Synthesis of the first spacer containing prodrug of a duocarmycin analogue and determination of its biological activity.
The synthesis of the first spacer containing, duocarmycin analogue prodrug was realised, its biological properties evaluated and compared to its counterpart prodrug without a spacer unit. The synthesis comprises the manufacture of the new acetylated derivatives and of two double spacer systems, their activation and coupling to the pharmacophoric seco-drug (+)-. Unprecedented biological results were found as the new prodrug showed a fairly low QIC(50) value of 20, but on the other hand a high stability and very low DNA alkylation efficiency. These findings indicate a changed cytostatic mode of action induced by the self-immolative spacer moiety which was employed.
Schuster
Heiko J
HJ
Institut for Organic and Biomolecular Chemistry, Georg-August-University Göttingen, Tammannstrasse 2, 37077, Göttingen, Germany.
Krewer
Birgit
B
von Hof
J Marian
JM
Schmuck
Kianga
K
Schuberth
Ingrid
I
Alves
Frauke
F
Tietze
Lutz F
LF
D000477:Alkylating Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D045744:Cell Line, Tumor; D054697:Cytostatic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D004247:DNA / Q000378:metabolism; D000080890:Duocarmycins; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D011355:Prodrugs / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D011758:Pyrroles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
D000477:Alkylating Agents; D000900:Anti-Bacterial Agents; D054697:Cytostatic Agents; D000080890:Duocarmycins; D007211:Indoles; D011355:Prodrugs; D011758:Pyrroles; C066098:duocarmycin SA; D004247:DNA