Lamellarin D bioconjugates I: Synthesis and cellular internalization of PEG-derivatives.
Herein is reported the design and synthesis of poly(ethylene glycol) derivatives of Lamellarin D with the aim of modulating their physicochemical properties and improving the biological activity. Mono-, di-, and tri-PEG conjugates with improved solubility were obtained in 18-57% overall yields from the corresponding partially protected phenolic derivatives of Lamellarin D. Conjugates 1-9 were tested in a panel of three human tumor cell lines (MDA-MB-231 breast, A-549 lung, and HT-29 colon) to evaluate their cytotoxicity. Several compounds exhibited enhanced cellular internalization, and more than 85% of the derivatives showed a lower GI(50) than Lam-D. Furthermore, cell cycle arrest at G2 phase and apoptotic cell-death pathways were determined for Lamellarin D and these derivatives.
Pla
Daniel
D
Institute for Research in Biomedicine, Barcelona Science Park-University of Barcelona, and CIBER-BBN Networking Centre on Bioengineering, Biomaterials, and Nanomedicine, Baldiri Reixac 10, E-08028 Barcelona, Spain.
Francesch
Andrés
A
Calvo
Pilar
P
Cuevas
Carmen
C
Aligué
Rosa
R
Albericio
Fernando
F
Alvarez
Mercedes
M
D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology; D001692:Biological Transport; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D003374:Coumarins / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology; 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; D011092:Polyethylene Glycols / Q000737:chemistry*
D000970:Antineoplastic Agents; D003374:Coumarins; D006576:Heterocyclic Compounds, 4 or More Rings; D007546:Isoquinolines; C455554:lamellarin D; D011092:Polyethylene Glycols