JPH08269085A - New scalarane derivative - Google Patents

Abstract

PURPOSE: To obtain the subject new derivative, such as a scalarane type sesquiterpene, having a strong antitumor action, and useful as an active ingredi ent for carcinostatic medicines, derived from a purified liposoluble extract obtained by extracting a sponge belonging to the genus Hirtios. CONSTITUTION: New scalarane type sesquiterpene antitumor substances are represented by formulas I, II and III, have strong antitumor actions and are useful as active ingredients for carcinostatic medicines, etc. These compounds are obtained by freezing a sponge: Hirtios erecta, belonging to the genus Hirtios and collected from a sea near Amamiohshima (Japan), grinding the frozen sponge with a blender, extracting the ground product with methanol, filtering the extract with a Celite layer, distilling off the solvent under vacuum, dissolving the residues in ethyl acetate, separating the ethyl acetate layer, distilling off the ethyl acetate under vacuum, distributing the residues with hexane and 90% aqueous methanol, and subsequently fractionating an obtained fraction with antitumor action through silica gel column chromatography.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a novel scalaran derivative having an antitumor effect, a method for producing the same, and an anticancer agent containing the scalaran derivative as an active ingredient.

[0002]

2. Description of the Related Art Conventionally, many compounds having an antitumor activity have been discovered from the natural world.

Vincristine and vinblastine (JH Cutt al, Can obtained from higher plants)
cer Res. , 1960, 20, 1023) and camptothecin (W. J. Slichenmyer an.
d D. D. Von Hoff, Therapeuti
c Rev. , 1990, 30, 770) and the like are actually used as anticancer agents.

Other substances obtained from higher plants include taxol (WP McGuire et.
al, Ann. Intern. Med. 1989, 1
11, 273; J. Slichenmyer an
d D. D. Von Hoff, J.M. Clin. Pha
rmacol. , 1990, 30, 770), maytansine (SM Kupchan, J. Med. Che.
m. , 1987, 21, 31) and podohirotoxin (JL Hartwell and AW Sch.
recher, Forschr. Chem. Org. N
atturst. J., 1958, 15, 83; K. Ba
tra et al, Mol. Pharmacol. ，
1988, 27, 94) and the like are known.

Anti-tumor substances obtained from microorganisms include
Ansamitocins (E. Higashiide et a
1, Nature, 1977, 270, 721), homopsin A (CCJ Culvenor et a.
l, J. Chem. Soc. Chem. Commu
n. , 1983, 1259), rhizoxin (S. Iwa
saki, Med. Res. Rev. , 1993, 1
3,183), Esperamicin (Konishi, Pharmacia,
1989, 25, 1033) and the like are known.

On the other hand, many compounds having a very strong antitumor action have been discovered from marine organisms. That is, from moss to Blayastatin (GR Pettit et a
1, US4816444), sponge statins [G. R. Pettitet al, EU060
8111A1, US5328929; idem, Mol.
ecular Pharmacol. , 1993, 4
4,757; idem, J .; Chem. Soc. Che
m. Commun. , 1994, 1606 (Althiltins: Kitagawa et al., JP-A-6-184160; I. Kit.
agawa et al, Tetrahedron Le
tt. , 1994, 35, 1243)], halichondrins (R. Bai et al, J. Biol. Che.
m. , 1991, 266, 15882), halistatins (Petit et al., JP-A-6-279450, 2794).
51) such as polyether macrolides and red algae to Venustatriols (S. Sakemi et a.
1, Tetrahedron Lett. , 1986, 2
7, 4287; Suzuki et al, ibi
d. , 1985, 26, 1329), from hemipoda to cephalostatins (GR Pettit).
et al, EU0608109A1) steroidal alkaloids, sponges to manzamines (R. Saka).
i et al. Am. Chem. Soc. , 19
86,108,6404) and other indole alkaloids, from molluscs to dolastatins (R. Bai et al.
al, Biochem. Pharmacol. , 199
0, 39, 1941), sponges to styrostatins (GR Pettit et al, J. Org. C.
hem, 1992, 57, 7217), the ascidian didemnins (KL Linehalt, J.
r. , Fed. Proc. , 1983, 42, 87), sponges to alagsterols (K. Iguchi et al, Tetrahedr).
on Lett. , 1993, 34, 6277; ide
m, J.M. Org. Chem. , 1994, 59, 749
9; Yamada et al., Japanese Unexamined Patent Publication No. 5-4998) has found a sterol.

