JP2011178734A - Izumiphenazine a - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a new chemical substance bringing a useful effect to a human body as a resource. <P>SOLUTION: This izumiphenazine A is expressed by formula in the drawing. Also, a medicine containing at least any of the izumiphenazine A or its salt as an active ingredient is provided. <P>COPYRIGHT: (C)2011,JPO&INPIT

Description

  The present invention relates to a novel compound, izumiphenazine A, and further to a drug using them.

  In our current life, chemicals contained in the body of natural animals and plants, microorganisms, etc. (hereinafter referred to as “natural products”) are effective in the use of crude drugs and pharmaceuticals that have a beneficial effect on the human body. Used as an ingredient. Moreover, such a thing has various roles also as a research material for developing a more useful pharmaceutical, and is very important.

  As described above, as a report on the search for natural products that have a beneficial effect on the human body, for example, Non-Patent Document 1 listed below extracts a bisindole compound, a naphthoquinone compound, a glyceride compound, and the like from a deformed bacterium.

Masami Ishibashi, “Recycling unused fungi: Search for natural products from deformed bacteria”, Journal of Synthetic Organic Chemistry, 2003, Vol. 61, No. 2, pp. 152-163

  However, on the other hand, despite the fact that many people have been searching for natural products, less than 10% of all the species on Earth have been studied and investigated as search materials. It is said.

  An object of this invention is to provide a novel chemical substance as a resource.

Izumiphenazine A according to one means of the present invention is represented by the following formula.

In addition, a drug according to another means of the present invention contains at least one of izumiphenazine A represented by the following formula and a salt thereof as an active ingredient.

  In addition, although said medicine is not necessarily limited, it is anticipated that it will be useful as a cancer therapeutic agent.

  According to the present invention, a novel chemical substance can be provided as a resource. In particular, the chemical substance according to the present invention is expected to be used, for example, as a therapeutic agent for cancer because it exhibits a cell growth inhibitory effect on cancer cells.

FIG. 2 is a diagram showing an outline of a scheme for isolation of Izumiphenazine A It is a diagram showing the ¹ H NMR spectrum of Izumifenajin A. It is a figure which shows the ¹³ C NMR spectrum of Izumiphenazine A. It is a figure which shows the COSY spectrum of Izumiphenazine A. It is a figure which shows the HMQC spectrum of Izumiphenazine A. It is a figure which shows the HMBC spectrum of Izumiphenazine A.

  Hereinafter, embodiments of the present invention will be described. However, the present invention can be implemented in many different forms, and should not be construed narrowly only in the description of the following embodiments.

Izumiphenazine A according to one embodiment of the present invention is represented by the following formula.

  The Izumifenadine A according to the present embodiment can be extracted from Japanese soil, as will be apparent from the examples described later, but is not limited thereto, and can be synthesized.

  Izumiphenazine A according to the present embodiment is expected to be used as a drug, for example, a cancer therapeutic drug, because it exhibits a cell growth inhibitory effect on cancer cells. In addition, when utilizing izumiphenazine A as a therapeutic agent for cancer, it is preferable to contain at least one of izumifenazine A and a salt thereof as an active ingredient.

  In addition, the therapeutic agent for cancer according to the present embodiment includes at least one of the above-described Izumifenadine A and salts thereof, as well as usual pharmaceutically acceptable carriers, binders, stabilizers, excipients, Various preparation ingredients such as a diluent (for example, distilled water), a pH buffer (for example, phosphate buffered saline), a disintegrant, a solubilizer, a solubilizer, and an isotonic agent can be contained.

  Moreover, the therapeutic agent for this cancer can be administered orally or parenterally in an appropriate dose suitable for the sex, weight and symptoms of the patient. For oral administration, commonly used administration forms such as powders, granules, tablets, capsules, solutions, suspensions, oils, emulsifiers and the like can be employed. In addition, as parenteral administration, a commonly used administration form, for example, a method of administering the above-mentioned solution, suspension or the like directly to the affected area, a form of administration by injection or the like can be adopted.

  In this example, Streptomyces sp. Isolated from the soil of Tomita-cho (Izumi Forest), Wakaba-ku, Chiba City, Chiba Prefecture. The result of having extracted Izumiphenazine A from IFM11204 strain | stump | stock is shown. FIG. 1 outlines a scheme for isolation of Izumiphenazine A.

