TY - JOUR
T1 - Psoralenamines. 3. Synthesis, pharmacological behavior, and DNA binding of 5-(aminomethyl)-8-methoxy-, 5-[[(3-aminopropyl)oxy]methyl]-, and 8-[(3-aminopropyl)oxy]psoralen derivatives
AU - Buchardt, O
AU - Ebbesen, P
AU - Kanstrup, A
AU - Karup, G
AU - Nordén, B
AU - Ygge, B
AU - Nielsen, Peter E.
PY - 1985/8
Y1 - 1985/8
N2 - A series of derivatives of 5-(aminomethyl)-8-methoxypsoralens, 8-[(3-aminopropyl)oxy]psoralens, and 5-[[[3-(tri-methylammonio)propyl]methyl]-8-methoxypsoralen has been synthesized and their potential as PUVA reagents examined. While the DNA association constants of selected psoralens were found to be 10(5)-10(6)L mol-1, corresponding to efficient binding, flow linear dichroism studies indicated that only the 8-substituted psoralens bind to DNA by intercalation. Furthermore, the ability to photoinduce interstrand cross-links in calf thymus DNA, in vitro, was as efficient as that of 8-methoxypsoralen for the 8-substituted psoralens, which were up to 25 times as efficient as the 5-substituted psoralens. Four of the psoralens studied were radiolabeled and used to study photobinding to DNA. Analogously to the cross-binding results, the 8-substituted psoralens were more efficiently photobound than the 5-substituted, while only slight differences were found in the photobinding-cross-linking ratio. The photoreactivity of the aminopsoralens toward cyclohexene and 2'-deoxythymidine was enhanced compared to that of 8-methoxypsoralen, the effect being most pronounced when the amino group is close to the furocoumarin ring system. Most of the new compounds were less photocytotoxic than 8-methoxypsoralen to NHIK 3025 cells, in vitro, and they caused less light-induced DNA interstrand cross-linking, in situ, in these cells. A clear correlation between the photocytotoxicity and the DNA cross-linking ability of the psoralens was observed. Several of the derivatives showed more pronounced effects in the light-dependent skin thickening (inflammatory) test on mice than 8-methoxypsoralen. No correlation between DNA cross-linking capacity, in vitro, and skin phototoxicity was found for this series of psoralens.
AB - A series of derivatives of 5-(aminomethyl)-8-methoxypsoralens, 8-[(3-aminopropyl)oxy]psoralens, and 5-[[[3-(tri-methylammonio)propyl]methyl]-8-methoxypsoralen has been synthesized and their potential as PUVA reagents examined. While the DNA association constants of selected psoralens were found to be 10(5)-10(6)L mol-1, corresponding to efficient binding, flow linear dichroism studies indicated that only the 8-substituted psoralens bind to DNA by intercalation. Furthermore, the ability to photoinduce interstrand cross-links in calf thymus DNA, in vitro, was as efficient as that of 8-methoxypsoralen for the 8-substituted psoralens, which were up to 25 times as efficient as the 5-substituted psoralens. Four of the psoralens studied were radiolabeled and used to study photobinding to DNA. Analogously to the cross-binding results, the 8-substituted psoralens were more efficiently photobound than the 5-substituted, while only slight differences were found in the photobinding-cross-linking ratio. The photoreactivity of the aminopsoralens toward cyclohexene and 2'-deoxythymidine was enhanced compared to that of 8-methoxypsoralen, the effect being most pronounced when the amino group is close to the furocoumarin ring system. Most of the new compounds were less photocytotoxic than 8-methoxypsoralen to NHIK 3025 cells, in vitro, and they caused less light-induced DNA interstrand cross-linking, in situ, in these cells. A clear correlation between the photocytotoxicity and the DNA cross-linking ability of the psoralens was observed. Several of the derivatives showed more pronounced effects in the light-dependent skin thickening (inflammatory) test on mice than 8-methoxypsoralen. No correlation between DNA cross-linking capacity, in vitro, and skin phototoxicity was found for this series of psoralens.
KW - Animals
KW - Cell Division/drug effects
KW - Cell Line
KW - Cross-Linking Reagents
KW - DNA/metabolism
KW - Female
KW - Furocoumarins/chemical synthesis
KW - Hemolysis/drug effects
KW - Humans
KW - Mice
KW - PUVA Therapy
KW - Photochemistry
KW - Photochemotherapy
KW - Psoriasis/drug therapy
KW - Skin/drug effects
KW - Structure-Activity Relationship
M3 - Journal article
C2 - 4020822
SN - 0022-2623
VL - 28
SP - 1001
EP - 1010
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 8
ER -