On the Synthesis of Chocolate Flavonoids (Propanols, Butanals) in the Interstellar Medium.

Complex organic molecules are ubiquitous in star- and planet-forming regions as well as on comets such as on 67P/Churyumov-Gerasimenko, but their origins have remained largely unexplained until now. Here, we report the first laboratory detection of distinct C3 H8 O (propanol, methyl ethyl ether) and C4 H8 O (n-butanal, i-butanal) isomers formed within interstellar analog ices through interaction with ionizing radiation. This study reveals that complex organics with propyl (C3 H7 ) and butyl (C4 H9 ) groups can be synthesized easily in deep space and may act as key evolutionary tracers of a cosmic ray driven non-equilibrium chemistry in low temperature interstellar ices at 10 K. These processes are of vital importance in initiating a chain of chemical reactions leading to complex organics-some of which are responsible for the flavors of chocolate-not only in the interstellar medium, but also on comet 67P/Churyumov-Gerasimenko.

Radiosynthesis of 1-iodo-2-[11 C]methylpropane and 2-methyl-1-[11 C]propanol and its application for alkylation reactions and C-C bond formation.

The multitude of biologically active compounds requires the availability of a broad spectrum of radiolabeled synthons for the development of positron emission tomography (PET) tracers. The aim of this study was to synthesize 1-iodo-2-[11 C]methylpropane and 2-methyl-1-[11 C]propanol and investigate the use of these reagents in further radiosynthesis reactions. 2-Methyl-1-[11 C]propanol was obtained with an average radiochemical yield of 46 ± 6% d.c. and used with fluorobenzene as starting material. High conversion rates of 85 ± 4% d.c. could be observed with HPLC, but large precursor amounts (32 mg, 333 µmol) were needed. 1-Iodo-2-[11 C]methylpropane was synthesized with a radiochemical yield of 25 ± 7% d.c. and with a radiochemical purity of 78 ± 7% d.c. The labelling agent 1-iodo-2-[11 C]methylpropane was coupled to thiophenol, phenol and phenylmagnesium bromide. Average radiochemical conversions of 83% d.c. for thiophenol, 40% d.c. for phenol, and 60% d.c. for phenylmagnesium bromide were obtained. In addition, [11 C]2-methyl-1-propyl phenyl sulphide was isolated with a radiochemical yield of 5 ± 1% d.c. and a molar activity of 346 ± 113 GBq/µmol at the end of synthesis. Altogether, the syntheses of 1-iodo-2-[11 C]methylpropane and 2-methyl-1-[11 C]propanol were achieved and applied as proof of their applicability.

Synthesis of new N-acryl-1-amino-2-phenylethanol and N-acyl-1-amino-3-aryloxypropanols and evaluation of their antihyperlipidemic, LDL-oxidation and antioxidant activity.

As a part of our drug discovery program, we identified an alkaloidal amide i.e. Aegeline (V) isolated from the leaves of Aegle marmelos as a dual acting agent (antihyperlipidemic and antihyperglycemic). In continuation of this program, we synthesized new N-acyl-1-amino-2-alcohols (N-acrylated-1-amino-2-phenylethanol and N-acylated-1-amino-3-aryloxypropanols) via Ritter reaction and screened for their in-vivo antihyperlipdemic activity in Triton induced hyperlipidemia model, LDL-oxidation and antioxidant activity. Compounds 3, 11 and 13 showed good antihyperlipidemic activity, LDL-oxidation as well as antioxidant activity and comparable activity with marketed antidyslipidemic drug.

Reactivity of N-(omega-haloalkyl)-beta-lactams with regard to lithium aluminium hydride: novel synthesis of 1-(1-aryl-3-hydroxypropyl)aziridines and 3-aryl-3-(N-propylamino)propan-1-ols.

