Journal article
Inhibition of IGF-1R and lipoxygenase by nordihydroguaiaretic acid (NDGA) analogs
Bioorganic & medicinal chemistry letters, Vol.17(14), pp.4026-4029
2007
Handle:
https://hdl.handle.net/2376/105781
PMCID: PMC2253493
PMID: 17502145
Abstract
Herein, we pursue the hypothesis that the structure of nordihydroguaiaretic acid (NDGA) can be refined for selective potency against the insulin-like growth factor 1 receptor (IGF-1R) as a potential therapeutic target for breast cancer while diminishing its action against other cellular targets. Thus, a set of NDGA analogs (
7a–
7h) was prepared and examined for inhibitory potency against IGF-1R kinase and an alternative target, 15-lipoxygenase (15 LOX). The anti-cancer effects of these compounds were determined by their ability to inhibit IGF-1 mediated cell growth of MCF-7 breast cancer cells. The design of the analogs was based upon a cursory Topliss approach in which one of NDGA’s aromatic rings was modified with various substituents. Structural modification of one of the two catechol rings of NDGA was found to have little effect upon the inhibitory potency against both kinase activity of the IGF-1R and IGF-1 mediated cell growth of MCF-7 cells. 15-LOX was found to be most sensitive to structural modifications of NDGA. From the limited series of NDGA analogs examined, the compound that exhibited the greatest selectivity for IGF-1 mediated growth compared to 15-LOX inhibition was a cyclic analog
7h with a framework similar to a natural product isolated from
Larrea divaricata. The results for
7h are significant because while NDGA displays biological promiscuity,
7h exhibits greater specificity toward the breast cancer target IGF-1R with that added benefit of possessing a 10-fold weaker potency against 15-LOX, an enzyme which has a purported tumor suppressing role in breast cancer. With increased specificity and potency,
7h may serve as a new lead in developing novel therapeutic agents for breast cancer.
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Details
- Title
- Inhibition of IGF-1R and lipoxygenase by nordihydroguaiaretic acid (NDGA) analogs
- Creators
- Joseph E Blecha - Department of Chemistry & Biochemistry, San Francisco State University, San Francisco, CA 94132-4163, USAMarc O Anderson - Department of Chemistry & Biochemistry, San Francisco State University, San Francisco, CA 94132-4163, USAJennifer M Chow - Department of Chemistry & Biochemistry, San Francisco State University, San Francisco, CA 94132-4163, USAChristle C Guevarra - Department of Chemistry & Biochemistry, San Francisco State University, San Francisco, CA 94132-4163, USACelia Pender - Diabetes and Endocrine Research, University of California, San Francisco/Mt. Zion Medical Center, Box 1616, San Francisco, CA 94143-1616, USACristina Penaranda - Diabetes and Endocrine Research, University of California, San Francisco/Mt. Zion Medical Center, Box 1616, San Francisco, CA 94143-1616, USAMarianna Zavodovskaya - Diabetes and Endocrine Research, University of California, San Francisco/Mt. Zion Medical Center, Box 1616, San Francisco, CA 94143-1616, USAJack F Youngren - Diabetes and Endocrine Research, University of California, San Francisco/Mt. Zion Medical Center, Box 1616, San Francisco, CA 94143-1616, USAClifford E Berkman - Department of Chemistry & Biochemistry, San Francisco State University, San Francisco, CA 94132-4163, USA
- Publication Details
- Bioorganic & medicinal chemistry letters, Vol.17(14), pp.4026-4029
- Academic Unit
- Chemistry, Department of
- Publisher
- Elsevier Ltd
- Identifiers
- 99900546834701842
- Language
- English
- Resource Type
- Journal article