- Base-modified thymidines capable of terminating DNA synthesis are novel bioactive compounds with activity in cancer cells
-
Current FDA-approved chemotherapeutic antimetabolites elicit severe side effects that warrant their improvement; therefore, we designed compounds with mechanisms of action focusing on inhibiting DNA replication rather than targeting multiple pathways. We previously discovered that 5-(α-substituted-2-nitrobenzyloxy)methyluridine-5′-triphosphates were exquisite DNA synthesis terminators; therefore, we synthesized a library of 35 thymidine analogs and evaluated their activity using an MTT cell viability assay of MCF7 breast cancer cells chosen for their vulnerability to these nucleoside derivatives. Compound 3a, having an α-tert-butyl-2-nitro-4-(phenyl)alkynylbenzyloxy group, showed an IC50 of 9 ± 1 μM. The compound is more selective for cancer cells than for fibroblast cells compared with 5-fluorouracil. Treatment of MCF7 cells with 3a elicits the DNA damage response as indicated by phosphorylation of γ-H2A. A primer extension assay of the 5′-triphosphate of 3a revealed that 3aTP is more likely to inhibit DNA polymerase than to lead to termination events upon incorporation into the DNA replication fork.
- Borland, Kayla M.,AbdulSalam, Safnas F.,Solivio, Morwena J.,Burke, Matthew P.,Wolfkiel, Patrick R.,Lawson, Sean M.,Stockman, Courtney A.,Andersen, Joel M.,Smith, Skyler,Tolstolutskaya, Julia N.,Gurjar, Purujit N.,Bercz, Aron P.,Merino, Edward J.,Litosh, Vladislav A.
-
supporting information
p. 1869 - 1881
(2015/03/30)
-
- NOVEL NANOCARRIER DELIVERED CANCER CHEMOTHERAPEUTIC AGENTS
-
Compositions and methods for treating cancer in a subject are described herein. The composition includes modified nucleobases and nucleosides that are converted in the cell to nucleotides that are incorporated into growing DNA and result in termination of
- -
-
Paragraph 0032-0035
(2014/12/12)
-
- Bu4N+ alkoxide-initiated/autocatalytic addition reactions with organotrimethylsilanes
-
The use of Me3SiO-/Bu4N+ as a general activator of organotrimethylsilanes for addition reactions has been established. The broad scope of the method offers trimethylsilanes (including acetate, allyl, propargyl, benzyl, dithiane, heteroaryl, and aryl derivatives) as bench-stable organometallics that can be readily utilized as carbanion equivalents for synthesis. Reactions are achieved at rt without the requirement of specialized precautions that are commonplace for other organometallics.
- Das, Manas,O'Shea, Donal F.
-
p. 5595 - 5607
(2014/07/08)
-