Betulinol derivatives as anti-HIV agents

a technology of betulinol and derivatives, which is applied in the direction of biocide, immunological disorders, drug compositions, etc., can solve the problems of limited anti-hiv-1 activity, difficult manufacturing, and high cost of drugs, and achieve superior anti-hiv-1 activity and anti-hiv-1 activity. superior

Inactive Publication Date: 2006-07-13
SAXENA BRIJ B +1
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0152] While the prior art discloses a number of different betulinol derivatives having antiviral activity, the betulinol derivatives of the present invention are particularly effective against Human Immunodeficiency Virus and, in particular, HIV-1. Moreover, the betulinol deriva

Problems solved by technology

However, these currently acceptable treatment drugs are limited by either their toxicity or the emergence of drug-resistant HIV strains (Evers et al., J. Med. Chem. 39:1056-1063 (1996)).
In addition, these drugs are costly, difficult to manufacture, and have adverse side effects.
Unfortunately, however, many of these betulinol derivative compounds have significant drawbacks to their use.
In addition, no current anti-HIV agent, with the exception of α-interferon, has any effect on release of virus from a chro

Method used

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  • Betulinol derivatives as anti-HIV agents
  • Betulinol derivatives as anti-HIV agents
  • Betulinol derivatives as anti-HIV agents

Examples

Experimental program
Comparison scheme
Effect test

example 1

Isolation and Structure of Betulinol and its Derivatives

[0417] Betulinol is isolated from the non-saponofiable fraction of the crude sulfate soap prepared by boiling the outer bark of the white birch tree in NaOH, Na2SO4, Na2SO3, and Na2S2O3 at 110-120° C. Betulinol is then crystallized by using solvents such as acetone, ethyl acetate, isopropanol, butanol, ethanol, etc. The chemical structure of betulinol is:

[0418] Betulinol is a non-steroidal, lupeol-derived, pentacyclical, lupan-row alcohol of the group of styrenes. Betulinol (also known as betulin) has a chemical formula of C30H50O2 and a molecular weight of 442.7 g / mol. The structure of betulinol is based on a 30-carbon skeleton of four, six-member rings and one, five-member E-ring containing an a-isopropyl group. The structural component of betulinol has a primary and a secondary hydroxyl group at C-3 and C-28. Betulinol has three sites (C-3, C-20, and C-28) where chemical modification can occur to yield derivatives. With t...

example 2

Synthesis of Betulonic Acid from Betulinol

[0420]

[0421] In a typical procedure, 500 mg of betulinol (1) was added to a suspension of 1.2 g of freshly activated 4 Å molecular sieves, 1.2 g of celite, 1.2 g of florisil, 500 mg of sodium acetate, and 1.2 g of pyridinium chlorochromate in 25 mL of CH2Cl2. The mixture was stirred for 2 hrs, and then filtered through a 2.5×15 cm column silica gel of 230-400 mesh and 60 Å (HF-254, E. Merck). The filtrate was evaporated in vacuum. The residue was subjected to column chromatography of silica gel to recover 370 mg of betulone aldehyde (2) as white solid. This betulone aldehyde was dissolved in 17 mL CH3CN—H2O containing 877 mg of NaH2PO4.H2O and cooled to 0-5° C. 220 μL of 30% of aqueous H2O2 and 200 mg of NaClO2 dissolved in 16 mL water were added in tandem. The mixture was brought up to room temperature and stirred for one hour. The reaction was quenched by the addition of 380 mg of Na2S2O5. The betulonic acid was extracted with 300 mL ethy...

example 3

Results of Chemistry Characterizations: GC

[0422] The purity of betulonic acid and its derivatives was studied by taking gas chromatographic profiles. 8 μL of each sample was injected to yield the following retention time (tR):

TABLE 2Retention Times from Gas Chromatogram ProfilesSampleRetention Time (tR)Betulonic Acid11.044Monomer10.936Dimer10.793

[0423] FIGS. 1A-C show a typical chromatogram of betulonic acid and its derivatives with their corresponding retention time. Close examination of these chromatograms reveals that the conjugated betulonic acid monomer and dimer, gave neat chromatograms.

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Abstract

The present invention relates to methods of treating HIV-1 infection in a subject. These methods involve administering to the subject with HIV-1 infection a therapeutically effective amount of a conjugated or immunoconjugated betulinol derivative compound, or a pharmaceutically acceptable salt or derivative thereof, under conditions effective to treat the subject for HIV-1 infection. Also disclosed are methods inhibiting HIV-1 activity in a cell. These methods involve providing a cell infected with HIV-1 and contacting the cell with a conjugated or immunoconjugated betulinol derivative compound, or a pharmaceutically acceptable salt or derivative thereof, under conditions effective to inhibit HIV-1 activity in the cell.

Description

[0001] This application claims the priority benefit of U.S. Provisional Patent Application Ser. No. 60 / 609,080, filed Sep. 10, 2004, U.S. Provisional Patent Application Ser. No. 60 / 630,103, filed Nov. 22, 2004, and U.S. Provisional Patent Application Ser. No. 60 / 630,150, filed Nov. 22, 2004, which are hereby incorporated by reference in their entirety.FIELD OF THE INVENTION [0002] The present invention relates generally to methods of treating HIV-1 infection in a subject and methods of inhibiting HIV-1 activity in a cell using betulinol derivative compounds. BACKGROUND OF THE INVENTION [0003] Human Immunodeficiency Virus (“HIV”), the virus that causes AIDS, has reached pandemic proportions in the world. Some one million people are infected with HIV in the U.S. alone, and more than forty million worldwide. Each day, approximately 12,000 adults and 1,800 children become infected. Currently, there are three classes of drug treatments for HIV, namely, reverse transcriptase (“RT”) inhibi...

Claims

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Application Information

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IPC IPC(8): A61K31/56
CPCA61K31/56A61P31/18A61P35/00A61P37/00
Inventor SAXENA, BRIJRATHNAM, PREMILA
Owner SAXENA BRIJ B
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