商品描述

Kojic acid dipalmitate

Chemical name: kojic acid dipalmitate; 5-hydroxyl-2-hydroxymethyl-1,4-pyrone
Molecular formula: C38H66O6;
Molecular weight: 618.9;
Compatibility: kojic acid dipalmitate solves in oil phase,it is compatible together with all kind of preservatives and sunscreen.

Stability: the chemical property of kojic acid dipalmitate is very stable.
Application: using in skin whitening and sunscreen product;
Usage: 1-5%

Accident: suitable to 5-8 ph value;advice to add antioxidant;

Effect:kojic acid dipalmitate is a new skin whitening agent,it can prevent the formation of melanin by inhibiting the activity of tyrase, effective ratio can be up to 80%,so it have a evidently whitening effect.

Kojic Acid Dipalmitate Specification:

Specification(Q/XXHG03-1999):
Appearance:	White needle crystal
Melting point:	153~156ºC
Assay:	≥99.0%
Loss on drying:	<0.5%
Ignition residue:	< 0.5%
Ferrum:	<10ppm
Heavy metal:	<3ppm
Arsenic:	<1ppm
Chloride:	<50ppm
Pathogen:	Bacteria count<300 CPU Fungus<100 CPU

Molecule structure:

Description:

Kojic acid was isolated from "Koji" or malted rice at the beginning of 1900. Since then, it has become known that Kojic acid has various effective features, such as antibacterial action, sequestering heavy metal ions which accelerate oxidation, retardation of melanism, and inhibition of the enzyme which deteriorates foodstuffs.We manufacture this product by the fermentation of carbohydrate using Aspergillus oryzae.

General property:

Soluble in water and ethanol.Chelating for many metal ions, and taking on a dark red color in the case of Fe(III).Has a weak antibacterial action.

Abstract:

Two natural products Polypodium leucotomos extract (PL) and kojic acid (KA) were tested for their ability to scavenge reactive oxygen species (•OH, •O2-, H2O2, 1O2) in phosphate buffer. Hydroxyl radicals were generated by the Fenton reaction, and the rate constants of scavenging were 1.6 x 109 M-1 s-1 for KA and 1.0 x 109 M-1 s-1 for PL, similar to that of ethanol (1.4 x 109 M-1 s-1). With superoxide anions generated by the xanthine/hypoxanthine system, KA and PL (0.2-1.0 mg/ml) inhibited •O2-dependent reduction of nitroblue tetrazolium by up to 30 and 31%, respectively. In the detection of 1O2 by rose bengal irradiation, PL at 1.0 mg/ml quenched singlet oxygen by 43% relative to azide and KA by 36%. The present study demonstrates that PL showed an antioxidant effect, scavenging three of four reactive oxygen species tested here. Unlike KA, PL did not significantly scavenge hydrogen peroxide.

Figure 1. Inhibitory effect of Polypodium leucotomos extract (PL) and kojic acid (KA) (0.0 to 1.0 mg/ml) on the reduction of nitroblue tetrazolium by superoxide anion radical (•O2-) generated by the hypoxanthine-xanthine oxidase system. PL (gray bars), KA (black bars), and SOD (light gray bars) used as control.

Figure2. Inhibitory effect of Polypodium leucotomos extract (PL) and kojic acid (KA) (0.0 to 0.1 mg/ml) on H2O2. PL (gray bars), KA (black bars), and catalase (light gray bars) used as control were detected by the scopoletin assay.

Figure3. Inhibitory effect of Polypodium leucotomos extract (triangles) and kojic acid (lozenges)(0.0 to 1.0 mg/ml) on singlet oxygen detected by bleaching of n,n-dimethyl-4-nitroso-aniline.Azide (circles) was used as control.

KOJIC ACID: A SUPERIOR SOURCE FOR PREPARATION OF BIOLOGICALLY ACTIVE COMPOUNDS (CURRENT EXPERIENCE) :

Kojic acid, known for its nonproblematic biodegradation with any undesirable effects on higher organisms, represents an attractive polyfunctional skeleton for the development of biologically active compounds via derivatization. One of the most important properties of kojic acid is its antifungal as well as antineoplastic activity and capability of chelating metals. Kojic acid may advantageously be used in the preparation of derivatives for the production of antiinflammatory preparations, bronchodilatators, local anaesthetics, fungicides, insecticides and/or pesticides. Kojic acid is used in cosmetics for its excellent whitening or UV-protective effects, as well.

