Evaluation of Manassantin A Tetrahydrofuran Core Region Analogues and Cooperative Therapeutic Effects with EGFR Inhibition.

Journal Article (Journal Article)

Tumors adapt to hypoxia by regulating angiogenesis, metastatic potential, and metabolism. These adaptations mediated by hypoxia-inducible factor 1 (HIF-1) make tumors more aggressive and resistant to chemotherapy and radiation. Therefore, HIF-1 is a validated therapeutic target for cancer. In order to develop new HIF-1 inhibitors for cancer chemotherapy by harnessing the potential of the natural product manassantin A, we synthesized and evaluated manassantin A analogues with modifications in the tetrahydrofuran core region of manassantin A. Our structure-activity relationship study indicated that the α,α'-trans -configuration of the central ring of manassantin A is critical to HIF-1 inhibition. We also demonstrated that a combination of manassantin A with an epidermal growth factor receptor inhibitor shows cooperative antitumor activity (∼80% inhibition for combination vs ∼30% inhibition for monotherapy). Our findings will provide important frameworks for the future therapeutic development of manassantin A-derived chemotherapeutic agents.

Full Text

Duke Authors

Cited Authors

  • Kwak, S-H; Stephenson, TN; Lee, H-E; Ge, Y; Lee, H; Min, SM; Kim, JH; Kwon, D-Y; Lee, YM; Hong, J

Published Date

  • July 2020

Published In

Volume / Issue

  • 63 / 13

Start / End Page

  • 6821 - 6833

PubMed ID

  • 32579356

Electronic International Standard Serial Number (EISSN)

  • 1520-4804

International Standard Serial Number (ISSN)

  • 0022-2623

Digital Object Identifier (DOI)

  • 10.1021/acs.jmedchem.0c00151


  • eng