Abstract
Nucleoside-derived drugs play an important role in the treatment of cancer. Here, we present the synthesis and characterization of an intriguing series of N3 conjugated Re(CO)3 thymidine complexes. The complexes were characterized by NMR spectroscopy and mass spectrometry and their cytotoxicity was assessed against A549 cells. A similar dependence on the spacer length and the toxicity has been found for N3 functionalized complexes as recently reported for their C5′ counterparts. A remarkable cytotoxic complex 22, carrying a dodecylene spacer at position N3 with a bis-quinoline metal chelate moiety, with an IC50 value of 3.4 ± 1.6 μM, has been identified. Addition of a 100-fold excess of thymidine did not statistically reduce the observed cytotoxicity of all complexes. Cellular uptake studies of complex 22 have been performed by fluorescent microscopy, showing that compound 22 was clearly internalized into A549 cells. Temperature dependent uptake studies, blocking experiments with thymidine, and endosomal co-localization suggest that uptake of 22 occurs via passive diffusion and endocytosis.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 6216-6225 |
| Number of pages | 10 |
| Journal | Dalton Transactions |
| Volume | 40 |
| Issue number | 23 |
| DOIs | |
| State | Published - Jun 21 2011 |
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ASJC Scopus subject areas
- Inorganic Chemistry
Cite this
Synthesis, cytotoxicity and cellular uptake studies of N3 functionalized Re(CO)3 thymidine complexes. / Bartholomä, Mark D.; Vortherms, Anthony R.; Hillier, Shawn; Joyal, John; Babich, John; Doyle, Robert Patrick; Zubieta, Jon A.
In: Dalton Transactions, Vol. 40, No. 23, 21.06.2011, p. 6216-6225.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Synthesis, cytotoxicity and cellular uptake studies of N3 functionalized Re(CO)3 thymidine complexes
AU - Bartholomä, Mark D.
AU - Vortherms, Anthony R.
AU - Hillier, Shawn
AU - Joyal, John
AU - Babich, John
AU - Doyle, Robert Patrick
AU - Zubieta, Jon A
PY - 2011/6/21
Y1 - 2011/6/21
N2 - Nucleoside-derived drugs play an important role in the treatment of cancer. Here, we present the synthesis and characterization of an intriguing series of N3 conjugated Re(CO)3 thymidine complexes. The complexes were characterized by NMR spectroscopy and mass spectrometry and their cytotoxicity was assessed against A549 cells. A similar dependence on the spacer length and the toxicity has been found for N3 functionalized complexes as recently reported for their C5′ counterparts. A remarkable cytotoxic complex 22, carrying a dodecylene spacer at position N3 with a bis-quinoline metal chelate moiety, with an IC50 value of 3.4 ± 1.6 μM, has been identified. Addition of a 100-fold excess of thymidine did not statistically reduce the observed cytotoxicity of all complexes. Cellular uptake studies of complex 22 have been performed by fluorescent microscopy, showing that compound 22 was clearly internalized into A549 cells. Temperature dependent uptake studies, blocking experiments with thymidine, and endosomal co-localization suggest that uptake of 22 occurs via passive diffusion and endocytosis.
AB - Nucleoside-derived drugs play an important role in the treatment of cancer. Here, we present the synthesis and characterization of an intriguing series of N3 conjugated Re(CO)3 thymidine complexes. The complexes were characterized by NMR spectroscopy and mass spectrometry and their cytotoxicity was assessed against A549 cells. A similar dependence on the spacer length and the toxicity has been found for N3 functionalized complexes as recently reported for their C5′ counterparts. A remarkable cytotoxic complex 22, carrying a dodecylene spacer at position N3 with a bis-quinoline metal chelate moiety, with an IC50 value of 3.4 ± 1.6 μM, has been identified. Addition of a 100-fold excess of thymidine did not statistically reduce the observed cytotoxicity of all complexes. Cellular uptake studies of complex 22 have been performed by fluorescent microscopy, showing that compound 22 was clearly internalized into A549 cells. Temperature dependent uptake studies, blocking experiments with thymidine, and endosomal co-localization suggest that uptake of 22 occurs via passive diffusion and endocytosis.
UR - http://www.scopus.com/inward/record.url?scp=79958241872&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=79958241872&partnerID=8YFLogxK
U2 - 10.1039/c0dt01452d
DO - 10.1039/c0dt01452d
M3 - Article
C2 - 21369609
AN - SCOPUS:79958241872
VL - 40
SP - 6216
EP - 6225
JO - Dalton Transactions
JF - Dalton Transactions
SN - 1477-9226
IS - 23
ER -