Kuniko Hashigaki

Asymmetric synthesis of 1-alkyltetrahydroisoquinolines using chiral oxazolo[2,3-a]tetrahydroisoquinolines

Abstract A new method of synthesizing enantiomerically pure (S)- and (R)-alkyl- and 1-aryltetrahydroisoquinolines has been achieved starting from isochroman with (R)- or (S)-phenylglycinol.

Syntheses of chiral oxazolo[2,3-a]tetrahydroisoquinoline and its asymmetric alkylation. Synthesis of (S)-(−)- and (R)-(+)-sa1solidines

Abstract The isoquinolinium bromide (4), on treatment with base, underwent cyclization to give the chiral oxazolotetrahydroisoquinoline (5) with a high diastereoselectivity, which was converted to optically pure salsolidine.

Imbalance of Deoxyribonucleoside Triphosphates and DNA Double-strand Breaks in Mouse Mammary Tumor FM3A Cells Treated in vitro with an Antineoplastic Tropolone Derivative

The mechanism by which α,α‐bis(2‐hydroxy‐6‐isopropyltropon‐3‐yl)‐4‐methoxytoluene (JCI‐3661) kills mouse mammary tumor FM3A (F28–7) cells was studied. When the cells were exposed to the drug at 3.7 μM, the intracellular dNTP pool became unbalanced because of decreases in dGTP and dATP and an increase in dTTP. The pattern of the dNTP imbalance was the same as that caused by hydroxyurea. When JCI‐3661 was added to the culture medium, mature DNA strands broke, giving fragments of 100–200 kilobase pairs long as found by orthogonal‐field‐alternation gel electrophoresis. DNA strand breaks, detected by this technique, were observed in the cells at 12 h after the addition. The beginning of cell death was observed at about 14 h (trypan blue staining) or at about 12 h (colony‐forming ability) after cultivation Breaks in the single and double strands of DNA, as measured by alkaline and neutral filter elution assay, became evident 24 h after treatment with 3.7 μM JCI‐3661. Comparison of the ratio of single‐ and double‐strand breaks caused by JCI‐3661 to that following radiation suggested that JCI‐3661 broke only double strands. Cycloheximide inhibited both the breakage of double strands and the cell death caused by JCI‐3661. JCI‐3661 decreased DNA synthesis more than RNA or protein synthesis. The breaks in double strands of DNA were probably important in the cell death caused by JCI‐3661.

Synthesis of 7-substituted indolo [3,2-b]-quinoline derivatives

Indolo [3,2-b] quinoline derivatives [7b-j] having the substituent, such as a nitro, amino, methyl, halogen, methoxy, or hydroxy group were prepared by three methods

Synthesis of tropolone derivatives

The reaction of tropolones with the benzaldehyde diethyl acetals (10) afforded the 3-(α-ethoxybenzyl)tropolones (11) and α,α-bis(2-hydroxy-1-oxocyclohepta-2,4,6-trien-3-yl)toluenes (12).

Immunological studies on delayed hypersensitivity to phenytoin — I. A new method for preparing phenytoin antiserum

The present study was initiated to produce an antiserum to phenytoin with high specificity and sensitivity which would be suitable not only for determination of blood phenytoin concentration but also for induction of a hypersensitivity reaction to phenytoin in experimental animals. p-Aminophenytoin was synthesized and identified by means of IR, 1H-NMR and mass spectroscopy. BSA-phenytoin conjugate was prepared by using p-aminophenytoin, BSA and, as a coupling reagent, glutaraldehyde. Satisfactory response to immunization was achieved at a 9.8:1 molar ratio of p-aminophenytoin to BSA. The antiserum obtained from rabbits immunized with BSA-phenytoin conjugate exhibited practically no cross-reactivity with either phenytoin metabolites or other anti-epileptic drugs, indicating that this antiserum provides sufficiently high specificity. In our experiments, the lower limit for detecting phenytoin was 2 ng using RIA, whereas 200 ng was the minimum amount detectable by HPLC. Thus, by a difference of two orders of magnitude, the present RIA method shows a much higher sensitivity than that of HPLC, though we found a good correlation of simultaneous determinations of serum phenytoin between the two methods. Reproducibility of phenytoin determination in plasma was confirmed by calculating the coefficient of variance. The values were less than 10%.