Actin is one of the two major components of the cytoskeleton in eukaryotic cells, and it participates in many important cellular processes, including cell division, motility, and signaling. Natural product small molecules that inhibit acti cytoskeleton dynamics have long been recognized as valuable molecular probes for elucidating the cellular functions of actin. However, their potential use as chemotherapeutic agents in the treatment of cancer has just started to be recognized. Selective inhibition of the actin cytoskeleton could be a powerful strategy for chemotherapeutic intervention in cancer treatment. This proposal presents a highly convergent approach for the asymmetric total synthesis of rhizopodin employing multi-component Anion Relay Chemistry (ARC) pioneered by the Smith group, in conjunction with modern methods in catalysis and stereoselective synthesis. This synthetic approach will be adapted for the synthesis of novel structural analogs. All synthetic products will be subjected to biological evaluation. The ultimate goals of the proposed project are to discover potent and selective actin- targeting small molecules as chemotherapeutic agents in cancer treatment as well as to provide molecular probes to elucidate the role of the dimeric nature of rhizopodin in its mode of action.

Public Health Relevance

Actin is one of the two major components of the cytoskeleton in eukaryotic cells and it participates in many important cellular processes, including muscle contraction, cell division, motility, and signaling. Discovery of small molecules that can selectively inhibit actin polymerization in cancer cells could lead to a powerful strategy for chemotherapeutic intervention in cancer treatment.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
5F32CA171736-02
Application #
8529192
Study Section
Special Emphasis Panel (ZRG1-F04-K (09))
Program Officer
Jakowlew, Sonia B
Project Start
2012-08-01
Project End
2014-07-31
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
2
Fiscal Year
2013
Total Cost
$49,214
Indirect Cost
Name
University of Pennsylvania
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Chen, Ming Z; Gutierrez, Osvaldo; Smith 3rd, Amos B (2014) Through-bond/through-space anion relay chemistry exploiting vinylepoxides as bifunctional linchpins. Angew Chem Int Ed Engl 53:1279-82