Diversity-oriented synthesis of tamoxifen-type tetrasubstituted olefins

A general synthetic scheme for tamoxifen-type tetrasubstituted olefins based on the novel Cu-catalyzed carbomagnesation across alkynyl(2-pyridyl)silane has been developed. A wide array of electronically and structurally diverse tetrasubstituted olefins can be prepared in a regiocontrolled, stereocontrolled, and diversity-oriented manner. Noteworthy features are that (i) the three aryl groups, which are believed to be important (essential) for anti-estrogenic activity, can be varied at will because they all stem from readily available aryl iodides, and (ii) any stereo- and regioisomers can, in principle, be prepared by simply changing the applying order of aryl iodides into the sequence.     

Copper-catalyzed allylation of carbonyl derivatives using allyl(2-pyridyl)silanes

[reaction: see text] We have developed an efficient copper-catalyzed allylation of carbonyl derivatives using allyl(2-pyridyl)silanes, in which the strong directing effect of the 2-pyridyl group was observed. A useful synthesis and allylation of substituted allyl(2-pyridyl)silanes is also described.     

XPS analysis (ESCA) of the surface composition of poly(styrene/2-hydroxyethyl methacrylate) microspheres produced by emulsifier-free emulsion polymerization

Polymer microspheres composed of various compositions of styrene and 2-hydroxyethyl methacrylate (HEMA) were produced by batch emulsifier-free emulsion polymerization. The HEMA content at the surface, [HEMA] _s , of the microspheres powdered by freeze-drying was determined by both quantitativeC ^1s /O ^1s analysis andC ^1s peak shape analysis of the x-ray photoelectron spectroscopic spectra. When the HEMA content in the microsphere, [HEMA] _p , was less than about 5 mole%, the [HEMA] _s values determined by the two different methods showed good agreement. At [HEMA]_p above 5 mole %, [HEMA]_s values determined by the first method were about 15 mole % greater than those determined by the second. They both showed a similar tendency with the [HEMA] _s being higher than the [HEMA] _p , e.g., when [HEMA] _p was 1 mole %, [HEMA] _s was 11 mole %. The intensity of the satellite peak due to the ^* transition of the benzene ring of the styrene component decreased with an increase in [HEMA] _p , to zero at 5 mole % of [HEMA] _p . These results indicate that the HEMA component is localized at the surface.Part CVIII of the series Studies on Suspension and Emulsion.     

Synthesis and pharmacological activity of 4-amino-5-chloro-2-methoxy-N-[(2S,4S)-1-ethyl-2-hydroxymethyl-4- pyrrolidinyl]benzamide (TKS159) and its optical isomers

Of 4-amino-5-chloro-2-methoxy-N-(1-ethyl-2-hydroxymethyl-4- pyrrolidinyl)benzamide, four optical isomers, (2S,4S)-1 (TKS159), (2S,4R)-25, (2R,4S)-26 and (2R,4R)-27, were prepared from optically active 4-amino-1-ethyl-2-hydroxymethylpyrrolidine di-p-toluenesulfonate [(2S,4S)-14, (2S,4R)-17, (2R,4S)-20 and (2R,4R)-23, respectively]. The requisites, (2S,4S)-14, (2S,4R)-17, (2R,4S)-20 and (2R,4R)-23, were prepared from a commercially available trans-4-hydroxy-L-proline. The absolute configurations of (2S,4S)-1 (TKS159), (2S,4R)-25, (2R,4S)-26 and (2R,4R)-27 were spectroscopically determined. Of the benzamide derivatives, four optical isomers, (2S,4S)-1, (2S,4R)-25, (2R,4S)-26 and (2R,4R)-27, showed a relatively potent affinity for 5-hydroxytryptamine 4 (5-HT4) receptors in a radioligand binding assay ([3H]GR113808). The activities of 25-27 were less effective than that of 1 for the gastric emptying of a phenol red semisolid meal in rats. All this suggests that the most potent of the isomers was 4-amino-5-chloro-2-methoxy-N-[(2S,4S)-1-ethyl-2- hydroxymethyl-4-pyrrolidinyl]benzamide (1).     

Glycation and insolubility of human lens protein.

