Bioreductively activatable prodrug conjugates of phenstatin designed to target tumor hypoxia
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Published on: December 26, 2016
Blake A Winn1, Zhe Shi1, Graham J Carlson1
1Department of Chemistry and Biochemistry, Baylor University, One Bear Place #97348, Waco, TX 76798-7348, United States.
Abstract:
A variety of solid tumor cancers contain significant regions of hypoxia, which provide unique challenges for targeting by potent anticancer agents. Bioreductively activatable prodrug conjugates (BAPCs) represent a promising strategy for therapeutic intervention. BAPCs are designed to be biologically inert until they come into contact with low oxygen tension, at which point reductase enzyme mediated cleavage releases the parent anticancer agent in a tumor-specific manner. Phenstatin is a potent inhibitor of tubulin polymerization, mimicking the chemical structure and biological activity of the natural product combretastatin A-4. Synthetic approaches have been established for nitrobenzyl, nitroimidazole, nitrofuranyl, and nitrothienyl prodrugs of phenstatin incorporating nor-methyl, mono-methyl, and gem-dimethyl variants of the attached nitro compounds. A series of BAPCs based on phenstatin have been prepared by chemical synthesis and evaluated against the tubulin-microtubule protein system. In a preliminary study using anaerobic conditions, the gem-dimethyl nitrothiophene and gem-dimethyl nitrofuran analogues were shown to undergo efficient enzymatic cleavage in the presence of NADPH cytochrome P450 oxidoreductase. Each of the eleven BAPCs evaluated in this study demonstrated significantly reduced inhibitory activity against tubulin in comparison to the parent anti-cancer agent phenstatin (IC50=1.0μM). In fact, the majority of the BAPCs (seven of the eleven analogues) were not inhibitors of tubulin polymerization (IC50>20μM), which represents an anticipated (and desirable) attribute for these prodrugs, since they are intended to be biologically inactive prior to enzyme-mediated cleavage to release phenstatin.
Insights
Hypoxia in solid tumors presents challenges for cancer drugs. Bioreductively activatable prodrug conjugates (BAPCs) are designed to release active anticancer agents like phenstatin specifically in low-oxygen tumor environments.
Area of Science:
- Medicinal Chemistry
- Oncology
- Biochemistry
Background:
- Solid tumors often contain hypoxic regions, hindering effective delivery of potent anticancer agents.
- Bioreductively activatable prodrug conjugates (BAPCs) offer a strategy to overcome tumor hypoxia by releasing drugs selectively under low-oxygen conditions.
- Phenstatin, a potent tubulin polymerization inhibitor, serves as the active agent in these novel prodrug designs.
Purpose of the Study:
- To synthesize and evaluate a series of phenstatin-based BAPCs for their potential as targeted cancer therapeutics.
- To assess the in vitro activity and prodrug characteristics of novel phenstatin conjugates.
- To investigate the tumor-specific activation mechanism of BAPCs in hypoxic conditions.
Main Methods:
- Chemical synthesis of eleven phenstatin-based BAPCs, incorporating various nitroaromatic moieties (nitrobenzyl, nitroimidazole, nitrofuranyl, nitrothienyl) and methyl substitutions.
- Evaluation of BAPCs against the tubulin-microtubule protein system in vitro.
- Preliminary assessment of enzymatic cleavage efficiency under anaerobic conditions using NADPH cytochrome P450 oxidoreductase.
Main Results:
- All eleven synthesized BAPCs exhibited significantly reduced inhibitory activity against tubulin polymerization compared to the parent drug phenstatin (IC50=1.0μM).
- Seven out of eleven BAPCs showed no significant inhibition of tubulin polymerization (IC50>20μM), indicating desirable prodrug inactivity.
- Gem-dimethyl nitrothiophene and gem-dimethyl nitrofuran analogues demonstrated efficient enzymatic cleavage under anaerobic conditions.
Conclusions:
- The synthesized phenstatin-based BAPCs are largely inactive prodrugs, as intended, with potential for tumor-specific activation.
- Specific analogues, particularly those with gem-dimethyl substitutions on nitrothiophene and nitrofuran moieties, show promise for efficient bioreductive activation.
- These findings support the development of BAPCs as a targeted therapeutic strategy for hypoxic solid tumors.
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