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Diarylalkanes as potent inhibitors of binuclear enzymes

Inactive Publication Date: 2005-12-01
UNIGEN PHARM INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0025] The method can also be used for preventing and treating skin darkening and damage resulting from exposure to ultraviolet (UV) radiation, chemicals, heat, wind and dry environments. Finally, the method can be used for preventing and treating wrinkles, saggy skin, lines and dark circles around the eyes, soothing sensitive skin and preventing and treating dermatitis and other allergy related conditions of the skin. In addition to their use for the prevention and treatment of the above described diseases and conditions of the skin, the therapeutic compositions described herein provide an efficacious composition that yields the benefit of smooth and youthful skin appearance with improved skin color, enhanced elasticity, reduced and delayed aging, enhanced youthful appearance and texture, and increased flexibility, firmness, smoothness and suppleness.
[0027] In yet another embodiment, the dialkylalkanes and dialkyl alkanols can be used in the food industry to prevent browning and color changes in fruits, mushrooms and other food products.

Problems solved by technology

Asians and light-skinned people have lower levels of eumelanin than dark-skinned people, and correspondingly less protection against the effects of radiation.
Any compound, which interferes with the access, ligand formation, or the oxidation of monophenols at the active site of tyrosinase, will be an efficient inhibitor of tyrosinase, potentially resulting in a decrease in the production of melanin and lighter skin color.
If applied over long periods of time or in high concentrations hydroquinones can have serious side effects.
Additionally, hydroquinones may lead to permanent de-pigmentation, and thus to increased photosensitivity of the skin when exposed to UV light.
However, two prenylated diarylpropanes isolated from the same plant exhibited cytotoxicity against several cancer cell lines (Ko et al.

Method used

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  • Diarylalkanes as potent inhibitors of binuclear enzymes
  • Diarylalkanes as potent inhibitors of binuclear enzymes
  • Diarylalkanes as potent inhibitors of binuclear enzymes

Examples

Experimental program
Comparison scheme
Effect test

example 1

Preparation of Organic Extracts from Dry Plants

[0118] Dried plant material was ground to a particle size of no larger than 2 mm and a portion (60 g) was transferred to an Erlenmeyer flask and extracted with 600 ml of methanol:dichloromethane (1:1). The mixture was shaken for one hour, filtered and the biomass was extracted again with methanol:dichloromethane (1:1) (600 ml). The organic extracts were combined and evaporated under vacuum to provide an organic extract from each plant material. Each extract (approximately 75 mg) was then dissolved in 1.5 ml DMSO to a concentration of 50 mg / ml, which was then stored in a −70° C. freezer. An aliquot of the extract solution was used for tyrosinase assay as described in Example 2.

example 2

Tyrosinase Inhibition Assay

[0119] A tyrosinase inhibition assay was carried out using the method reported by Jones et al. (2002) Pigment. Cell Res. 15:335. Using this method, the conversion of L-Dopa, a substrate of tyrosinase, into dopachrome is followed by monitoring absorption at 450 nm. Tyrosinase was prepared in 50 mM potassium phosphate buffer, pH 6.8 (assay buffer) at 2000 U / ml and stored at −20° C. in 1 ml aliquots prior to use. For use in assays, stock enzyme solutions were thawed and diluted to 200 U / ml with assay buffer. A 2 mM working solution of substrate, L-DOPA, was prepared in assay buffer for each assay. Samples were dissolved in 10% DMSO (0.5 ml) and diluted to 5 ml with assay buffer. The reaction mixture consisted of 0.050 ml 2 mM L-DOPA, 0.050 ml 200 U / ml mushroom tyrosinase and 0.050 ml inhibitor. Reaction volume was adjusted to 200 μl with assay buffer. Assays were performed in 96 well Falcon 3097 flat-bottom microtiter plates (Beckton Dickinson, N.J.). Appear...

