Squalenoyl Gemcitabine Monophosphate: Synthesis, Characterisation of Nanoassemblies and Biological Evaluation

Trialkylammonium 4‐(N)‐1,1′,2‐trisnor‐squalenoylgemcitabine monophosphate (SQdFdC‐MP) salts were prepared from 1,1′,2‐trisnor‐squalenoylgemcitabine by phosphoramidite‐type chemistry. This amphiphilic molecule self‐assembled into nanoassemblies of about 100 nm in size in aqueous solutions. Cryo‐TEM a...

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Bibliographic Details
Published in:European Journal of Organic Chemistry 2011-05, Vol.2011 (14), p.2615-2628
Main Authors: Caron, Joachim, Lepeltier, Elise, Reddy, L. Harivardhan, Lepêtre-Mouelhi, Sinda, Wack, Séverine, Bourgaux, Claudie, Couvreur, Patrick, Desmaële, Didier
Format: Article
Language:English
Subjects:
Antineoplastic agents
Antitumor agents
Biological and medical sciences
Carbohydrates. Nucleosides and nucleotides
Chemistry
Cross-disciplinary physics: materials science
rheology
Exact sciences and technology
General aspects
Materials science
Medical sciences
Medicinal chemistry
Methods of nanofabrication
Nanostructures
Nucleosides
Nucleosides, nucleotides and oligonucleotides
Nucleotides
Organic chemistry
Pharmacology. Drug treatments
Physics
Preparations and properties
Prodrugs
Supramolecular and biochemical assembly
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Summary:Trialkylammonium 4‐(N)‐1,1′,2‐trisnor‐squalenoylgemcitabine monophosphate (SQdFdC‐MP) salts were prepared from 1,1′,2‐trisnor‐squalenoylgemcitabine by phosphoramidite‐type chemistry. This amphiphilic molecule self‐assembled into nanoassemblies of about 100 nm in size in aqueous solutions. Cryo‐TEM and small‐angle X‐ray scattering (SAXS) investigations revealed that SQdFdC‐MP molecules self‐organized into unilamellar liposomes with a membrane thickness of about 70 Å. Such liposomal trialkylammonium SQdFdC‐MP formulations displayed significant anticancer activity on leukaemia cells. These results suggested that squalene conjugates of negatively charged nucleotide analogues efficiently penetrated into tumour cells. Furthermore, triethylammonium SQdFdC‐MP nanoassemblies were found to be more active than the parent nucleoside towards the L1210 10 K resistant cell line. Triethylammonium squalenoyl‐gemcitabine monophosphate self‐assembles into unilamellar liposomes of about one hundred nanometres in size. These nanoassemblies displayed a pronounced anticancer effect on leukaemia cell lines including a gemcitabine‐resistant cell line with down‐regulation of deoxycytidine kinase enzyme.
ISSN:1434-193X
1099-0690
DOI:10.1002/ejoc.201100036