Design, synthesis, and biological evaluation of novel quinoline-based molecules with potential anticancer activity

Amoozgar, Zohreh (2007) Design, synthesis, and biological evaluation of novel quinoline-based molecules with potential anticancer activity. Masters thesis, Memorial University of Newfoundland.

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Abstract

Quinolone derivatives have recently been introduced as inhibitors of eukaryotic topisomerase-II with potential anticancer activity. In an attempt to discover novel quinolones with potential anticancer properties, compound A, a clinical candidate with drug-like properties in different animal models, attracted our attention. Based on molecular modeling study using Alchemy-3™, compound B was designed in such a way that at its optimized steric/energetic configuration it overlapped perfectly with compound A. -- [diagram omitted; please refer to thesis] -- Different synthetic methodologies were utilized to synthesize compound B (6a) and its N₁-analogues (6b-n). During the structural optimization, a Mitsunobu-type reaction was used for regioselective N₁-alkylation of quinolones. Some of the final products (6a, 6c, 6k) and intermediates (4d and 13a,b,f) were randomly screened for possible cytotoxic activity on different cancer and normal cell lines at 100 μg/ml concentration. The preliminary results indicate the cytotoxic potential of this class of compounds, especially compound 6c, but a more detailed structure-activity relationships study is needed to confirm this hypothesis.

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