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Perillyl alcohol-3-bromopyruvate conjugates and methods of treating cancer

A technology of bromopyruvate and perillyl alcohol, applied in the field of cancer treatment, can solve the problems of patient death and low anticancer effect

Active Publication Date: 2022-04-19
UNIV OF SOUTHERN CALIFORNIA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This treatment appeared to be the least toxic, but its anticancer efficacy was low and the patient eventually died [25]

Method used

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  • Perillyl alcohol-3-bromopyruvate conjugates and methods of treating cancer
  • Perillyl alcohol-3-bromopyruvate conjugates and methods of treating cancer
  • Perillyl alcohol-3-bromopyruvate conjugates and methods of treating cancer

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0073] Example 1: Preparation of POH-bromopyruvate (3-bromo-2-oxoylidene-propionic acid 4-isopropenyl-cyclohex-1-enylmethyl ester);

[0074]

[0075] 1,1-Dichlorodimethyl ether (2.5 g, 21.74 mmol) was slowly added to solid bromopyruvic acid (1) while keeping the temperature below 20°C. The resulting slurry was slowly heated to 50 °C and stirred for 2.5 h. The clear liquid was cooled and the excess dichlorodimethyl ether was concentrated in vacuo to obtain 3-bromopyruvyl chloride (2) in greater than 95% yield.

[0076] 3-Bromopyruvyl chloride (2.0 g, 10.78 mmol) was added to a low temperature mixture of perillyl alcohol (3) (1.5 g, 9.85 mmol), sodium bicarbonate (11.90 mmol) and n-heptane (180 mL) while maintaining the temperature at below 10°C. The mixture was stirred at 10 °C for 20 min and then allowed to warm to room temperature. The reaction mixture was stirred for 18 h and quenched with water (75 mL). The organic layer was separated and washed with brine (75 mL) an...

Embodiment 2

[0224] Example 2 Perillyl alcohol-conjugated 3-bromopyruvate analogs, cellular uptake is independent of monocarboxylic acid transporter 1 and is active in 3-BP-resistant tumor cells

[0225] Abbreviations: 3-BP: 3-bromopyruvate; CFA: colony formation assay; GAPDH: glyceraldehyde 3-phosphate dehydrogenase; GSH: glutathione; MCT-1: monocarboxylic acid transporter 1; NAC: N - Acetylcysteine; NEO218: perillyl alcohol conjugated to 3-bromopyruvate; POH: perillyl alcohol; ROS: reactive oxygen species; SDH: succinate dehydrogenase complex.

[0226] Summary

[0227] The anticancer agent 3-bromopyruvate (3-BP) is considered a glycolytic inhibitor that preferentially kills glycolytic cancer cells through energy depletion. However, its cytotoxic activity is dependent on drug import into cells via transmembrane monocarboxylate transporter 1 (MCT-1), which limits its anticancer potential to MCT-1-positive tumor cells. We produced and characterized an MCT-1-independent 3-BP analog, termed...

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PUM

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Abstract

NEO218 (3-bromo-2-oxyylidene-propionic acid 4-isopropenyl-cyclohex-1-enyl methyl ester) (see formula I) is produced from two unrelated reagents: 3-bromopyruvate (3‑BP; an alkylating agent that inhibits cancer cell metabolism) and perillyl alcohol (POH; a natural monoterpene with anticancer properties) resulting in a novel molecule. Also disclosed are methods of synthesizing NEO218, pharmaceutical compositions comprising NEO218, and methods of using NEO218 to treat cancer.

Description

technical field [0001] The present invention relates to novel conjugates of perillyl alcohol and 3-bromopyruvate, and the use of said compounds in the treatment of cancer. Background technique [0002] Perillyl alcohol (“POH”) is a monoterpene and is a natural constituent of caraway, lavender and clove oils, cherry, cranberry, sage, peppermint, celery seed, and certain other plants [1] ]. The findings that this monoterpenoid was able to inhibit the growth of tumor cells in cell culture and exerted both preventive and therapeutic activity against cancer in a variety of animal tumor models led to medical interest in this compound (for details, see ref. [2]). Its mode of action is thought to involve inhibition of Ras oncoprotein function [3], but newer studies suggest that additional intracellular targets may mediate its biological effects, such as telomerase [4], mammalian target of rapamycin (mTOR) [5,6] and sodium / potassium adenosine triphosphatase (Na / K-ATPase) [7]. In ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A01N43/52A61K31/045A61K31/05A61K31/27
CPCA61K31/22C07C69/716C07C2601/16A61K2300/00A61P35/00A61P35/04A61K31/19A61K31/045A61K35/00C07C67/08
Inventor T·陈
Owner UNIV OF SOUTHERN CALIFORNIA
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