On the other hand, sponge Hyrthios erecta
Some more scalaran-type Sesterterpenes (PC
rew and P.A. Bescanca, J .; Nat.
Prod. , 1986, 49, 1041), and more a homologue than other marine organisms (DJ Faulkner,
Nat. Prod. Rep. , 1994, 355) has been isolated, but is different from the novel compounds of the present invention. or,
Some reports have been reported that these known compounds have weak antitumor activity (F. Yasuda et al, E.
xperientia, 1981, 110; Zen
g et al. Nat. Prod. , 1991,
54, 421), but no compound having a strong antitumor action like the compound of the present invention is known. In addition to this, as the pharmacological action of the scalaran-type sesterterpenes,
Platelet aggregation inhibitory action (M. Kanagawa et a
1, Tetrahedron Lett. , 1987,
28, 431), anti-inflammatory action (LA Marshal)
I et al. Pharmacol. Exp. T
her. , 1994, 268, 709) and the like are known.

[0008]

DISCLOSURE OF THE INVENTION The present inventor has further searched for a substance derived from a natural product and exhibiting an antitumor action. As a result, it was found that the fat-soluble extract of sponge Hyrtios erecta has a strong antitumor effect, and a novel scalaran-type sesterterpene antitumor substance was isolated from this extract to complete the present invention.

[0009]

The present invention provides (1) a compound represented by the following formula (I):

[0010]

[Chemical 4]

(2) A compound represented by the following formula (II):

[0012]

Embedded image

(3) Compound represented by the following formula (III):

[0014]

[Chemical 6]

(4) A compound represented by the formula (I) is extracted and purified from a sponge belonging to the genus Hyrtios having the ability to produce the compound represented by the formula (I) described in (1). A method of producing a compound represented by the formula (I), a sponge belonging to the genus Hyrtios having the ability to produce the compound represented by the formula (II) described in (5) and (2) is represented by the formula (II) A method for producing a compound represented by the formula (II), which comprises extracting and purifying the compound, and belongs to the genus Hyrtios having the ability to produce the compound represented by the formula (III) described in (6) and (3). A method for producing a compound represented by the formula (III), which comprises extracting and purifying the compound represented by the formula (III) from sponge, (7) a compound represented by the formula (I) described in (1), In the formula (II) described in (2), The compounds and / or (3), wherein the sponge Hirutiosu erecta capable of producing the compound represented by (III) (Hyrtios ercta
), (8) An anticancer agent containing the compound represented by formula (I) described in (1) as an active ingredient, and the formula (II) described in (9) (2).
An anticancer agent containing the compound represented by the formula (10)
(3) A carcinostatic agent comprising the compound represented by the formula (III) as described above as an active ingredient.

In the present invention, the formula (I) described in (1) is used.
The compound represented by the formula (II) described in the compound 1, (2)
The compound represented by the formula (II)
The compound represented by I) is referred to as Compound 3.

The compounds 1, 2 and 3 of the present invention have the following physical properties. [Compound 1] Property of substance: colorless crystal Melting point: 195-196 ° C Optical rotation: + 40.3 ° (c = 0.65, chloroform) Molecular formula: C ₂₅ H ₃₈ O ₄ (from high resolution FABMS) Molecular weight: 402. 6 (from high resolution FABMS) Ultraviolet absorption spectrum (in methanol): Terminal absorption Infrared absorption spectrum (KBr): ν _max cm ^-1 : 3451,
3357, 2937, 2862,1690, 1463, 1452, 1386, 1322, 110
0, 1062, 1049, 978, 957, 815 EI mass spectrum: m / z 384, 372, 369, 351, 329, 3
11, 205 ¹ H-nuclear magnetic resonance spectrum: δppm A ¹ H nuclear magnetic resonance spectrum (400 MHz) using tetramethylsilane as an internal standard in heavy pyridine is shown below.

0.86 (3H, s), 0.91 (3H, s), 1.04 (3H, s), 1.
09 (3H, s), 1.14 (3H, s), 0.7-1.5 (7H, m), 1.6-1.9 (4H,
m), 1.9-2.1 (2H, m), 2.4-2.6 (2H, m), 2.67 (1H, m), 3.85
(1H, ddd, J = 3.0,3.7,11.0Hz), 4.37 (1H, dd, J = 1.8,11.9H
z), 4.74 (1H, dd, J = 1.8,11.9Hz), 5.51 (1H, br.s), 5.56 (1
H, d, J = 3.0Hz), 5.88 (1H, dd, J = 5.1,5.9Hz), 9.41 (1H, J =
5.1 Hz) ¹³ C-nuclear magnetic resonance spectrum: δ ppm A ¹³ C nuclear magnetic resonance spectrum (100 MHz) using tetramethylsilane as an internal standard in heavy pyridine is shown below.