The reactivity of 4-aryl-1-(2-chloroethyl)azetidin-2-ones and 4-aryl-1-(3-bromopropyl)azetidin-2-ones with regard to lithium aluminium hydride has been evaluated for the first time. 4-Aryl-1-(2-chloroethyl)azetidin-2-ones were transformed into novel 1-(1-aryl-3-hydroxypropyl)aziridines through an unprecedented conversion of beta-lactams into 2,3-unsubstituted aziridine derivatives. Unexpectedly, 4-aryl-1-(3-bromopropyl)azetidin-2-ones underwent dehalogenation towards 3-aryl-3-(N-propylamino)propan-1-ols upon treatment with LiAlH(4). 1-(1-Aryl-3-hydroxypropyl)aziridines were further elaborated by means of ring opening reactions using benzyl bromide in acetonitrile towards 3-aryl-3-[N-benzyl-N-(2-bromoethyl)amino]propan-1-ols and using aluminium(iii) chloride in diethyl ether, affording 3-aryl-3-[N-(2-chloroethyl)amino]propan-1-ols.

Design, synthesis and evaluation of racemic 1-(4-hydroxyphenyl)-2-[3-(substituted phenoxy)-2-hydroxy-1-propyl]amino-1-propanol hydrochlorides as novel uterine relaxants.

Novel 1-(4-hydroxyphenyl)-2-[3-(substituted phenoxy)-2-hydroxy-1-propyl]amino-1-propanol hydrochlorides were designed based on the pharmacophore for potent uterine relaxant activity and by utilizing the principles of structural hybridization. The designed molecules were synthesized as racemates by a novel route and were evaluated for uterine relaxant activity in vitro on isolated rat uterus and in vivo in pregnant rats. Their cAMP-releasing potential was studied using rat uterus tissue homogenates by the cAMP [(3)H] assay, and cardiac stimulant potential was evaluated on isolated guinea pig right atrium. All compounds exhibited potent uterine relaxant activity in vitro and produced a significant delay in the onset of labour in pregnant rats; their cAMP-releasing potential was slightly less, while their cardiac stimulant potential was insignificant as compared to isoxsuprine hydrochloride.

Comparative studies on beta-adrenolytic potencies of some new phenoxyaminopropanol derivatives and celiprolol.

The influence of different substitutions in 4-position of the phenyl ring of three recently developed l-alkylamino-3-phenoxy-2-propanol derivatives on the beta-adrenolytic potency and tissue specificity has been investigated and compared to the cardioselective beta-adrenoceptor antagonist celiprolol. The pA2 values against the isoprenaline tachycardia in isolated right atria (beta 1) and the relaxation of tracheal muscle (beta 2) both of guinea-pigs were expressed as beta 1/beta 2 selectivity ratio. The efficiencies and cardioselectivity of 4-propoxycarbonylderivative (BL 345 Ac) as well as celiprolol were similar, whereas 4-propoxymetylsubstitution (FoA 34t) decreased the inhibiting potency to the heart tissue nearly three times. The elimination of the 4-substitutent leads to the total loss of cardioselectivity (FoA 04). In addition, the character of the 4-substition has also influenced the nonspecific membrane activity expressed as local anesthetic efficiency in experiments on rabbit eyes and guinea-pig skin.

[Preparation and pharmacologic characteristics of aryloxyaminopropanol derivatives with an assumed cardiovascular effect]. / Príprava a farmakologická charakteristika aryloxyaminopropanolových derivátov s predpokladaným kardiovaskulárnym pôsobením.

In an attempt to prepare drugs favourably influencing pathologically changed functions of the cardiovascular system, such as hypertension and ischemic cardiac disease, several chemical compounds were prepared in which benzhydrylpiperazine, alkyl, or substituted phenylpiperazine (fragments of the structures of calcium antagonists) were bound to the fundamental aryloxyamino-propanol skeleton (the carrier of beta-adrenolytic effect). The selected four compounds underwent basic pharmacological analysis. In experiments on the isolated spontaneously beating guinea-pig atria (beta 1), three compounds competitively inhibited the positively chronotropic effect of isoprenaline (pA2 = 6.40-7.24) and in experiments on the isolated tracheal guinea-pig muscle they antagonised the relaxation effect of isoprenaline beta 2, the pA2 values ranging from 5.90-7.58. It follows from the experiments on the isolated guinea-pig aorta contracted with 50 mM KCl that all compounds under study possess mild relaxation effects, the intensity of which is, however, lower than in the used standards flunarizine and verapamil.

