr. The urine was fractionated by reverse-phase HPLC, monitoring both radioactivity and UV. Synthetic standards were prepared; a comparison of their spectra with the isolated metabolites was used for identification. Citral was rapidly metabolized and excreted as metabolites, including several acids and a biliary glucuronide. Seven urinary metabolites were isolated and identified: 3-hydroxy-3,7-dimethyl-6-octenedioic acid; 3,8-dihydroxy-3,7-dimethyl-6-octenoic acid; 3,9-dihydroxy-3,7-dimethyl-6-octenoic acid; E- and Z-3,7-dimethyl-2,6-octadienedioic acid; 3,7-dimethyl-6-octenedioic acid; and E-3,7-dimethyl-2,6-octadienoic acid. Although citral is an alpha,beta-unsaturated aldehyde and has the potential of being reactive, the urinary metabolites of citral appear to arise from metabolic pathways other than nucleophilic addition to the double bond.     

碱和水份对7-氯-6-氟-4-羟基喹啉-3-羧酸乙酯的N-或O-乙基化产物比例的影响

7-氯-6-氟-4-羟基喹啉-3-羧酸乙酯(3)的乙基化使用无水 K_2CO_3或无水 Na_2CO_3作脱酸剂,用HPLC 法测定 N-及 O-乙基化物(2与1)的相对含量。考察了溶剂中水份对2和1生成比例的影响。     

Synthesis and carcinogenic activity of 5-fluoro-7-(oxygenated methyl)-12-methylvenz[a]anthracenes.

Treatment of 7,12-benz[a]anthraquinone (2) with methylmagnesium iodide or methyllithium yields mixtures of cis- and trans-7,12-dihydro-7,12-dihydroxy-7,12-dimethylbenz[a]anthracenes (3a,b), in which the ratio of cis to trans lies in the 3--4:1 region. Each isomer afforded high yields of 7-chloromethyl-12-methylbenz[a]anthracene (5) on treatment with hydrogen chloride in ethyl acetate. Similarly, 5-fluoro-7,12-benz[a]anthraquinone (8) afforded a mixture of cis- and trans-5-fluoro-7,12-dihydro-7,12-dihydroxy-7,12-dimethylbenz[a]anthracenes (9) which yielded 7-chloromethyl-5-fluoro-12-methylbenz[a]anthracene (10) on treatment with HCl. The chloromethyl compounds, 5 and 10, yielded 7-acetoxymethyl-12-methylbenz[a]anthracene (6) and 7-acetoxymethyl-5-fluoro-12-methylbenz[a]anthracene (11) on treatment with acetate ion. Hydrolysis of 6 and 11 yielded 7-hydroxymethyl-12-methylbenz[a]anthracene (7) and 5-fluoro-7-hydroxymethyl-12-methylbenz[a]anthracene (12), respectively. Since neither 11 nor 12 is appreciably carcinogenic, the carcinogenic metabolism of 7,12-dimethylbenz[a]anthracene (DMBA) probably does not involve attack at the 7-methyl group.     

Nitrosation of glycine ethyl ester and ethyl diazoacetate to give the alkylating agent and mutagen ethyl chloro(hydroximino)acetate

Whereas nitrosation of secondary amines produces nitrosamines, amino acids with primary amino groups and glycine ethyl ester were reported to react with nitrite to give unidentified agents that alkylated 4-(p-nitrobenzyl)pyridine to produce purple dyes and be direct mutagens in the Ames test. We report here that treatment of glycine ethyl ester at 37 degrees C with excess nitrite acidified with HCl, followed by ether extraction, gave 30-40% yields of a product identified as ethyl chloro(hydroximino)acetate [ClC(=NOH)COOEt, ECHA] and a 9% yield of ethyl chloroacetate. The ECHA was identical to that synthesized by a known method from ethyl acetoacetate, strongly alkylated nitrobenzylpyridine, and may have arisen by N-nitrosation of glycine ethyl ester to give ethyl diazoacetate, which was C-nitrosated and reacted with chloride to give ECHA. Nitrosation of ethyl diazoacetate also yielded ECHA. Ethyl nitroacetate was not an intermediate as its nitrosation did not produce ECHA. ECHA reacted with aniline to give ethyl (hydroxamino)(phenylimino)acetate [PhN=C(NHOH)CO2Et]. This product was different from ethyl [(phenylamino)carbonyl]carbamate [PhNHC(=O)NHCO2Et], which was synthesized by reacting ethyl isocyanatoformate (OCN.CO2Et) with aniline. ECHA reacted with guanosine to give a derivative, which may have been a guanine-C(=NOH)CO2Et derivative. ECHA showed moderate toxicity and weak but significant mutagenicity without activation in Salmonella typhimurium TA-100 (mean, 1.31 x control value for 12-18 microg/plats) and for V79 mammalian cells (1.5-1.7 x control value for 60-100 microM). In conclusion, gastric nitrosation of glycine derivatives such as peptides with a N-terminal glycine might produce ECHA analogues that alkylate bases of gastric mucosal DNA and thereby initiate gastric cancer.     

