JPS63277680A - Porphyrin compound, its production and fluorescent color-developing agent containing said compound - Google Patents

Abstract

NEW MATERIAL:The porphyrin compound of formula I (R1 is alkyl; R2 is aryl) containing pyranonaphthoquinones in the molecule. EXAMPLE:The compound of formula II. USE:Useful as a diagnostic and remedy for various bacterial diseases and tumors and also as a fluorescent color-developing agent taking advantage of fluorescent color-developing activity of the porphyrin skeleton. PREPARATION:The compound of formula I can be produced by reacting a compound of formula III, 5-(4-aminophenyl)-10,15,20-triaryl-porphyrin and a condensation agent (preferably dicyclohexyl-carbodiimide) in an aprotic organic solvent preferably under ice cooling or at room temperature.

Description

DETAILED DESCRIPTION OF THE INVENTION (Field of Industrial Application) The present invention relates to a porphyrin compound having antibacterial pyranonaphthoquinones in its molecule, a method for producing the same, and a fluorescent coloring agent containing the compound.

(Prior art and its problems) Among porphyrin-based compounds, hematoporphyrin derivatives are decomposition products of hemoglobin and show high accumulation in tumor tissue. Furthermore, this derivative emits strong fluorescence, so it is a good candidate for cancer. Used for diagnosis. In addition, singlet oxygen, which has high cell-destructive ability, can be easily generated by photoexcitation of this derivative, which has been used in the treatment of cancer.
Science No., p. 6.98 (1984)).

On the other hand, bicyclic pyranonaphthoquinones, represented by nanaomycin A, have excellent antibacterial properties, and are particularly effective against White Rui bacteria, and also have potential antitumor properties. [Journal of Organic Chemistry (J, Org, Chem,
51.350 pages (1986)).

Pyranonaphthoquinones and porphyrin derivatives can be used alone as antibacterial or antitumor therapeutic agents, but each of them is effective only against a limited number of specific bacteria or tumors. It's nothing more than that.

The purpose of the present invention is to provide a new compound that can be used as a diagnostic/therapeutic agent against more bacteria and tumors by covalently bonding antibacterial/antitumor pyranonaphthoquinones to a porphyrin derivative. .

(Means for solving the problems) The porphyrin compound of the present invention has the following formula (wherein R
1 represents an alkyl group, and R2 represents an alkyl group. ) and is a covalent compound of pyranonaphthoquinones and porphyrin derivatives.

Antibacterial pyranonaphthoquinones are easily decomposed by acid or heat, so they need to be combined with porphyrin derivatives at neutral and low temperatures. Therefore, the carboxyl group in the side chain of the pyranonaphthoquinone skeleton and the amino group of the porphyrin derivative were covalently bonded through an amide bond by the action of a dehydration condensation agent.

Moreover, the fluorescent coloring agent of the present invention contains this porphyrin compound.

The state that allows porphyrin derivatives to emit fluorescence is the excited-multiplet state, but quinones easily deactivate this state. This is particularly noticeable when the quinone skeleton and porphyrin skeleton are close to each other within the molecule. Therefore, pyranonaphthoquinones were introduced at the para position of the benzene ring at the meso position of the porphyrin so that the quinone skeleton and the porphyrin skeleton did not interact within the molecule and sufficient fluorescence emission could occur. The porphyrin compound of the present invention is produced as follows.

(However, in the formula, R1 represents an alkyl group.) A compound represented by 5-(4-aminophenyl)-10°15,2
Using 0-triarylporphyrin and a condensing agent,
The reaction is carried out in an aprotic organic solvent.

Usually, 1 mol of antibacterial pyranonaphthoquinones having a carboxyl group in the molecule represented by the above formula and 1 mol of 5-(4-aminophenyl')-10,15,20-triarylphorphyrin are mixed in dichloromethane, chloroform ,
Dissolve in an aprotic organic solvent such as benzene, toluene, diethyl ether, tetrahydrofuran, dimethylformamide or dimethyl sulfoxide. It is preferable to add 1 to 2 moles of dicyclohexylcarbodiimide as a dehydration condensation agent to this solution and carry out the amidation reaction at ice temperature or room temperature while passing an inert gas.

After distilling off the solvent under reduced pressure, the resulting reaction mixture was filtered by adding dichloromethane, the filtrate was treated with silica gel chromatography using dichloromethane-methanol as an eluent, the crude product was separated, and the product was reconstituted with chloroform-methanol. A purified product of the porphyrin compound of the present invention is obtained by crystallization.

(Effects of the Invention) According to the present invention, since pyranonaphthoquinones are covalently bonded to porphyrin derivatives, they are more effective against bacteria and tumors than when conventional pyranonaphthoquinones and porphyrin derivatives are used alone. It has uses as a medicine.