Synthesis and antiplatelet activity of 1-tert-butylamino-3-(3-thienyloxy)-2-propanols.

The synthesis of new 1-tert-butylamino-3-(3-thienyloxy)-2-propanols by two alternative methods is described. Their initial antiplatelet activity evaluation against ADP, adrenaline, and collagen is reported, and the preliminary structure-activity relationships are established. The appropriateness of further pharmacological investigations, especially for the best compound of the series 1f, is indicated.

[Studies on antiulcer agents. III. Synthesis and antiulcer activity of phenylpropanol derivatives].

It was found that (+/-)ethyl 2-[2-(3-hydroxypropyl)-4-oxocyclohexylidene]-propionate (1), (+/-)ethyl 2-[2-(3-hydroxypropyl)-4,5-dimethoxyphenyl]propionate (2) and (+/-)3-[2-(3-hydroxypropyl)-4,5-dimethoxyphenyl]-2-butanone (3) had excellent antiulcer activities. In order to study structure-activity relationships, (+/-)2-[(3-hydroxypropyl)phenyl]cyclopentanone derivatives (4, 5) and (+/-)2-[(3-hydroxypropyl)phenyl]cyclopentanol derivatives (6, 7) were synthesized and tested for antiulcer activities. As a result, (+/-)2-[2-(3-hydroxypropyl)-4-methoxy-5-(2- piperidinoethoxy)phenyl]cyclopentanone (5k) exhibited potent antiulcer activities.

[Studies on antiulcer agents. IV. Synthesis and antiulcer activity of phenylpropanol derivatives].

It was found that (+/-)ethyl 2-[2-(3-hydroxypropyl)-4-oxocyclohexylidene-propionate (1), (+/-)ethyl 2-[2-(3-hydroxypropyl)-4,5-dimethoxyphenyl]propionate (2), (+/-)3-[2-(3-hydroxypropyl)-4,5-dimethoxyphenyl]-2-butanone (3) and (+/-)2-[2-(3-hydroxypropyl)-4-methoxy-5-(2- piperidinoethoxy)phenyl]cyclopentanone (4) had potent antiulcer activities. In order to study structure-activity relationships, (+/-)3-[(3-hydroxypropyl)phenoxy]-2-butanone derivatives (5, 6) were synthesized and tested for antiulcer activities. Among them, (+/-)3-[2-(3-hydroxypropyl)-4-methoxy-5-[3-(4- methylpiperidino)propoxy]phenoxy]-2-butanone.3/2 oxalate (6k) was selected as a preferred antiulcer agent.

[Studies on antiulcer agents. II. Synthesis and antiulcer activity of phenylpropanol derivatives].

It was found that gamma-irigermanal, obtained from the methanol extract of root of Iris germanica, exhibited a potent antiulcer activity. Therefore, this compound was selected as a lead-compound, and related compounds were synthesized and tested for antiulcer activities. It was found that (+/-) ethyl 2-[2-(3-hydroxypropyl)-4-oxocyclohexylidene]- propionate (1) had excellent antiulcer activities. Then phenylpropanol derivatives, obtained by changing from cyclohexane ring of 1 to benzene ring, were synthesized and tested for antiulcer activities in order to study structure activity relationships. As a result, (+/-) ethyl 2-[2-(3-hydroxypropyl)-4,5-dimethoxy-phenyl]propionate (2b) and (+/-) 3-[2-(3-hydroxypropyl)-4,5-dimethoxyphenyl]-2-butanone (5) were shown to have antiulcer activities.

Synthesis and enantiomeric purity determination of chiral 3-benzylglycidol, a key synthon for HIV protease inhibitors.

The detailed synthesis of (2R,3R)-3-benzylglycidol by the Sharpless asymmetric epoxidation route is described. The enantiomeric purity determination of this compound is complicated by the presence of small quantities of the diastereometric (2R,3S)-3-benzylglycidol from the asymmetric epoxidation of the cis-allylic alcohol, and the unreacted allylic alcohols that are not removed in the product isolation steps. We have developed a direct chiral HPLC method that can resolve all these components for the precise determination of enantiomeric excesses of chiral 3-benzylglycidols.