9.4 (q), 16.4 (q), 16.5 (q), 19.3 (t), 21.
0 (q), 22.8 (t), 26.7 (q), 27.1 (t), 34.2 (t), 36.8 (s),
37.4 (s), 39.1 (t), 40.6 (s), 40.8 (s), 47.3 (s), 53.6
(d), 54.5 (d), 57.8 (d), 61.8 (d), 68.3 (d), 81.0 (d), 1
00.0 (d), 116.6 (d), 137.2 (s), 216.3 (s) Solubility: Soluble in chloroform, pyridine, dimethylformamide, dimethylsulfoxide, sparingly soluble in methanol, ethanol, ethyl acetate, water, hexane ,ether,
Insoluble in benzene.

[Compound 2] Property of substance: colorless amorphous Optical rotation: -10.5 ° (c = 1.51, chloroform) Molecular formula: C ₂₇ H ₄₂ O ₅ (from high resolution FABMS) Molecular weight: 446.6 ( High resolution FABMS) Ultraviolet absorption spectrum (in methanol): Terminal absorption Infrared absorption spectrum (KBr): ν _max cm ^-1 3442, 2
934, 1717, 1466, 1452, 1390, 1371, 1254, 1014 EI mass spectrum: m / z 387, 386, 368, 358, 340, 3
25,207 ¹ H-nuclear magnetic resonance spectrum: δppm A ¹ H nuclear magnetic resonance spectrum (400 MHz) using tetramethylsilane as an internal standard in heavy pyridine is shown below.

0.77 (3H, s), 0.88 (3H, s), 0.90 (3H, s), 0.
96 (3H, s), 0.98 (3H, s), 0.9-2.1 (H, m), 2.03 (3H, s), 2.
75 (1H, br.s), 3.43 (1H, m), 4.34 (1H, d, J = 11.2Hz), 4.68
(1H, d, J = 11.2Hz), 5.05 (1H, dd, J = 4.4,11.5Hz), 5.50 (1
H, br.s), 5.80 (1H, d, J = 5.4Hz), 6.01 (1H, t, J = 4.6Hz),
7.99 (1H, d, J = 4.6Hz) ¹³ C-nuclear magnetic resonance spectrum: δppm A ¹³ C nuclear magnetic resonance spectrum (100 MHz) using tetramethylsilane as an internal standard in deuterated methanol is shown below.

10.3 (q), 15.6 (q), 17.0 (q), 17.2 (q), 1
9.0 (t), 21.5 (q), 23.3 (t), 24.6 (t), 28.0 (t), 28.5
(q), 38.3 (s), 38.5 (s), 39.2 (s), 39.6 (t), 40.0 (s),
42.7 (t), 55.3 (d), 56.7 (d), 59.5 (d), 62.2 (d), 69.0
(t), 79.5 (d), 84.3 (d), 100.7 (d), 117.4 (d), 137.8
(s), 172.8 (s) Solubility: Soluble in methanol, ethanol, dimethylformamide and dimethylsulfoxide, sparingly soluble in chloroform and ethyl acetate, insoluble in water, hexane, ether and benzene.

[Compound 3] Property of substance: colorless crystal Melting point:> 260 ° C. Optical rotation: -2.7 ° (c = 0.925,50% methanol / chloroform) Molecular formula: C ₂₅ H ₃₈ O ₄ (high resolution) Molecular weight: 402.6 (from high resolution FABMS) UV absorption spectrum (in ethanol): 219 nm (ε,
10,900) Infrared absorption spectrum (KBr): ν _max cm ^-1 3558,
3533, 3467, 2959, 2923, 1786, 1751, 1648, 1486, 14
59, 1387, 1293, 1156, 1125, 1077, 1052, 873 EI mass spectrum: m / z 402, 384, 191 1 H- nuclear magnetic resonance spectrum: tetramethyl as an internal standard [delta] ppm 50% heavy methanol / deuterated chloroform The ¹ H nuclear magnetic resonance spectrum (400 MHz) using silane is shown below.

0.71 (3H, s), 0.83 (3H, s), 0.87 (6H, s), 0.
90 (3H, s), 0.9-1.2 (6H, m), 1.4-1.9 (10H, m), 2.18 (1H,
m), 3.67 (1H, dd, J = 4.3,11.2Hz), 4.46 (1H, m), 4.62 (1H,
br, s), 5.94 (1H, s) ¹³ C-nuclear magnetic resonance spectrum: δppm ¹³ C nuclear magnetic resonance spectrum (100 MHz) using tetramethylsilane as an internal standard in 50% deuterated methanol / deuterated chloroform. Show.