A great variety of different kojic acid derivatives have been prepared by the authors and the regulation of selected biological processes in neoplastic cell lines were studied. 5-Benzyloxy-2-thiocyanatomethyl-4-pyranone, a novel kojic acid derivative was prepared and the effects on neoplastic cell growth were subsequently determined. We found that the above new 4-pyranone derivatives inhibits significantly neoplastic cell growth, and inhibits DNA synthesis. In addition, novel azidometalkojates were synthesized and tested for antibacterial, antifungal and cytotoxic effects. In conclusion, the ascertained biological activity of kojic acid derivatives may advantageously be used in the construction of new, even more biologically active preparations.

INTRODUCTION:

Kojic acid was originally discovered in Japan by Saito in 1907, who isolated that "new" compound from mycelium of the fungus Aspergillus oryzae grown on steamed rice - which is called "koji" in Japanese, and this name was given to that organic compound by Yabuta in 1913. Later in 1924, Yabuta succeded in clarifying the structure of kojic acid, and introduced that fungal metabolite as 5-hydroxy-2-hydroxymethyl-4-pyranone (1). Kojic acid can be produced from various carbohydrate sources in an aerobic condition by a variety of microorganisms. Its lethal dose (LD50) evaluated in mammals was found to be approximately 1 g/kg (2). In spite of a fact that the molecule of kojic acid contains a polyfunctional heterocyclic, an oxygen containing skeleton with several important reaction centres enabling addition reactions, oxidation and reduction, alkylation and acylation, substitution nucleophilic reactions, a ring opening of the molecule, substitution electrophilic reactions, and finally chelation (Fig. 1), only a weak bacteriostatic effect of kojic acid reported in 1945 by Morton and independently by Jennings and Williams (1) might cause that many research laboratories searching for new antibiotics focused their attention on other, more perspective fungal metabolites. Some of the kojic acid physicochemical and biological properties were "rediscovered" in the laboratories of the Slovak Technical University and the Slovak Academy of Sciences in Bratislava, and twenty years later, we succeeded in preparation of novel two mutant strains of fungus Aspergillus tamarii (CCM-F-780, CCM-F-781) producing kojic acid in large quantities when compared to different species of wild strains of Aspergillus tamarii (3, 4). Protocols for the fermentation process utilizing various carbohydrates containing media and the CCM-F-780 or CCM-F-781 kojic acid producing mutant strains have been established (5), and also novel data on enlargement of the kojic acid production by fermentation process were reported (6). The fermentation process comprises several well-known steps starting from inoculation cultivation media by the kojic acid producing microorganism and resulting in yielding pale white-yellow prismatic needles of kojic acid. Since it is freely soluble in water, ethanol, acetone or ethyl acetate, kojic acid was advantageously employed for the preparation over one hundred and fifty various kojic acid derivatives, a part of them even represented new chemical individuals, never synthesised before (7, 8). Physicochemical properties (hydrophobicity, acidity, metal complexing ability), which are expected to play a significant role in biological activity of kojic acid derivatives were determined for a reasonable number of compounds by use of the quantitative structure - time-activity relationship method (QSTAR) with the aim to predict properties of new derivatives and also to obtain the data for formulation of the quantitative structure-time-activity relationships (9 - 11).

Figure 1. Kojic acid: Description of important reaction centres.

Antifungal activity of 4-pyranone halogenderivatives and their cooper (II) salts:

We have reported a new class of fungicides that may be used as principal constituents of biologically active preparations and have brought evidence showing significant antifungal effects of 5-hydroxy-2-chloromethyl-4-pyranone, 5-hy-droxy-2-bromomethyl-4-pyranone and 5-hydroxy-2-iodo-methyl-4-pyranone on a variety strains of dermatophytes and/or micro-mycetes (Fig. 2) (12, 13). Our results showing a comparison of the antifungal activity of halogen-substituted kojic acid derivatives with that of their cooper salts are summarized in Table 1 (14, 15). Kojic acid does not exert any antifungal activity, however, cooper (II) salts of kojic acid halogenderivatives were found to be even more active than halogen-substituted kojic acid derivatives, and thus they might serve as principal constituents for therapy in human dermatology.

Figure 2. 5-Hydroxy-2-halogenmethyl-4H-pyran-4-ones: Principal constituents for novel fungicide preparations.

Table1. A comparison of the antifungal activity of halogen-substituted kojic acid derivatives with that of their cooper salts. (+) Antifungal action, (-) Noneffectiv.

