title: Prenylation at the indole ring leads to a significant increase of cytotoxicity of tryptophan-containing cyclic dipeptides.
abstract: Fourteen tryptophan-containing cyclic dipeptides 1a-14a, including all four stereoisomers of cyclo-Trp-Pro and cyclo-Trp-Ala, were converted to their C2-regularly prenylated derivatives 1b-14b in the presence of dimethylallyl diphosphate by using the purified recombinant FtmPT1 as catalyst. The enzyme products were isolated on HPLC in preparative scales and their structures were elucidated by NMR and MS analyses. The cytotoxic effects of the prenylated products and their substrates were tested with human leukemia K562 and ovarian cancer A2780 sens and A2780 CisR cell lines. Preliminary results have been clearly shown that prenylation at C2 led to a significant increase of the cytotoxicity of the tested cyclic dipeptides in all the 14 cases. The second amino acid and the stereochemistry of tryptophan moiety of the cyclic dipeptides showed less influence on the cytotoxicity of the tested compounds.
authors.affiliation: Institut für Pharmazeutische Biologie und Biotechnologie, Philipps Universität Marburg, Deutschhausstrasse 17A, 35037 Marburg, Germany.
authors.forename: Beate
authors.initials: B
authors.lastname: Wollinsky
authors.forename: Lena
authors.initials: L
authors.lastname: Ludwig
authors.forename: Alexandra
authors.initials: A
authors.lastname: Hamacher
authors.forename: Xia
authors.initials: X
authors.lastname: Yu
authors.forename: Matthias U
authors.initials: MU
authors.lastname: Kassack
authors.forename: Shu-Ming
authors.initials: SM
authors.lastname: Li
mesh_terms: D000409:Alanine / Q000737:chemistry; D055162:Biocatalysis; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D004122:Dimethylallyltranstransferase / Q000737:chemistry*; D004151:Dipeptides / Q000138:chemical synthesis* / Q000494:pharmacology; D005656:Fungal Proteins / Q000737:chemistry*; D045782:Hemiterpenes / Q000737:chemistry; D006801:Humans; D007211:Indoles / Q000737:chemistry; D020128:Inhibitory Concentration 50; D009682:Magnetic Resonance Spectroscopy; D009943:Organophosphorus Compounds / Q000737:chemistry; D010456:Peptides, Cyclic / Q000138:chemical synthesis* / Q000494:pharmacology; D054876:Prenylation; D011392:Proline / Q000737:chemistry; D011994:Recombinant Proteins / Q000737:chemistry; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D014364:Tryptophan / Q000737:chemistry*
chemical_list: D004151:Dipeptides; D005656:Fungal Proteins; D045782:Hemiterpenes; D007211:Indoles; D009943:Organophosphorus Compounds; D010456:Peptides, Cyclic; D011994:Recombinant Proteins; C043060:3,3-dimethylallyl pyrophosphate; D014364:Tryptophan; D011392:Proline; D004122:Dimethylallyltranstransferase; C534854:FtmPT1 protein, Aspergillus fumigatus; D000409:Alanine