Lamellarin D bioconjugates II: Synthesis and cellular internalization of dendrimer and nuclear location signal derivatives.
The design and synthesis of Lamellarin D conjugates with a nuclear localization signal peptide and a poly(ethylene glycol)-based dendrimer are described. Conjugates 1-4 were obtained in 8-84% overall yields from the corresponding protected Lamellarin D. Conjugates 1 and 4 are 1.4- to 3.3-fold more cytotoxic than the parent compound against three human tumor cell lines (MDA-MB-231 breast, A-549 lung, and HT-29 colon). Besides, conjugates 3 and 4 showed a decrease in activity potency in BJ skin fibroblasts, a normal cell culture. Cellular internalization was analyzed, and a nuclear distribution pattern was observed for 4, which contains a nuclear localization signaling sequence.
Pla
Daniel
D
Institute for Research in Biomedicine, Barcelona Science Park-University of Barcelona, Baldiri Reixac 10, E-08028 Barcelona, Spain.
Martí
Marc
M
Farrera-Sinfreu
Josep
J
Pulido
Daniel
D
Francesch
Andrés
A
Calvo
Pilar
P
Cuevas
Carmen
C
Royo
Miriam
M
Aligué
Rosa
R
Albericio
Fernando
F
Alvarez
Mercedes
M
D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology; D001692:Biological Transport; D045744:Cell Line, Tumor; D003374:Coumarins / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology; D004264:DNA Topoisomerases, Type I / Q000378:metabolism; D050091:Dendrimers / Q000737:chemistry*; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006576:Heterocyclic Compounds, 4 or More Rings / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D007546:Isoquinolines / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology; D019913:Nuclear Localization Signals / Q000737:chemistry*; D011092:Polyethylene Glycols / Q000737:chemistry; D014162:Transfection
D000970:Antineoplastic Agents; D003374:Coumarins; D050091:Dendrimers; D006576:Heterocyclic Compounds, 4 or More Rings; D007546:Isoquinolines; D019913:Nuclear Localization Signals; C455554:lamellarin D; D049452:Green Fluorescent Proteins; D011092:Polyethylene Glycols; D004264:DNA Topoisomerases, Type I