Synthesis, characterization, and biological evaluation of bioreductively activatable prodrug conjugates (BAPCs) of phenstatin, KGP18, OXi6196, combretastatin A-1, and combretastatin A-4.

Winn, Blake A., 1986-

Synthesis, characterization, and biological evaluation of bioreductively activatable prodrug conjugates (BAPCs) of phenstatin, KGP18, OXi6196, combretastatin A-1, and combretastatin A-4.

dc.contributor.advisor	Pinney, Kevin G.
dc.creator	Winn, Blake A., 1986-
dc.date.accessioned	2017-06-05T13:55:19Z
dc.date.available	2017-06-05T13:55:19Z
dc.date.created	2017-05
dc.date.issued	2017-01-20
dc.date.submitted	May 2017
dc.date.updated	2017-06-05T13:55:19Z
dc.description.abstract	Selective targeting of tumors with anticancer agents represents a universally important strategy to improve efficacy and reduce patient side effects. Targeting tumor-associated hypoxia (low oxygen tension) represents one type of promising therapeutic regimen. Bioreductively activatable prodrug conjugates (BAPCs) are designed to be biologically inert under normoxia, however in hypoxic environments they will selectively release their parent anticancer agent. Inhibitors of tubulin polymerization (assembly) are promising anticancer agents for functionalization as their corresponding BAPCs. Upon hypoxia-selective release, these compounds function biologically as antimitotic agents with a subset demonstrating dual mechanistic capability as potent vascular disrupting agents (VDAs), which selectively damage tumor-associated vasculature leading to enhanced tumor necrosis. Phenstatin, OXi6196, combretastatin A-1(CA1), combretastatin A-4 (CA4), and KGP18 are promising anticancer agents for development as BAPCs. These compounds are effective inhibitors of tubulin assembly and demonstrate potent activity in vitro against human cancer cell lines. Synthetic pathways have been identified for the preparation of nitrothienyl prodrugs of CA1 and CA4 using the nor-methyl, mono-methyl, and gem-dimethyl nitrothiophene-based triggers. A regioselective protecting group strategy was utilized in order to synthesize the nitrothiophene triggers regioselectively to the C-2 and C-3 positions of CA1. Tosyl, isopropyl, and tert-butyldimethylsilyl protecting groups were important in establishing this CA1 regioselectivity. Several series of BAPCs were also developed based on phenstatin, KGP18, and Oxi6196 using nor-methyl, mono-methyl, and gem-dimethyl variants of the nitrothiophene, nitrobenzyl, nitroimidazole, and nitrofuran triggers. A selection of the CA1, CA4, and phenstatin BAPCs were evaluated biologically for their ability to inhibit tubulin assembly as well as their stability in aqueous conditions and their ability to undergo enzymatic cleavage in the presence of NADPH cytochrome P450 oxidoreductase.
dc.format.mimetype	application/pdf
dc.identifier.uri	http://hdl.handle.net/2104/10085
dc.language.iso	en
dc.rights.accessrights	Worldwide access
dc.rights.accessrights	Access changed 8/24/22
dc.subject	Hypoxia. Bioreductive. Vascular disrupting agent.
dc.title	Synthesis, characterization, and biological evaluation of bioreductively activatable prodrug conjugates (BAPCs) of phenstatin, KGP18, OXi6196, combretastatin A-1, and combretastatin A-4.
dc.type	Thesis
dc.type.material	text
local.embargo.lift	2022-05-01
local.embargo.terms	2022-05-01
thesis.degree.department	Baylor University. Dept. of Chemistry & Biochemistry.
thesis.degree.grantor	Baylor University
thesis.degree.level	Doctoral
thesis.degree.name	Ph.D.