title: Synthesis of the first spacer containing prodrug of a duocarmycin analogue and determination of its biological activity.
abstract: 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.
authors.affiliation: Institut for Organic and Biomolecular Chemistry, Georg-August-University Göttingen, Tammannstrasse 2, 37077, Göttingen, Germany.
authors.forename: Heiko J
authors.initials: HJ
authors.lastname: Schuster
authors.forename: Birgit
authors.initials: B
authors.lastname: Krewer
authors.forename: J Marian
authors.initials: JM
authors.lastname: von Hof
authors.forename: Kianga
authors.initials: K
authors.lastname: Schmuck
authors.forename: Ingrid
authors.initials: I
authors.lastname: Schuberth
authors.forename: Frauke
authors.initials: F
authors.lastname: Alves
authors.forename: Lutz F
authors.initials: LF
authors.lastname: Tietze
mesh_terms: 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
chemical_list: D000477:Alkylating Agents; D000900:Anti-Bacterial Agents; D054697:Cytostatic Agents; D000080890:Duocarmycins; D007211:Indoles; D011355:Prodrugs; D011758:Pyrroles; C066098:duocarmycin SA; D004247:DNA