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Betulinol derivatives as anti-cancer agents

a technology of betulinol and derivatives, applied in the field of cancer treatment, can solve the problems of limited use of terpenoids such as betulinol and its derivatives as pharmaceuticals, impeded or completely absent biological activity of such mammals (including humans), and achieve the effect of high bioavailability and effective

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

AI Technical Summary

Benefits of technology

[0145] An advantage of betulinol derivative compounds of the present invention is that they are soluble in biocompatible solvent. This advantage allows the compounds of the present invention to be used as injectables to yield higher biovailability as drug compounds and therefore makes them more effective in the treatment of cancerous conditions than compounds that have been previously described. The compounds of the present invention are also suitable for forming desirable ratios of drug to immunoconjugates to allow optimum dose-response.

Problems solved by technology

Development of early diagnostic methods as well as drugs to treat cancer remains one of the most challenging demands on medical research.
However, betulonic acid and the known betulinol derivatives are generally insoluble in aqueous environment or other pharmaceutically acceptable solvents.
Absent this property, administration of the pharmaceutical agent to mammals can be difficult and biologically activity in such mammals (including humans) may be impeded or entirely absent.
Due to their limited solubility in aqueous solutions, the use of terpenoids such as betulinol and it derivatives as pharmaceuticals has been limited.

Method used

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  • Betulinol derivatives as anti-cancer agents
  • Betulinol derivatives as anti-cancer agents
  • Betulinol derivatives as anti-cancer agents

Examples

Experimental program
Comparison scheme
Effect test

example 1

Isolation and Structure of Betulinol and its Derivatives

[0362] 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:

[0363] 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

[0366]

[0367] 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

[0368] 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 3Retention Times from Gas Chromatogram ProfilesSampleRetention Time (tR)Betulonic Acid11.044Monomer10.936Dimer10.793

[0369] 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 betulonic acid, monomer and dimer, gave neat chromatograms.

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Abstract

The present invention relates to a method of treating cancer selected from the group of cancers consisting of prostate cancer, renal cancer, breast cancer, ovarian cancer, CNS cancer, melanoma, lung cancer, and bladder cancer. This method involves administering to a patient in need of such treatment a therapeutically effective amount of a betulinol derivative compound of Formula I Also disclosed are conjugated and immunoconjugated derivatives of the compound of Formula I as well as methods of making and using them.

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 cancer as well as conjugated and immunoconjugated betulinol derivative compounds and methods of making them. BACKGROUND OF THE INVENTION [0003] Development of early diagnostic methods as well as drugs to treat cancer remains one of the most challenging demands on medical research. There is also an increasing interest in tumor-associated antigens as potential targets for the diagnosis and as targets for site directed drug delivery of cancer chemotherapeutic agents. Use of immunoconjugates of drugs with antibodies directed to tumor associated ant...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/56
CPCA61K31/56A61P31/18A61P35/00A61P37/00
Inventor SAXENA, BRIJRATHNAM, PREMILA
Owner SAXENA BRIJ B
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