To learn whether glycation plays a role in insolubilization or in senile cataractogenesis, the reactivity of lens protein from normal and senile cataractous lenses and individual crystallin prepared from human lens with various sugars [glucose, glucose-1-phosphate (G-1-P), glucose-6-phosphate (G-6-P) and fructose], and the insolubility of those proteins were determined. The reactivity of human lens protein to glucose was increased in a dose-dependent manner, and it was demonstrated that 17.9, 18.5 and 24 kDa proteins were susceptible to glycation with sugars. The study also showed that alpha-, beta-crystallins and high molecular weight (HMW) aggregate obtained from cataractous lens have some weak reactivity against sugars. It was demonstrated that the proteins obtained from normal lens of older age and from cataractous lenses have higher insolubilities to glucose than do normal younger ones. Measurement of glycosylated protein by affinity column chromatography revealed that cataractous lenses contained a larger amount of glycosylated protein than normal ones. These results suggest that there is an age-related increase of glycation in normal human lens protein, and that such glycation increases the amount of insolubilized protein with the effect of aging. The author also speculates that an abnormal acceleration of glycation in the human lens may induce senile cataract formation.     

Synthesis and pharmacological evaluation of pyrroloazepine derivatives as potent antihypertensive agents with antiplatelet aggregation activity

A series of 1-aminoalkyl-pyrrolo[2,3-c]azepin-8-one derivatives was synthesized and evaluated as alpha 1 adrenergic and serotonin 2 (5-HT2) receptor antagonists, with the aim of finding a novel antihypertensive agent potently exhibiting both activities. Some compounds with a 4-[4-(4-fluorobenzoyl)piperidino]butyl group at the 1-position exhibited both activities, and varied significantly in terms of the substituents at the 4-position of the pyrroloazepine ring. Among the compounds obtained in this study, (E)-1-[4-[4-(4-fluorobenzoyl)piperidino]-butyl]-4-hydroxyimino-7- methyl-1,4,5,6,7,8-hexahydropyrrolo[2,3-c]azepin-8-one (15a, SUN9221) displayed potent alpha 1-adrenergic antagonistic activity (pA2 = 8.89 +/- 0.21) and 5-HT2 antagonistic activity (pA2 = 8.74 +/- 0.22) in isolated guinea pig arteries. This compound exhibited antihypertensive activity and a duration of action equivalent to orally administered prazosin or doxazosin, 3 mg/kg, in conscious spontaneously hypertensive rats, as well as potent antiplatelet aggregation activity.     

Attenuation correction of SPECT imaging by dual energy method--quantification of 111In-labeled monoclonal anti-tumor antibody localization

Application of radiolabeled monoclonal anti-tumor antibodies for diagnosis and therapy has made remarkable progress in the past few years. Quantification of radiopharmaceutical localization is required adequate attenuation correction in SPECT imaging. Attenuation correction by transmission CT (TCT) data is one of the best method at present time. However, if a patient is moved between TCT and SPECT, this method is no more applicable. We developed a new attenuation correction algorithm by dual energy method, using 99mTc and 111In because of similarity of these linear attenuation coefficients. The new algorithm uses data of TCT with an external source of 99mTc, and requires another data from SPECT of 111In labeled monoclonal anti-tumor antibody, which are simultaneously obtained. TCT results in an attenuation map, which then serves as input into the final intrinsic correction algorithm to uncorrected SPECT data. In chest phantom experiment, the attenuation corrected SPECT images revealed nearly same distribution of actual radioactivity of 111In as compared to that of uncorrected one.     

Immunoactivity of polymer microspheres with their hydrophilic/hydrophobic heterogeneous surface sensitized with an antibody

Styrene/2-hydroxyethyl methacrylate polymer microspheres consisting of various polymer compositions were produced by emulsifier-free seeded emulsion polymerization technique. Using these microspheres, which should have hydrophilic/hydrophobic heterogeneous surface, the effects of surface hydrophilicity on the main, fundamental requirements for an immunomicrosphere — high colloidal stability, sensitive immunologic agglutinability and insensitive non-specific agglutinability — were studied in detail. There was a region of the surface hydrophilicity that satisfied the three requirements simultaneously.Part CII of the series Studies on Suspension and Emulsion.