Synthesis and biological evaluation of 4-fluoro-, 7-fluoro-, and 4,7-difluoro-5,6-dihydroxytryptamines.
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.
Kawase
M
M
Department of Medicinal Chemistry, School of Pharmacy, University of Kansas, Lawrence 66045.
Sinhababu
A K
AK
McGhee
E M
EM
Milby
T
T
Borchardt
R T
RT
D015115:5,6-Dihydroxytryptamine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects; D055598:Chemical Phenomena; D002621:Chemistry; D004563:Electrochemistry; D005461:Fluorine; D015394:Molecular Structure; D009447:Neuroblastoma; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D010084:Oxidation-Reduction; D014407:Tumor Cells, Cultured
C065059:5,6-dihydroxy-7-fluorotryptamine creatinine; C065058:5,6-dihydroxy-4-fluorotryptamine creatinine; C065060:4,7-difluoro-5,6-dihydroxytryptamine creatinine; D005461:Fluorine; D015115:5,6-Dihydroxytryptamine