Recently the Peterson lab discovered a promising anticancer adenosine derivative-- 2´,3´-bis-O-tert-butyldimethylsilyl-5´-deoxy-5´-[N-(methylcarbamoyl)amino]-N6-(N-phenylcarbamoyl)adenosine. This compound showed selective toxicity against human colon cancer cells in vitro with LC50's = 6--10 µM. It was hypothesized that the lead compound exerted its cytotoxic effects by interacting with a protein kinase. A systematic Structure Activity Relationship (SAR) was undertaken in an attempt to increase the kinase-binding affinity of the lead compound. Many regions of the lead compound were examined: the N6-phenyl urea moiety, the 5´-N-methyl urea group, the 2´,3´-bis-O-TBS groups, the nucleobase, and the ribose sugar. Results of these studies produced some promising new derivatives. In particular, one analogue exhibited potent cancer cell growth inhibition with an average GI50 of 0.58 μM (NCI-60). In addition, another compound showed selective toxicity for the non-small cell adenocarcinoma cell line NCI-H522 with an LC50 of 10 nM. Efficient methods for the preparation of a wide variety of N6-aryl and -alkyl substituted derivatives were developed. One versatile route involved the installation of an N6-ethoxy carbonyl and subsequent displacement with an alkly- or arylamine. Synthetic routes for the preparation of of a variety of 2´,3´-bis-O-acylated analogues were also developed. Nucleoside mono-, di-, and triphosphate bioisosteres in which the phosphoester or phosphoanhydride have been replaced by an unnatural functional group have been extensively investigated. A simple and efficient method was developed for the preparation of carbamoyl analogues of nucleoside mono-, di-, and triphosphate surrogates. This method uses a modified version of the Kočovský reaction to install mono-, di-, and triphosphate mimics in good to excellent yields (ave = 75%).
College and Department
Physical and Mathematical Sciences; Chemistry and Biochemistry
BYU ScholarsArchive Citation
Shelton, Jadd R., "Synthesis and Biological Evaluation of Various Derivatives of a Broad-Spectrum Anticancer Nucleoside" (2012). Theses and Dissertations. 3743.
Anticancer Nucleosides, N6, 5´-Bis-ureidoadensoines, Antiproliferative Activity, BMPR1b, Nucleotide Surrogates