| Summary: | 碩士 === 台北醫學院 === 藥學研究所 === 86 === Synthesis and Stereochemistry of Spirobenzylisoquinoline Analogues
JKL 1067 ( 2,3-methylenedioxy-9,10-dimethoxyspirobenzylisoquinoline ) (4),
a synthetic antiarrhythmic drug can slow down the heart rate and enhance the
cardiac contractility. In the previous study, three spirobenzylisoquinoline
analogues, show the equal or somewhat even more potent effect compared with
JKL 1067 (4) in cardiac tissues. In the present study, spirobenzylisoquinoline
26 were prepared based on the structure modification of these three analogues.
Protoberberine42 was synthesized from the Mannich condensation of the benzyl-
isoquinoline 41 with formalin and followed reaction with methiodide to yield
the N-methyltetrahydroprotoberberinium iodide 43. Finally, Stevens rearrange-
ment of 43 catalyzed by dimsyl sodium in DMSO gave the target compound 26.
In order to study the enantioselectivity of JKL 1067 (4) on cardiac tissue,
JKL 1067 (4) was prepared and then resoluted by S-(+)-binaphthylphosphoric
acid (53a) and R-(-)-binaphthylphosphoric acid (53b) to gave two enantiomers,
(-)-JKL 1067 (4a) and (+)-JKL 1067 (4b). Optical purity of the enatiomer was
conformed by specific rotation, chiral HPLC, and CD spectra. Analog 4, 4a, 4b
and 26 will be tested on the isolated cardiac tissue. Several spirobenzyliso-
quinoline 19, 20, 21, 22 and 25 were also well-resolved in a cellulose-base
chiral column by HPLC ( separation factor a = 1.3~2.8 ).
A computer program of Catalyst, was utilized to perform conformational analysis
of the fifteen analogues. Two three-dimensional pharmacophore models of hypo-R.V.
and hypo-L.A. were generated. These composed of two hydrogen bond acceptors
and three hydrophobic groups. Then we could use these models to search the
biosteric compounds from the several databases such as NCI, Minibiobyte and
Sample. The three-dimensional pharmacophore could be further utilized as one
of the tools to design more active antiarrythemic drug.
|
|---|