基于Qrt-RNA技术筛选藏药湿生扁蕾抗溃疡性结肠炎肠纤维化活性成分的研究

目的：研究藏药湿生扁蕾抗溃疡性结肠炎肠纤维化的药效物质基础。方法采用2,4,6-三硝基苯磺酸（TNBS）诱导的大鼠溃疡性结肠炎肠纤维化模型,灌胃给予藏药湿生扁蕾用乙酸乙酯萃取的活性提取物,以硅胶色谱分离、薄层定性得到的活性部位,采用荧光定量 RT-PCR 法检测大鼠结肠组织胶原ⅠmRNA、胶原Ⅲ mRNA、α-SMA mRNA、E-cad mRNA 的表达,筛选其活性成分。结果湿生扁蕾乙酸乙酯萃取物分离得到的活性部位经纯化得到4个单体化合物,用光谱分析等鉴定为1-hydroxy-3,7,8-Trimethoxyxanthones、1,8-Dihydroxy-3,7-Dimethoxyx-anthones、1-hydroxy-3,7-Dimethoxyxanthones 和1,7-Dihydroxy-3,8-Dimethoxyxanthones,4种单体化合物对溃疡性结肠炎肠纤维化大鼠模型均有明显的活性。结论湿生扁蕾抗溃疡性结肠炎肠纤维化的物质基础集中在乙酸乙酯部位,活性成分主要体现为4种酮类化合物。     

Catechol estrogens of the 1,1,2-triphenylbut-1-ene type: relationship between structure, estradiol receptor affinity, estrogenic and antiestrogenic properties, and mammary tumor inhibiting activities

1,1,2-Triphenylbut-1-enes (26-35), which are substituted with one or two 3,4-diacetoxy groups or with one 3,4-diacetoxy and one 3- or 4-acetoxy group in two aromatic rings, were synthesized. The occurring E and Z isomers were isolated, and their identity was established by 1H NMR spectroscopy. A study on structure-activity relationship was carried out with regard to estradiol receptor affinity in vitro, estrogenic and antiestrogenic properties in the immature mouse, and inhibition of the hormone-dependent MXT mammary tumor of the mouse in vivo. Among the tested compounds, most of the 1,1-disubstituted 1,1,2-triphenylbut-1-enes (29, Z-30, Z,E-31) and (E)-1-(3-acetoxyphenyl)-1-phenyl-2-(3,4-diacetoxyphenyl)but- 1-ene (E-35) as well as its respective Z isomer (Z-35) exerted antiestrogenic properties. Compounds Z-30, Z,E-31, Z-35, and E-35 inhibited the growth of the hormone-dependent MXT tumor. The best antitumor effect without estrogenic side effects during therapy was shown by E-35.     

Examination of the nitric oxide production-suppressing component in Tinospora tuberculata

The component of aqueous Tinospora tuberculata extract that inhibits nitric oxide (NO) production was examined using macrophages activated by the addition of lipopolysaccharide. The aqueous extract was partitioned with ethyl acetate. The aqueous layer was fractionated with a Diaion column. The residue of the aqueous extract was extracted with methanol, and partitioned with ethyl acetate. The ethyl acetate layer was found to be associated with a distinct decrease in the NO level and inducible NO synthase. On further fractionation, the subfraction of E-3 showed high anti-NO activity. N-trans-Feruloyltyramine isolated from E-3 was identified as exhibiting strong anti-NO activity. This compound is the most active component of Tinospora tuberculata with respect to the suppression of NO production.     

Pethidin-Analoga mit eingeschränkter Konformation, 2. Mitt.: Stereoselektive Synthese von trans-4-Methyl-10b-carbethoxy-1,2,3,4,4a,5,6,10b-octahydrobenzo(f)chinolin

Pethidine Analogs with Restricted Conformation, II¹⁾: Stereoselective Synthesis of trans-4-Methyl-10b-ethoxycarbonyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinoline Compound 6 , readily available from 4 , reacts with benzylamine to give trans- 9 . The reaction is thermodynamically controled. N-methylation of trans- 9 yields 11 . This can be alkylated by allyl bromide with inversion at C-1 to yield 12 . Subsequent hydroboration and iodation furnish the heterocycle trans- 14 which is catalytically debenzylated to yield the title compound 2a . The configuration of 2 is nmr-spectroscopically assigned with the aid of trans-methoiodide 15a , trans- 1 , and trans- 16 . Compound 12 is converted to the carbinol 13 by hydroboration. Halogenation of 13 causes cyclisation to 14 which, when prepared by this route, fails to undergo hydrogenolysis to 2a . The hydroxy esters 4 , accessible from 3 , can be alkylated to 7 which in turn is oxidized to 8 . Halogen nitrogen exchange or reductive amination fail to yield 2a . Compound 3 resists cyanoethylation, whereas under identical conditions 5 is transformed into 6 by elimination.     

Synthesis of new 2-thiouracil-5-sulfonamide derivatives with biological activity

2-Thiouracil-5-sulfonylchloride 1 reacted with a series of aromatic and heterocyclic amines to give 2a-j. The same compound 1 was reacted with a series of sulphonamides giving different sulphonamides of type 3a-e. On the other hand compound 1 was allowed to react with p-aminoacetophenone givining compound 4 which in turn was allowed to react with derivatives of alkyl thiosemicarbazides to give thiosemicarbazones of type 5a-e, also compound 4 was monobrominated to give compound 6 which in turn was reacted thiosemicarbazones of some aldehydes to give the corresponding thiazole derivatives 7a-f. In the same time compound 4 was reacted with a series of aromatic and heterocyclic aldehydes givining chalcones 8a-g (Claisen-Schemidt reaction). Also compound 4 was allowed to react with a series of aromatic and heterocyclic aldehydes, ethyl cyano acetate and/or malononitrile, and ammonium acetate giving pyridine derivatives 9a-d and 10a-e respectively. The biological effects of some of the new synthesized compounds was also investigated.