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Trioxane dimer compound having antiproliferative and antitumor activities

a trioxane dimer and antiproliferative technology, applied in the field of new trioxane dimers, can solve the problems of difficult task for scientists to modify qhs chemically

Inactive Publication Date: 2003-05-06
THE JOHN HOPKINS UNIV SCHOOL OF MEDICINE
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although QHS is effective at suppressing the parasitemias of P. vivax and P. falciparum, the problems encountered with recrudescence, and the compound's insolubility in water, led scientists to modify QHS chemically, a difficult task because of the chemical reactivity of the peroxide linkage which is an essential moiety for antimalarial activity.

Method used

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  • Trioxane dimer compound having antiproliferative and antitumor activities
  • Trioxane dimer compound having antiproliferative and antitumor activities
  • Trioxane dimer compound having antiproliferative and antitumor activities

Examples

Experimental program
Comparison scheme
Effect test

example 1

Preparation of Trioxane Ether Dimer (6)

A flame-dried 10 mL round-bottomed flash was charged with 2,6-di-tert-butyl-4-methylpyridine (30.0 mg, 0.15 mmole) and methylene chloride (2 mL) at room temperature. To this mixture at 0.degree. C. was added trifluoromethanesulfonic anhydride (25.0 .mu.L, 0.15 mmole) via gas-tight syringe. A solution of trioxane alcohol (20.0 mg, 0.07 mmole) in methylene chloride (0.5 mL) was cooled to 0.degree. C. and added to the reaction mixture via cannula. The reaction was stirred at 0.degree. C. for 3 hours. The reaction was monitored by TLC until all trioxane alcohol was consumed.

The reaction was quenched with saturated sodium bicarbonate (3 mL) at 0.degree. C. and diluted with methylene chloride (5 mL). Two layers were separated and the aqueous phase was extracted with methylene chloride (3.times.5 mL). The combined organic layers were washed with brine (15 mL), dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude pr...

example 2

Preparation of Trioxane Dimer (7)

To a flame-dried round-bottomed flask charged with 2,6-di-t-butyl-4-methylpyridine (22 mg, 0.11 mmol) in dry methylene chloride (1 mL) at 0.degree. C. was added freshly opened triflic anhydride (18 .mu.L, 0.11 mmol) via a syringe under argon atmosphere. After being stirred for 5 minutes the reaction mixture was slowly treated with a precooled solution of 4.beta.-methyltrioxane alcohol (15 mg, 0.053 mmol) in methylene chloride (0.5 mL) at 0.degree. C. via a cannula. The resultant mixture was stirred for 2.5 hours at 0.degree. C., quenched with water (3 mL) at 0.degree. C. and diluted with ether (5 mL), the organic layer was separated, and the aqueous layer was extracted twice with ether (5 mL.times.2). The combined organic layer was washed with brine solution (5 mL), and dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to yield a crude product which was purified by silica gel column chromatography using 2:98 et...

example 3

Preparation of Trioxane Dimer (8)

To a flame-dried round-bottomed flask charged with 2,6-di-t-butyl-4-methylpyridine (22 mg, 0.11 mmol) in dry methylene chloride (1 mL) at 0.degree. C. was added freshly opened triflic anhydride (18 .mu.L, 0.11 mmol) via a syringe under argon atmosphere. After being stirred for 5 minutes the reaction mixture was slowly treated with a precooled solution of 4.beta.-benzyltrioxane alcohol (15 mg, 0.053 mmol) in methylene chloride (0.5 mL) at 0.degree. C. via a cannula. The resultant mixture was stirred for 2.5 hours at 0.degree. C., quenched with water (3 mL) at 0.degree. C. and diluted with ether (5 mL), the organic layer was separated, and the aqueous layer was extracted twice with ether (5 mL.times.2). The combined organic layer was washed with brine solution (5 mL), and dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to yield a crude product which was purified by silica gel column chromatography using 2:98 et...

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Abstract

Described herein are novel trioxane dimers of structurewhich possess antiproliferative and antitumor activities.

Description

CONTRACTUAL ORIGIN OF THE INVENTIONThe study was supported by National Institutes of Health grant A1 34885 (to G. H. P.) and joint inventors G. H. P. and P. P. have assigned their rights to the Johns Hopkins University.BACKGROUND OF THE INVENTION1. Field of the InventionThe present invention relates to a novel class of trioxane dimers which demonstrate potent and potentially therapeutically valuable antiproliferative and antitumor activities.2. Description of the State of ArtArtemisia annua L., also known as qing hao or sweet wormwood, is a pervasive weed that has been used for many centuries in Chinese traditional medicine as a treatment for fever and malaria. Its earliest mention, for use in hemorrhoids, occurs in the Recipes for 52 Kinds of Diseases found in the Mawangdui Han dynasty tomb dating from 168 B.C. Nearly, five hundred years later Ge Hong wrote the Zhou Hou Bei Ji Fang (Handbook of Prescriptions for Emergency Treatments) in which he advised that a water extract of qing...

Claims

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Application Information

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Patent Type & Authority Patents(United States)
IPC IPC(8): C07D519/00
CPCC07D519/00A61K47/55
Inventor ZHENG, QUN Y.MURRAY, CHRISTOPHERDAUGHENBAUGH, RANDALL J.PLOYPRADITH, POONSAKDIPOSNER, GARY H.
Owner THE JOHN HOPKINS UNIV SCHOOL OF MEDICINE
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