Taccalonolide microtubule stabilizers

A technology of hydroxyl and compound, applied in the field of arrowroot diosconolactone microtubule stabilizer, can solve problems that need to be elucidated

Inactive Publication Date: 2019-12-27
BOARD OF RGT THE UNIV OF TEXAS SYST +3
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, a full understanding of the structure-activity relationship of diosconolactone remains to be elucidated

Method used

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  • Taccalonolide microtubule stabilizers
  • Taccalonolide microtubule stabilizers
  • Taccalonolide microtubule stabilizers

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Embodiment Construction

[0067] Arrown diostrogenolides are a unique class of microtubule stabilizers that are active against drug-resistant cells in vitro and in vivo. In the work described below, the present inventors generated novel diostrolides, including diostrolides AF, AJ and AI-epoxides, by isolation and semisynthesis.

[0068] The dioscolide structure was determined by 1D and 2D NMR methods. Each of these dioscolides stabilizes cellular microtubules, leading to the formation of microtubule bundles and mitotic accumulation in cancer cells with multiple aberrant mitotic spindles. IC 50 Values ​​range from the low nanomolar range of diostenolactone AI-epoxide (0.73 nM) and diostonolactone AJ (4.3 nM) to the low micromolar range of diostenolactone R (13 μM) . These studies demonstrate that a variety of diosconolides have microtubule-stabilizing properties and significant structure-activity relationships. These and other aspects of the invention are discussed further below.

[0069] Arrowroot...

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Abstract

The present disclosure relates to the fields of medicine and pharmaceuticals. In particular, the invention relates to the identification of epoxytaccalonolide microtubule stabilizers for use in inhibiting cell proliferation and disrupting normal cellular microtubule processes leading to cell death. This abstract is intended as a scanning tool for purposes of searching in the particular art and isnot intended to be limiting of the present invention.

Description

[0001] Cross References to Related Applications [0002] This application claims the benefit of US Provisional Application No. 62 / 434,919, filed December 15, 2016, which is hereby incorporated by reference in its entirety. [0003] thank you [0004] This invention was made with government support under Grant Number CA121138 awarded by the National Institutes of Health. The government has certain rights in this invention. Background technique [0005] Microtubules are cellular structures important for normal cell metabolism, cell transport, and cell division. Disruption of microtubule-dependent processes leads to cellular defects, including inhibition of proliferation and cellular trafficking, leading to initiation of cell death pathways. Microtubule disruptors, including microtubule stabilizers, are among the most important anticancer therapies in clinical use today. Additionally, microtubule stabilizers are used in other human hyperproliferative diseases, including cardi...

Claims

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Application Information

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IPC IPC(8): A61K31/585A61K36/894
CPCA61K36/894A61K31/585A61P35/00C07J17/00C07J71/0005
Inventor 安东尼奥斯·奥拉余倩文苏珊·L·莫贝里艾普尔·L·赖辛格罗伯特·H·希彻维茨杜林李静彭江南
Owner BOARD OF RGT THE UNIV OF TEXAS SYST
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