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Estrogen amino-acid ester compound with antitumor activity as well as synthetic method thereof

A technology of steroidal amino acid ester and anti-tumor activity, applied in the field of medicine, can solve the problems of poor water solubility, low bioavailability, and restrictions on wide application, and achieve the effect of good water solubility

Active Publication Date: 2012-10-03
ZHENGZHOU UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, 2-ME has defects such as poor water solubility and low bioavailability, which limit its wide application.

Method used

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  • Estrogen amino-acid ester compound with antitumor activity as well as synthetic method thereof
  • Estrogen amino-acid ester compound with antitumor activity as well as synthetic method thereof
  • Estrogen amino-acid ester compound with antitumor activity as well as synthetic method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0034] Example 1: Preparation of 2-methoxy-3,17β-dihydroxy-1,3,5(10)-estratriene-17-β-alanine ester

[0035] (1), the preparation of N-benzyloxycarbonyl-beta-alanine

[0036] At 5°C, 10 mmol of β-alanine was dissolved in 4.0 ml of 10% sodium hydroxide (NaOH) aqueous solution to obtain a solution, and 14 mmol (i.e. 1.8 ml) of benzyl chloroformate was added while stirring. Add dropwise to the solution solution at a speed of 1 drop / 4 seconds for reaction, and add dropwise a 10% sodium hydroxide (NaOH) aqueous solution to keep the pH at 8. After the drop is complete, place it at 10°C and stir for 15 minutes. After 1 hour, use ninhydrin as the color developing agent to develop the color without purple color, then wash with 5ml / time ether for 3 times, discard the ether to obtain the aqueous phase, and adjust the pH of the aqueous phase to 3 with concentrated hydrochloric acid with a mass concentration of 30%. A milky white solid appeared, and the liquid after the milky white solid ...

Embodiment 2

[0041] Example 2: Preparation of 16α-ethyl-2-methoxy-3,17β-dihydroxy-1,3,5(10)-estratriene-17-L-phenylalanine ester

[0042] (1), the preparation of N-benzyloxycarbonyl-L-phenylalanine

[0043] At -3°C, 10 mmol of L-phenylalanine was dissolved in 4.0 ml of 9% sodium hydroxide (NaOH) aqueous solution to obtain a solution, and 14 mmol (i.e. 1.8 ml) of chloroformic acid was added while stirring. The benzyl ester is added dropwise to the solution at a speed of 1 drop / 5 seconds for reaction, and a 9% sodium hydroxide (NaOH) aqueous solution is added dropwise to keep the pH at 8. After the drop is completed, place it at 15°C and stir React for 15 hours, do TLC detection, after the solution is completely reacted, wash 3 times with 5ml / time of diethyl ether, discard the diethyl ether to obtain the water phase, and adjust the pH of the water phase to 2 with concentrated hydrochloric acid with a mass concentration of 35%. , a milky white solid appeared, and the liquid after the milky w...

Embodiment 3

[0048] Example 3: 16α-(N,N-dimethyl)aminomethyl-2-methoxy-3,17β-dihydroxy-1,3,5(10)-estratriene-17-L-leu Preparation of Amino Acid Esters

[0049] (1), the preparation of N-benzyloxycarbonyl-L-leucine

[0050] At 2°C, 10 mmol of L-leucine was dissolved in 4.0 ml of 8% sodium hydroxide (NaOH) aqueous solution to obtain a solution, and 14 mmol (i.e. 1.8 ml) of benzyl chloroformate was added while stirring. Add dropwise to the solution solution at a speed of 1 drop / 6 seconds for reaction, and add dropwise an aqueous solution of sodium hydroxide (NaOH) with a mass concentration of 8% to keep the pH at 9. After the drop is complete, place it at 20°C and stir for 15 minutes. After 1 hour, use ninhydrin as the color developing agent to develop the color without purple color, then wash with 5ml / time of diethyl ether for 3 times, discard the diethyl ether to obtain the aqueous phase, and adjust the pH of the aqueous phase to 1 with concentrated hydrochloric acid with a mass concentrat...

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Abstract

The invention relates to an estrogen amino-acid ester compound with antitumor activity as well as a synthetic method thereof, effectively solving the preparation problems of the estrogen amino-acid ester compound with the antitumor activity. The synthetic method comprises the following steps of: dissolving amino acids or small molecule peptides to an aqueous solution of sodium hydroxide or a saturated solution of sodium bicarbonate, dripping carbobenzoxy chloride, making the solution react until the solution is not purple by developing with ninhydrin or carrying out film detection; washing with aether, removing aether, adjusting the pH value of the water phase with hydrochloric acid until milky white solid occurs and extracting with ethyl acetate; washing mixed solution with distilled water and saturated common salt solution, drying with anhydrous magnesium sulfate, carrying out suction filtration, concentrating and purifying; and then, mixing the mixed solution with sterides nucleus and dissolving the mixture to a reaction solvent, adding a condensing agent and a catalyst, supplementing an additional condensing agent, carrying out film detection, filtering, concentrating and purifying, dissolving in a dissolving solvent, adding palladium carbon for catalytic hydrogenation, detecting the film, filtering, concentrating and purifying. The estrogen amino-acid ester compound withantitumor activity, provided by the invention, has favorable water solubility and is superior to 2-methoxyestradiol in the tumor cell resistance action.

Description

1. Technical field [0001] The invention relates to the field of medicine, in particular to an estroamino acid ester compound with antitumor activity and a synthesis method thereof. 2. Background technology [0002] 2-Methoxyestradiol (2-ME), as a hormone compound, is the end product of estradiol metabolism in the body. In recent years, it has been found that it has a very broad-spectrum anti-tumor activity, which can be used to treat multiple myeloma, prostate cancer, breast cancer, thyroid cancer and other diseases. It has a broad-spectrum anti-tumor effect, and some cancer cells that have developed resistance to 2-ME is very sensitive. The mechanism of 2-ME is different from that of traditional antitumor drugs. Its antitumor mechanism is mainly: inhibiting cell proliferation; inducing apoptosis of tumor cells and endothelial cells; anti-angiogenesis; promoting cell cycle arrest; enhancing the radiation resistance of tumor cells. Sensitivity and more. However, 2-ME has d...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07J41/00C07J43/00C07K5/06C07K5/08C07K5/10C07K5/12A61P35/00
Inventor 张振中施秀芳张崇威张红岭马岩
Owner ZHENGZHOU UNIV
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