example 3

HTP Fractionation of Active Plant Extracts

[0121] Active organic extract (400 mg) was loaded onto a prepacked, normal phase, flash column. (2 cm ID×8.2 cm, 10 g silica gel). The column was eluted using a Hitachi high throughput purification (HTP) system with a gradient mobile phase of (A) 50:50 EtOAc:hexane and (B) methanol from 100% A to 100% B in 30 minutes at a flow rate of 5 mL / min. The separation was monitored using a broadband wavelength UV detector and the fractions were collected in a 96-deep-well plate at 1.9 mL / well using a Gilson fraction collector. The sample plate was dried under low vacuum and centrifugation. DMSO (1.5 mL) was used to dissolve the samples in each cell and a portion (100 μL) was taken for the tyrosinase inhibition assay in duplicate.

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Abstract

The present invention implements a strategy that combines an enzyme inhibition assay with a chemical dereplication process to identify active plant extracts and the particular compounds—diarylalkanes and / or diarylalkanols within those extracts that specifically inhibit binuclear enzyme function. Included in the present invention are compositions of matter comprised of one or more of diarylalkanes and / or diarylalkanols, which inhibit the activity of binuclear enzymes, particularly tyrosinase and which prevent melanin overproduction. The present invention also provides a method for inhibiting the activity of a binuclear enzyme, particularly tyrosinase and a method for preventing and treating diseases and conditions related to binuclear enzyme function. The present invention further includes a method for preventing and treating melanin overproduction and diseases and conditions of the skin related thereto. The method for preventing and treating diseases and conditions related to binuclear enzyme function and melanin overproduction is comprised of administering to a host in need thereof an effective amount of a composition comprising one or more diarylalkanes and / or diarylalkanols synthesized and / or isolated from one or more plants together with a pharmaceutically acceptable carrier.

Description

RELATED APPLICATIONS [0001] This application claims the benefit of U.S. Provisional Application Ser. No. 60 / 575,599, filed May 28, 2004, entitled “Diarylalkanes as Potent Inhibitors of Binuclear Enzymes,” which is incorporated herein by reference in its entirety.FIELD OF THE INVENTION [0002] This invention relates generally to the prevention and treatment of diseases and conditions mediated by binuclear enzymes. Specifically, the present invention includes a method for inhibiting the activity of an enzyme having a binuclear active site. Included in the present invention are novel compositions comprised of one or more diarylalkane(s). The diarylalkanes of the present invention can be isolated from one or more plant sources or can be obtained by organic synthesis. Further included in the present invention are methods for isolating these compounds from a natural source and methods for synthesizing these compounds. In one embodiment, the diarylalkanes are obtained by synthetic modificat...

Claims

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Application Information

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IPC IPC(8): A61K31/015A61K31/05A61K31/704C07C39/15C07C39/367C07C43/23C07C45/67C07C49/835C07C215/74C07D321/12
CPCA61K31/015C07C41/32A61K31/085A61K31/09A61K31/357A61K31/40A61K31/704C07C39/15C07C39/367C07C43/23C07C45/673C07C49/835C07C215/74C07D321/12A61K31/05C07C41/26A61K8/347A61Q19/02A61K8/31A61K2800/782A61K8/9789A61K8/9794A61P1/02A61P1/12A61P1/16A61P15/00A61P15/08A61P17/00A61P17/02A61P17/16A61P17/18A61P19/02A61P19/10A61P25/00A61P25/04A61P25/08A61P25/16A61P25/20A61P25/28A61P27/02A61P29/00A61P3/00A61P3/04A61P3/12A61P31/04A61P31/10A61P31/12A61P33/06A61P35/00A61P3/06A61P37/02A61P37/04A61P37/08A61P39/06A61P43/00A61P7/06A61P9/00A61P9/10A61P9/12A61P3/10Y02A50/30A61K8/4973
Inventor JIA, QIZHAO, JI-FU
Owner UNIGEN PHARM INC
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