The design, synthesis, and biological evaluation of indole-based anticancer agents.
MacDonough, Matthew T.
MetadataShow full item record
Solid tumors depend on a vascular network that delivers nutrients and oxygen, thus selectively targeting the developed tumor vasculature represents a feasible strategy for the treatment of cancer. Both small-molecules and biologics that function in this manner are referred to as vascular disrupting agents (VDAs). Two benchmark VDAs, combretastatin A-1 (CA1) and combretastatin A-4 (CA4), that are both natural products inhibit the dynamic tubulin-microtubule protein system responsible, in part, for the cellular shape of endothelial cells lining tumor blood vessels. This inhibition ultimately results in morphological changes of endothelial cells, from flat to round, and leads to vessel collapse precluding blood flow to the tumor. The success of CA1P and CA4P (corresponding phosphate salts of CA1 and CA4) as VDAs has inspired the development of inhibitors of tubulin that bear structural similarities and incorporate the indole molecular template. 2-(3ʹ′-Hydroxy-4ʹ′-methoxyphenyl)-3-(3ʹ′ʹ′, 4ʹ′ʹ′, 5ʹ′ʹ′-trimethoxybenzoyl)-6- methoxyindole (OXi8006), prepared as its water-soluble phosphate prodrug salt (OXi8007), is a lead VDA discovered by the Pinney Research Group. Scale-up syntheses were necessary to facilitate planned biological studies. To investigate structure activity relationship considerations, analogues of OXi8006 were prepared which incorporate functional group modifications of the 3-aroyl ring, the 2-aryl ring, and the indole fused-ring. These derivatives were evaluated for their ability to inhibit tubulin assembly and for their cytotoxicity against three human cancer cell lines (NCI-H460, SKOV- 3, and DU-145) through collaborative studies with the Trawick Research Group. Bioreductively activatable prodrug conjugates (BAPCs) of OXi8006 that incorporate nitro-thiophenyl bioreductive triggers were synthesized to target tumor hypoxia. The mechanistic pathway for 2-aryl indole formation via the Bischler-Mohlau indole reaction was explored through isotopic labeling of key intermediates. This strategy was also applied to benzo[b]furan and benzo[b]thiophene analogues. Results suggest formation of an imine intermediate for 2-aryl indoles as evidenced by key ¹³C NMR signatures. Similar studies suggest the formation of 3-aryl benzo[b]furans and benzo[b]thiophenes via a pathway in which no aryl shift (2- to 3-position) was observed when hydroxyl substitution is present on the bromoacetophenone starting material. In summary, OXi8006 and OXi8007, a focused library of analogues including BAPCs, as well as isotopically labeled indoles, benzo[b]thiophenes, and benzo[b]furans were prepared.