Design and synthesis of benzosuberene and tetracyclic-based molecules inspired by natural products as inhibitors of tubulin polymerization and preparation of drug-linker constructs to facilitate tumor selective targeted delivery.

One primary research interest of the Pinney Research Group centers on the design and synthesis (and biological evaluation through long-standing collaborations) of small-molecule inhibitors of tubulin polymerization and development of targeting strategies that facilitate selective delivery of therapeutic agents to tumors and the tumor microenvironment. The tubulin-microtubule protein has been established as a prime target for anti-cancer agents specifically with inhibitors of tubulin polymerization finding significant clinical relevance. Natural products such as combretastatin A-4 and colchicine that bind to the colchicine site (functioning as potent inhibitors of tubulin polymerization and antiproliferative agents) have been evaluated clinically and have inspired countless analogues and derivatives. The Pinney group has established a small library of bioactive molecules with benzosuberene, dihydronaphthalene, and indole-based molecular scaffolds as representative examples. Many of these compounds have demonstrated highly potent activity as both inhibitors of tubulin polymerization and cytotoxins. A subset of these molecules function through a unique dual-mechanism of action as potent cytotoxins and vascular disrupting agents (VDAs)(distinct from other tubulin-binding agents). VDAs result in selective blood flow shutdown to existing tumor vasculature, causing irreparable damage and rapid tumor necrosis. Ongoing efforts include diversifying the structure-activity relationship (SAR) knowledge of molecules that interact with tubulin, as well as improving selectivity of active compounds via prodrug and drug-linker strategies. A series of benzosuberene and tetracyclic analogues were designed and synthesized, structurally inspired by related molecules discovered and developed by the Pinney Laboratory as promising anti-cancer agents. These new analogues were assessed for their antiproliferative activity, inhibition of tubulin polymerization, and in vivo efficacy as VDAs for the most active molecules. Tetracyclic compounds were synthesized through treatment of benzosuberenes with chlorosulfonyl isocyanate (CSI), also leading to the discovery of a new application of this reagent. The substrate scope to synthesize these tetracycles with CSI was explored. Antibody-drug conjugates (ADCs) represent a prominent strategy for cancer therapeutics that selectively targets the tumors and/or the tumor microenvironment. Previously established lead molecules were incorporated into drug-linker constructs and evaluated for their enzymatic cleavage. To improve release of phenolic payloads, constructs with alternative self-immolative spacers were prepared and evaluated for their release.

Name thesis:degree_name

Ph.D.

Level thesis:degree_level

Doctoral

Grantor

Baylor University.

Year dc:date.issued

2024

Author dc:creator

• VanNatta, Jenny M. (Jennifer M.), 1996-

Advisor dc:contributor.advisor

• Pinney, Kevin G.

• Synthesis.
• Inhibitors of tubulin polymerization.
• Bioactive anti-cancer agents.
• Targeted cancer drug delivery.

Statement dc:rights

• Baylor University works are protected by copyright. They may be viewed from this source for any purpose, but reproduction or distribution in any format is prohibited without written permission. Contact libraryquestions@baylor.edu for inquiries about permission.

Language dc:language.iso

en

Handle dc:identifier.uri

https://hdl.handle.net/2104/13108

OAI identifier oai:identifier

oai:baylor-ir.tdl.org:2104/13108