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 towards 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.Nordihydroguaiaretic acid (NDGA, Figure 1) is isolated from the resinous extract of the creosote bush Larrea divaricata. 1 It has also been reported that NDGA inhibits the growth of tumors, both in vitro and in vivo 2 but relatively high concentrations are required to achieve efficacy in most cases. Preliminary in vivo studies have revealed that NDGA inhibits tumor growth by inhibiting receptor tyrosine kinase (RTK) phosphorylation. 3 NDGA has been shown to inhibit several RTKs overexpressed in certain cancer cells. In a previous study, we noted that NDGA inhibits both the IGF-1R and HER2/neu with moderate potency and impairs subsequent signaling through the anti-apoptotic pathway in breast cancer cell. 3, 4 These and other RTKs such as the epidermal growth factor receptor (EGFR) are overexpressed in breast and other cancers and contribute to a poor prognosis 5-7 .Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal ...
A concise and enantioselective total synthesis of (+)-aigialospirol is described here, featuring the first complex natural product synthesis that employs a cyclic ketal-tethered ring-closing metathesis strategy and an unexpected stereoselective epimerization of a benzylic hydroxyl group. The 15-step synthetic sequence illustrates the proof-of-concept that such an approach can be competitive with the classical spiroketal formation in the natural product synthesis.
Two remarkable epimerization processes were uncovered during our pursuit of an enantioselective synthesis of (+)-aigialospirol featuring a cyclic acetal tethered ring-closing metathesis. Through modeling, we were able to turn these two unexpected epimerizations to our advantage via modeling to ensure a successful and concise total synthesis, thereby firmly establishing cyclic acetal tethered RCM as a powerful strategy in natural product synthesis. Most importantly, calculations allowed us to fully understand the nature and the mechanistic course of these two epimerizations that were imperative to the total synthesis efforts.
The Somatic Connection" highlights and summarizes important contributions to the growing body of literature on the musculoskeletal system's role in health and disease. This section of The Journal of the American Osteopathic Association (JAOA) strives to chronicle the significant increase in published research on manipulative methods and treatments in the United States and the renewed interest in manual medicine internationally, especially in Europe. To submit scientific reports for possible inclusion in "The Somatic Connection," readers are encouraged to contact JAOA Associate Editor Michael A. Seffinger, DO
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