Mortality study of ethanol and isopropanol production workers at two facilities.

The mortality experience of alcohol process workers (N = 1031) from two chemical plants was followed from the early 1940s to 1983. Reported associations of the production of ethanol and isopropanol by the strong-acid process with upper respiratory tract cancers, heart disease, and lympho- and reticulosarcoma were tested with both external and internal comparisons. Excesses of cancers of the larynx, buccal cavity, and pharynx, based on very small numbers, were observed. There was one death due to sinus cancer. It could not be concluded that there were work-related effects on mortality due to heart disease or lympho- or reticulosarcoma. Workers assigned to the production of isopropanol by the weak-acid method showed no evidence of excess cancer mortality (0 observed, 1.9 expected cancer deaths). The absence of major risks among strong-acid workers can be explained by the initiation of engineering controls and health monitoring that took place after the original medical observations.

Synthesis of some 2-benzoxazolinone derivatives and their analgesic properties.

In this study, eight new 1-(2-benzoxazolinone-6-yl)-2-(4-arylpiperazine-1-yl)ethanol and -propanol derivatives have been prepared. Their structures have been elucidated by IR- and 1H-NMR-spectra and by elementary analysis. The analgesic activities of these compounds, using modified Koster's test have been investigated. 1-(5-Chloro-3-methyl-2-benzoxazolone-6-yl)-2-[4-(2-methoxyphenyl)p iperazine-1- yl]ethanol has been found more active than O-acetyl-salicylic acid, respectively.

Synthesis and oral antifungal activity of novel azolylpropanolones and related compounds.

To find orally active antifungal agents, novel imidazolyl- and 1,2,4-triazolylpropanolones I and related compounds II-IV were synthesized. Compounds I were derived from ketones V (method A), alpha-diketone IX (method B), alpha-hydroxy ketones X (method C), alpha-chloro ketone XII (method D), and enones VI (method E). Diols II, synthesized from I with NaBH4, were cyclized to five-membered cyclic compounds III by using N,N'-carbonyldiimidazole, thionyl chloride, N,N'-(thiocarbonyl)diimidazole, bromochloromethane, 2,2-dimethoxypropane, and cyclohexanone dimethyl ketal. Diols IV were synthesized from I by Grignard reaction (method F), hydroxymethylation of X (method G), and reaction of ketones XXI with 1-[(trimethylsily)methyl]-1,2,4-triazole (method H). Compounds I-IV were examined for their antifungal activities in vitro by evaluation of broth dilution MIC values against three species of fungi and the inhibitory effect on pseudomycelium of Candida albicans, and they were examined for oral efficacy in vivo against subacute systemic candidiasis in mice and superficial dermatophytosis in guinea pigs. Compounds 2, 12, 38, 39, and 92 exhibited strong oral antifungal activity. An asymmetric synthesis and the structure-activity relationships of the compounds examined are discussed.

An association of upper respiratory cancer with exposure to diethyl sulfate.

A morbidity and mortality study of workers at an alcohol manufacturing plant which included several weak acid isopropyl alcohol units and a strong acid ethanol unit is described. An excess mortality of upper respiratory cancer was found and associated with work on the strong acid ethanol unit. The strong acid ethanol process used resulted in high concentrations of diethyl sulfate, which has been shown to be carcinogenic in animals, and the unit, which closed on 1975, had significant opportunities for worker exposure to diethyl sulfate. These facts, plus previous reports of excess upper respiratory cancer on strong acid isopropyl alcohol units with similarly high concentrations of the animal carcinogen diisopropyl sulfate, lead to the tentative conclusion that diethyl sulfate was primarily responsible for the ethanol unit cancer cases. In the modern weak acid isopropyl alcohol plants, where only trace amounts of diisopropyl sulfate are present and exposures are much lower, the problems found on the old strong acid units do not exist.