Browsing by Subject "Vascular disrupting agents."
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Item The design, synthesis, and biological evaluation of indole-based anticancer agents.(2014-01-28) MacDonough, Matthew T.; Pinney, Kevin G.; Chemistry and Biochemistry.; Baylor University. Dept. of Chemistry and Biochemistry.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.Item Targeting cancer through inhibition of cathepsin B by non-peptidic small molecule thiosemicarbazones and disruption of pre-existing vasculature by colchicine-like benzosuberene analogues.(2014-01-28) Sevcik, Amanda K.; Trawick, Mary Lynn.; Chemistry and Biochemistry.; Baylor University. Dept. of Chemistry and Biochemistry.Cancer is a leading cause of death in men and women under in the United States and is characterized by uncontrolled cellular proliferation and migration (metastasis) which can impinge on surrounding organs, modify ordinary biological functions, and lead to death. This study focuses on two strategies for cancer therapy: targeting cathepsin B, an enzyme linked to tumor metastasis and progression, and the disruption of pre-existing tumor vasculature as a means to starve tumors of oxygen and nutrients. Cathepsin B is a cysteine protease involved in intra- and extracellular degradation of proteins. Increased expression of cathepsin B has been documented in a number of different cancers and is associated with a poor disease prognosis, and increased tumor vascularization, degradation of the extracellular matrix, invasion, and metastasis. Inhibition of cathepsin B has the potential to arrest cancer cell invasion and metastasis. In a collaborative project between the Trawick and Pinney laboratories at Baylor University, a focused synthetic library of non-peptidic, small molecule thiosemicarbazone derivatives was screened for their ability to inhibit cathepsin B activity as monitored by a fluorogenic enzyme assay. Five compounds were found to be effective inhibitors of cathepsin B in the low micromolar range, and the best four were characterized for their mode of inhibition. Kinetic analysis revealed that two of the active thiosemicarbazone compounds were time dependent, competitive, tight binding, slowly reversible inhibitors of cathepsin B. The other compounds analyzed were rapidly reversible, competitive inhibitors with KI values in the low micromolar range. Vascular disrupting agents (VDAs) are a promising class of anticancer drugs that selectively disrupt tumor vasculature. Tubulin-binding VDAs disrupt microtubule dynamics of endothelial cells lining tumor vasculature. A lead benzosuberene analogue exhibited extreme cytotoxicity against a panel of human cancer cell lines. The lead compound and several of its analogues were investigated for their ability to inhibit tubulin polymerization, bind to the colchicine binding site of tubulin as determined by a competitive radiometric binding assay and arrest human breast cancer cells in the G2/M phase of the cell cycle as indicated by flow cytometry. The results support the mechanism of action of the lead benzosuberene analogues as VDAs.