Isomer-dependent daunomycin release and in vitro antitumour effect of cis-aconityl-daunomycin.
Two isomers of cis-aconytil-daunomycin (cAD) were isolated after the reaction of daunomycin with cis-aconitic-anhydride. The structure of the isomers was identified by MS-spectroscopy and 1H and 13C NMR experiments. In contrast with the assumptions described earlier, our results show that the two isomers belong to the cis- and trans-isomers of the alpha-monoamide of cis-aconityl-daunomycin, respectively. We found that the pH dependent daunomycin release is different for the two isomers. Comparative analysis of the in vitro antitumour effect of the isomers on c26 colon carcinoma and on MDA-MB 435P human breast carcinoma cell lines showed that cAD-1 is more potent than cAD-2, but the extent of differences is tumour cell dependent. The results of this study might be appreciated in the light of the use of acid-labile spacer for the design and preparation of protein/peptide conjugates of drugs by indicating that isomers could possess markedly different biological activity.
Reményi
Judit
J
Research Group of Peptide Chemistry, Hungarian Academy of Sciences, Eötvös L. University, Pázmány P. sétány 1A, Budapest 112, POB 32, H-1117, Hungary.
Balázs
Barbara
B
Tóth
Sára
S
Falus
András
A
Tóth
Gábor
G
Hudecz
Ferenc
F
D000970:Antineoplastic Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000633:toxicity; D001943:Breast Neoplasms; D002470:Cell Survival / Q000187:drug effects; D003110:Colonic Neoplasms; D003630:Daunorubicin / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D005260:Female; D006801:Humans; D007202:Indicators and Reagents; D007536:Isomerism; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D007202:Indicators and Reagents; C062167:aconityldoxorubicin; D004317:Doxorubicin; D003630:Daunorubicin