Novel Ring-Expanded Heterocycles and Nucleosides as Anticancer Agents

The research project was initiated after the discovery of potent, broad spectrum in vitro anticancer activity of parent ring-expanded nucleoside previously synthesized in this laboratory by my predecessors. The parent compound exhibited tumor growth inhibition in vitro in more than 50 human tumor cell lines at micro or submicromolar concentration levels (GI₅₀=10⁻⁵-10⁻⁶ ℳ and 10⁻⁵-10⁻⁷ ℳ respectively) with no apparent host toxicity. Later in our lab, the heterocyclic aglycon containing a long C₁₈ alkyl chain at N⁶ was also found to exhibit potent in vitro anti-cancer activity against prostate, breast, ovarian and lung cancers. In light of the promising biological results described above, this dissertation represents a continuation of the efforts in order to fully explore the anticancer potential of the compounds containing the 5:7-fused 4,6,8-triaminoimidazo [4,5-e] [1,3] diazepine ring system. The first part of my project concerns synthesis of a series of analogues with various substituents at the 1-position e.g., benzyl, para-methoxy benzyl, para-fluoro group, etc.) and/or 2-position e.g., halogen, methoxy, hydroxyl, amino, thiol group, etc.) and/or N⁶ -position ((e.g., alkyl, aryl, and aralkyl group, etc.) of the parent heterocyclic ring. The second part of my project is to synthesize a series of nucleoside analogues with ribosyl or (2-hydroxyethoxy)methyl substituent at 1-position (acyclic &ldquofat&rdquo nucleosides), along with alkyl, aryl, or arakyl substituents at the 6-amino position. The third part of my project is to explore anticancer activities as well as structure-activity relationships (SAR) of the above compounds against the speculated target enzyme DDX3, known to be involved in a number of cancers, including but not limited to breast, prostate and lung cancers. The anticancer screening against a variety of tumor cell lines was performed at the Greenbaum Cancer Center of the University of Maryland School of Medicine. A series of ring-expanded heterocyclic bases with modifications at N-1, and/or N⁶ as well as a series of ring-expanded nucleosides with modifications at N⁶ have been synthesized and tested against six different cancer cell lines. The biological results indicate that even without the &beta-ribose attached at N-1, the heterocyclic bases with various aglycons at N-1 exhibit promising anticancer activity.