  First, the actinomycete Streptomyces sp. IFM 11204 strain was inoculated on Waxman agar medium and cultured at 28 ° C. for 3 days. After confirming the formation of colonies and spores, these were scraped and seeded on Waxmann liquid medium in a Sakaguchi flask, and cultured with shaking at 28 ° C. for 5 days. Thereafter, in order to culture the strain in large quantities, the above pre-cultured culture solution was inoculated into a newly prepared Waxman liquid medium and cultured with shaking at 28 ° C. for 5 days using a turnip flask. After culturing, 5 L of the obtained culture broth was centrifuged and divided into cells and supernatant. Here, the composition of the Waxmann medium was 2% glucose, 0.5% peptone, 0.5% meat extract, 0.3% yeast extract, 0.5% sodium chloride, and 0.3% calcium carbonate. In the case of an agar medium, 1.5% agar was included in the Waxman medium.

  The cells were extracted with acetone and concentrated under reduced pressure. The obtained acetone extract was suspended in water, and the solvent was partitioned with ethyl acetate to obtain an ethyl acetate layer. Further, the supernatant was extracted with ethyl acetate, and the obtained ethyl acetate extract and the ethyl acetate layer obtained from the cells were combined and concentrated under reduced pressure to obtain 2.1 g of a crude extract.

  The obtained crude extract was applied to a column (φ25 × 600 mm) using Sephadex LH-20 as a carrier, eluted with methanol, and 1A-1D fractions were obtained in the order of elution.

  1B (220 mg) was applied to a column (φ45 × 250 mm) using Silicagel 60N as a carrier and eluted with chloroform-methanol to obtain 2A-2C in the order of elution. Further, 2B (41 mg) was separated and purified by silica gel preparative TLC (chloroform / methanol 87/13) to isolate Izumiphenazine A (1.8 mg).

(Structure of Izumiphenazine A)
Izumiphenazine A was obtained as a red amorphous solid. This compound was presumed to be an alkaloid compound because it was a reddish-brown spot when sprayed with the Dragendorf reagent in TLC analysis.

In addition, HRESIMS was performed on Izumiphenazine A, and a peak at m / z 467.1004 estimated to be [M−H] ⁻ was observed. The molecular formula was determined as C ₂₅ H ₁₆ N ₄ O ₆ by ¹ H NMR, ¹³ C NMR, DEPT, and HMQC. 2 shows the ¹ H NMR spectrum of Izumiphenazine A, FIG. 3 shows the ¹³ C NMR spectrum of Izumiphenazine A, FIG. 4 shows the COZY spectrum of Izumiphenazine A, and FIG. 5 shows the HMQC spectrum of Izumiphenazine A. FIG. 6 shows the HMBC spectrum of Izumiphenazine A, and in particular, the following table shows ¹ H NMR and ¹³ C NMR data of Izumiphenazine A.

As shown in the above table, in the ¹ H NMR spectrum, 7 aromatic hydrogens were observed, and 4 exchangeable hydrogen signals disappearing when heavy water was added. Among them, the hydrogen signal observed as a broad singlet at δ 14.34 ppm was suggested to be derived from the hydroxyl group of carboxylic acid from the chemical shift value. In the ¹³ C NMR spectrum, a total of 25 signals including one carbonyl carbon and 20 aromatic carbon signals were observed.

In addition, ultraviolet absorption measurement (hereinafter referred to as “UV measurement”) was performed on Izumiphenazine A to obtain an ultraviolet absorption spectrum (hereinafter referred to as “UV spectrum”). This ultraviolet absorption measurement was carried out using methanol as a solvent at a concentration of 3 × 10 ⁻⁵ mol / l and a cell length of 0.2 cm. It was.

Further, specific rotation [α] _D was measured for Izumi phenazine A. The concentration of Izumiphenazine A was 0.14 g / dl in methanol solvent. As a result, the specific rotation was −480 degrees, and it was confirmed to have optical activity.

In addition, circular dichroism spectrum (CD) was measured for Izumiphenazine A. As a result, the cotton effect was exhibited at 288.4 nm (Δε-14.2), 277.6 nm (Δε8.2), 249.2 nm (Δε34.1), and 203.6 nm (Δε17.2). The strength of the cotton effect is shown in parentheses. Table 2 below shows the results of specific rotation, HRESIMS, UV measurement, CD measurement, and IR measurement.

As described above, each proton signal and each carbon signal are assigned from detailed analysis of COSY, HMQC, and HMBC spectra, and further, referring to the results of the above UV spectrum and the like, this compound has two skeletons based on phenazine as shown below. The unit was found to be a dimerized novel compound.

  The present invention comprises a novel compound as an active ingredient and has industrial applicability as a drug.

Claims (3)

Izumiphenazine A represented by the following formula.
A drug containing as an active ingredient at least one of Izumifenadine A represented by the following formula and a salt thereof.
  The drug according to claim 2, which is a therapeutic drug for cancer.