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The 5,6-dihydroxytryptamine (5,6-DHT) derivatives 4-fluoro- and 7-fluoro-5,6-DHTs (26a,b) and 4,7-difluoro-5,6-DHT (26c) were synthesized from 3-fluoroanisole (1) and 1,4-difluoro-2,3-dimethoxybenzene (13), respectively. Efficient methods were developed for the conversion of 1 to 4-fluoro- and 7-fluoro-5,6-bis(benzyloxy)indoles (12a,b, respectively), and 13 to 4,7-difluoro-5,6-[( diphenylmethylene)dioxy]indole (19) via reductive cyclization of 2-nitro-beta-(dialkylamino)styrenes prepared in situ from 2-nitrotoluenes. Indoles 12a,b and 19 were then converted to 26a-c via the corresponding indole-3-acetonitriles. The fluorine-substituted 5,6-DHTs displayed increased phenol acidities, determined spectrophotometrically, and decreased inherent potential to undergo oxidation as determined by cyclic voltammetry. Fluorine substitution did not have a significant adverse effect on the cytotoxic potential as judged from the IC50 values of 117, 125, 135, and 92 microM for 26a,c and 5,6-DHT, respectively, for the inhibition of incorporation of [3H]thymidine into the DNA of neuroblastoma clone N-2a cells in culture. Surprisingly, 26a-c exhibited 32-, 23-, and 13-fold higher affinities, respectively, compared to 5,6-DHT for the serotonergic uptake system of N-2a cells as measured by the ability of 26a-c and 5,6-DHT to antagonize the uptake of [3H]5-HT into the N-2a cells. These desirable chemical and biological properties of 26a-c should make them useful tools for the study of the molecular mechanism of neurodegenerative action of 5,6-DHT.
M Kawase, and
A K Sinhababu, and
E M McGhee, and
T Milby, and
R T Borchardt
September 1985,
Journal of medicinal chemistry,
M Kawase, and
A K Sinhababu, and
E M McGhee, and
T Milby, and
R T Borchardt
January 1996,
Advances in experimental medicine and biology,
M Kawase, and
A K Sinhababu, and
E M McGhee, and
T Milby, and
R T Borchardt
January 1997,
Zeitschrift fur Naturforschung. C, Journal of biosciences,
M Kawase, and
A K Sinhababu, and
E M McGhee, and
T Milby, and
R T Borchardt
June 1983,
Journal of medicinal chemistry,
M Kawase, and
A K Sinhababu, and
E M McGhee, and
T Milby, and
R T Borchardt
May 1998,
Yao xue xue bao = Acta pharmaceutica Sinica,
M Kawase, and
A K Sinhababu, and
E M McGhee, and
T Milby, and
R T Borchardt
May 2013,
Bioorganic & medicinal chemistry letters,
M Kawase, and
A K Sinhababu, and
E M McGhee, and
T Milby, and
R T Borchardt
December 2018,
The Journal of organic chemistry,
M Kawase, and
A K Sinhababu, and
E M McGhee, and
T Milby, and
R T Borchardt
December 2013,
Organic letters,
M Kawase, and
A K Sinhababu, and
E M McGhee, and
T Milby, and
R T Borchardt
November 1975,
Nucleic acids research,
M Kawase, and
A K Sinhababu, and
E M McGhee, and
T Milby, and
R T Borchardt
January 2010,
Bioorganicheskaia khimiia,
