Clustered ergot alkaloids modulate cell-mediated cytotoxicity.
Dimers of agroclavine (1) and terguride (2), as well as a series of terguride oligomers, for example trimers (5, 6), tetramer (7), hexamer (8) and functionalized tergurides for further complex clustering were synthesized. Terguride oligomers were screened for their direct cellular toxicity on lymphoma cell lines in vitro and for their immunomodulating activities, represented by the natural killer (NK) cell-mediated cytotoxicity, as the most sensitive screening marker during immune responses. Dimers linked via aromatic spacer showed a high toxicity (1 microM) to lymphoma cells, which was not detected in other derivatives. In vitro and ex vivo experiments performed on mouse spleen lymphocytes in the presence of terguride oligomers demonstrated an immunosuppressive effect of dimers with aromatic spacer (4c-d) and NK cell stimulatory effect of terguride hexamer (8) and trimer with aliphatic spacer (5c). There is a considerable evidence that indolic part of molecule contributes to immunosuppressive action of terguride, which is potentiated in dimers carrying aromatic linker. This effect can be reversed by higher oligomerization of the respective alkaloids.
Kren
Vladimír
V
Institute of Microbiology, Academy of Sciences of the Czech Republic, Vídenská 1083, CZ 142 20 4, Prague, Czech Republic. kren@biomed.cas.cz
Fiserová
Anna
A
Weignerová
Lenka
L
Stibor
Ivan
I
Halada
Petr
P
Prikrylová
Vera
V
Sedmera
Petr
P
Pospísil
Miloslav
M
D000276:Adjuvants, Immunologic / Q000737:chemistry* / Q000494:pharmacology*; D000818:Animals; D002219:Carbamates / Q000737:chemistry / Q000494:pharmacology; D019281:Dimerization; D004353:Drug Evaluation, Preclinical / Q000379:methods; D004873:Ergolines / Q000737:chemistry* / Q000494:pharmacology*; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents / Q000737:chemistry / Q000494:pharmacology; D007694:Killer Cells, Natural / Q000187:drug effects / Q000502:physiology; D008090:Lisuride / Q000031:analogs & derivatives* / Q000737:chemistry* / Q000494:pharmacology*; D051379:Mice; D008807:Mice, Inbred BALB C; D013154:Spleen / Q000166:cytology / Q000187:drug effects; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
C453020:1,2,3,4,5,6-hexa(6-methyl-8-(diethylcarbamoylamino)-ergoline-1-yl-methyl); C453019:1-bromo-2,2-di(6-methyl-methyl-8-(diethylcarbamoylamino)-ergoline-1-yl-methyl)-3-(6-methyl-8-(diethylcarbamoylamino)-ergoline-1-yl)propane; D000276:Adjuvants, Immunologic; D002219:Carbamates; D004873:Ergolines; D007166:Immunosuppressive Agents; C006208:dironyl; C004465:agroclavine; D008090:Lisuride