The compound of the present invention has a pyranonaphthoquinone skeleton and a porphyrin skeleton in one molecule, but there is no intramolecular interaction, and each function is maintained independently. , can be used as a fluorescent coloring agent.

(Example) Next, the present invention will be explained with reference to Examples and Comparative Examples.

Example 1 (±)-Nanaomycin A 302 mg (1,0 mmol), 5-(4-aminophenyl) -10,15,
20-tris(paratolyl)porphyrin 671B(1
,0 mmol), dicyclohexylcarbodiimide 24
8 mg (1.2 mmol) was dissolved in 400 mmol of alcohol-free dichloromethane, placed in an airtight reaction vessel, and stirred at 0° C. for 70 hours under a nitrogen gas atmosphere. After the reaction was completed, silica gel chromatography was performed using dichloromethane containing 0.1% methanol as an eluent.
Unreacted raw materials and condensation product (1) were separated.

Chromatography was performed as follows to obtain product 11011I.

Column diameter 2Qmmφ, silica gel (Merck Kieselgel 60H1300 mesh) After separation using Log, dissolved in 1-dichloromethane at room temperature, methanol 9
- was slowly added and placed in the freezer (-20°C) overnight to obtain a pure product.

The condensation product (1) was purified by recrystallization with chloroform-methanol to obtain 586 mg of purple crystals (yield 77% based on the raw material). Melting point 300℃ or higher, amide (C,
0) infrared absorption of 1635 arm-'.

The δ value of the nuclear magnetic resonance spectrum, the absorption maximum wavelength of the visible absorption spectrum, and the emission maximum wavelength of the fluorescence emission spectrum of this purple crystal were as follows.

Nuclear magnetic resonance spectrum (in deuterated chloroform, ppm)2
．． 78 (s, 2 H), 1.70 (d,
J = 7 Hz.

3H), 2.36 (2d, J=I0.18
Hz, IH).

2.70 (s, 9H), 2.74-2.8
8 (m, 3H).

4.41 (m, LH), 5.12
(q, J=IHz, LH), 7.2
2-7.26 (m, IH), 7.55 (
d, J=7 Hz, 6 H), 7.56
~7.60 (m, 2H).

7.91 (d, J=7Hz, 2H),
8.09 (d, J=7Hz, 6H), 8
．． 18 (d, J=7Hz, 2H).

8.43 (s, I H), 8.85 (
s, 8H), 11.94 (s.

IH).

Visible absorption spectrum (in benzene, nm) 421.5
, 483.5 , 516.5 , 552.0 , 593
．． 0.

649.5° Fluorescence emission spectrum (in benzene, nm) 655,7
15゜ Compound (I) emits fluorescence strongly enough by excitation of light of 300 to 700 nm, and the krypton laser (4
10nm), argon laser (514,5nm)
), dye laser (630 nm), and other lasers. Furthermore, since there is almost no difference in the δ values in the nuclear magnetic resonance spectra of compound (1) and the raw material, the pyranonaphthoquinone skeleton and the porphyrin skeleton coexist within the molecule but do not interact, indicating that their respective functions are It was found that it held.

Comparative Example 1 2-chloro-1 which generates acid during the reaction as a condensing agent
-An amidation reaction was attempted under the same conditions as in Example 1 except for using methylpyridyl iodide, but compound (1)
was not obtained.

Comparative Example 2 Using tetrahydrofuran as a solvent, boiling (66°C)
An amidation reaction was attempted under the same conditions as in Example 1 except that the reaction was carried out below, but compound (1) could not be obtained.

The compound shown in Comparative Example 3 hardly emits fluorescence, because the excited-heavy state of the porphyrin skeleton is quickly deactivated by the quinone skeleton.

Furthermore, the δ value of the nuclear magnetic resonance spectrum in the quinone skeleton is shifted significantly up the magnetic field compared to the value without the porphyrin skeleton, indicating that it is influenced by the ring current of the porphyrin skeleton. In other words, when a porphyrin skeleton and a quinone skeleton are bonded at the ortho position, an intramolecular interaction is observed, which reduces the ability to diagnose or treat tumors.

Claims (5)

[Claims] (1) ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (However, in the formula, R_1 represents an alkyl group and R_2 represents an aryl group.) A porphyrin compound that has pyranonaphthoquinones in its molecule. (2) ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (However, in the formula, R_1 represents an alkyl group and R_2 represents an aryl group.) Fluorescence containing a porphyrin compound having pyranonaphthoquinones in the molecule Coloring agent. (3) ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (However, in the formula, R_1 represents an alkyl group.) Compound, 5-(4-aminophenyl)-10,15,2
Using 0-triarylporphyrin and a condensing agent,
A method for producing a porphyrin compound by reacting in an aprotic organic solvent. (4) The method according to claim 3, in which dicyclohexylcarbodiimide is used as a condensing agent. (5) The method according to claim 3 or 4, wherein the reaction temperature is from ice temperature to room temperature.