化合物	皮蘚菌
	1	2	3	4	5	6	7	8
DMSO	-	-	-	-	-	-	-	-
C H O Cl	+	+	-	-	+	-	+	+
Cu (C H O Cl)	+	+	+	+	+	+	+	+
C H O Br	+	-	+	+	-	-	-	-
Cu (C H O Br)	+	+	+	+	-	+	+	-
C H O I	+	+	+	+	+	+	-	+
Cu (C H O I)	+	+	+	+	+	+	+	+

Recently, novel azidometalkojates (Cu, Mn Mg, Zn and Ni salts of 5-hydroxy-2-azidomethyl-4H-pyran-4-one) (Fig. 3) as well as derivatives of 4H-pyran-4-one derivative with the atom of sulfur in the side chain of the molecule have been prepared at the Slovak Technical University. It has been shown that the nickel derivative of the azidokojate exerts the strongest antifungal activity when compared to other newly prepared azidometalkojates (8). Similarly, several sulfur-containing derivatives of kojic acid were found to exert antifungal activity 16).

Figure 3.Azidometalkojates: Alternative constituents for novel fungicide preparations.

Antiinflammatory and antineoplasic effects of kojic acid derivatives:

It has been shown that kojic acid may exert slight anti-inflammatory effects that may advantageously enhanced by subsequent derivatization of selected kojic acid derivatives. In search for new compounds possessing antitumour activity, we examined the effects of kojic acid halogen derivatives on the proliferation of both the leukemia L 1210 cells and the rat pituitary GH4C1 tumour cells. We have reported for the first time that a group of several halogen derivatives of 5-hydroxy-2-hydroxymethyl-4-pyran-4-one may act as drugs with antileukemic activity. Moreover, we have found that the effect of 5-hydroxy-2-halogenmethyl-4-pyran-4-one derivatives is not due to the metal ion chelating ability. Two halogen derivatives of kojic acid (5-hydroxy-2-chloromethyl-4-pyran-4-one and 5-hydroxy-2-bromomethyl-4-pyran-4-one) were found to inhibit DNA, RNA and protein synthesis. Recently, we have prepared a novel kojic acid derivative, 5-benzyloxy-2-thiocyanatomethyl-4-pyran-4-one which in vitro, at 2.6 µM inhibits significantly neoplastic cell growth as well as it inhibits DNA synthesis and cytoplasmic phosporylation. Also, the antineoplastic/cytotoxic effect of selected azidometalkojates (Cu, Zn, Mn, Mg and Ni salts) was evaluated on HeLa cells, and the highest antitumour effect was demonstrated by the zinc salt of the azidokojate (Table 2). On the other hand, we have also tested the polagrographic behaviour and potential carcinogenity of kojic acid derivatives. The most of kojic acid derivatives prepared by our research group ("Gamma Pyrone Research Group") was found to possess a very low or almost no potential carcinogenity. Since, the above mentioned novel kojic acid derivatives and their effects on neoplastic cell growth in vitro have been found very recently, the further investigation on its, especially, in vivo biological activity, is highly desirable.

Table 2.In vitro effect of azidometalkojates (Cu, Mn Mg, Zn and Ni salts of 5-hydroxy-2-azidomethyl-4H-4-one) on HeLa cell proliferation. (IC50) Inhibition concentration.

結為螯合物的金屬	IC [ .g/ml ]
Cu	25
Zu	5
Mn	>100
鎂	>100
Ni	35

Kojic acid is used in concentrations between 1%-4%. In a split-face study of Chinese women with epidermal melasma, kojic acid 2% plus glycolic acid 10% and hydroquinone 2% was compared with glycolic acid 10% and hydroquinone 2%. Better results were obtained with the cream that contained kojic acid.

Kojic acid has been reported to have a high-sensitizing potential and may cause irritant contact dermatitis. However, it is useful in patients who cannot tolerate hydroquinone and may be combined with a topical corticosteroid to reduce irritation. A study in Thailand of 4% kojic acid in combination with tretinoin and betamethasone found that 12% of 200 patients had an excellent response, 48% had a satisfactory response, 27% had a slight response and 13% had no response. The main side effect noted was mild facial erythema in a few patients. Skin lightening products that contain kojic acid are typically used twice per day for one or two months.

Kojic Acid is produced biologically by fermentation of bacteria from aspergillus of rice or soybean on carbon hydrates. It is synthetised by glucose, i.e hexose. Kojic Acid has an anti-microbial effect and is an inhibitor for tyrosinase, it helps depigmentation of the skin; it further forms chelates. Before use the aflatoxines, which appear during fermentation, are separated. The name is japanese and comes from koji=culture of aspergillus oryzae (rice).