7.1 (q), 16.7 (q), 17.7 (q), 18.8 (t), 19.
0 (t), 21.5 (q), 26.3 (t), 31.2 (t), 33.5 (s), 33.7 (q),
38.0 (s), 38.3 (s), 40.5 (t), 42.5 (t), 42.6 (t), 47.5
(s), 48.3 (d), 57.1 (d), 58.8 (d), 68.2 (d), 80.9 (d), 9
0.9 (d), 111.7 (d), 174.4 (s), 174.6 (s) The scalaran derivatives of the present invention (compounds 1 to 3) are produced from sponges. That is, the sponge phylum (Porif
era) Dictyoceratida (Dictyoce)
ratida) can be obtained by extraction and separation from sponges belonging to the genus Hirthios.
Such sponges belonging to the genus Hyrtios are preferably Hyrtios erecta.
Erecta).

The extraction method can be carried out according to the method for general animals and plants. That is, the collected Hiltios erecta was first hydrated, then methanol, ethanol,
Extraction with a hydrophilic solvent such as acetone, followed by extraction with an organic solvent such as methanol, ethanol, acetone, ethyl acetate, methylene chloride, chloroform, toluene, alone or in combination, to obtain an extract containing the compound You can In order to purify the above compound from the extract thus obtained, adsorption chromatography using a carrier such as silica gel, alumina, florisil, activated carbon, Avicel [Asahi Kasei Kogyo KK], Diaion HP-20, CHP-20, H
Partition chromatography using P-50 [Mitsubishi Kasei Kogyo Co., Ltd.] or the like, or an extraction method utilizing the difference in distribution ratio of impurities mixed with the solvent is effective. The above compounds can be obtained by appropriately combining the above-mentioned purification means and repeatedly using them. The extract thus obtained was further subjected to Sephadex LH-20 (Pharmacia), low-pressure adsorption liquid chromatography using silica gel as a filler [Si-60 (Merck)], high-pressure adsorption liquid chromatography. Graphite [silica, Senshu Kagaku Co., Ltd.], octyl, low-pressure reversed-phase partition chromatography using octadecylated silica gel as a filler [RP-8, RP-18 (Merck)], octyl,
High pressure reverse phase partition chromatography [ODS-H, using octadecyl and dodecylated silica gel as a packing material.
ODS-S, Pegacil ODS, docosyl (manufactured by Senshu Scientific Co., Ltd.)] and the like. In extracting and purifying the compound of the present invention, the activity calculated by the method described below can be used as an index.

The scalaran derivatives (Compounds 1 to 3) of the present invention are compounds having a strong antitumor action. The antitumor effect can be calculated by the following method.

Among the cancer cells, mouse leukemia P388 strain, human gastric cancer MKN-1 strain, human gastric cancer MKN-7 strain, human gastric cancer M
The cell growth inhibitory effect on the KN-74 strain can be measured according to the MTT method (Sugawara et al., Medical History, 1984, 128, 733). That is, each of the above cells is seeded in an appropriate number of media and cultured for 24 hours. Various concentrations of the compound of the present invention are added thereto, and the mixture is further cultured for 48 hours. After completion of the culture, the medium is washed 3 times to remove the compound. 9 more cells
After culturing for 6 hours, MTT [3- (4,5-dimet
hylthiazol-2-yl) -2,5-diph
enyltetrazolium bromide] is added and the mixture is cultured for 4 hours. DMSO after removing the medium
And stir for 5 minutes.

[0029] MTT is cleaved by an enzyme involved in respiration existing in mitochondria of living cells to become MTT formazan. Since the amount of MTT formazan correlates well with the number of living cells, this MT
The number of viable cells (or the number of killed cells) can be determined by dissolving T-formazan in DMSO and performing colorimetric quantification at 540 nm. Absorbance of control group (no compound added) (O
D) was set to 100, the OD value was calculated for each concentration of the compound, and the ratio of viable cells was calculated according to the following formula.

Proportion of live cells (%) = (OD value at each concentration of inhibitor / OD value of control group) × 100 From the proportion (%) of live cells, an inhibition curve was prepared on a semilogarithmic graph, and then IC ₅₀ was calculated.

The above-mentioned compound having a strong cell growth inhibitory action thus obtained further includes mouse leukemia P388.
The antitumor effect can be examined by administering each strain by intraperitoneal injection to a mouse transplanted with the strain, and determining the life prolonging period.

The scalaran derivatives of the present invention (compounds 1 to 3) are novel compounds which have not been described in the literature. For example, they exhibit a strong life-prolonging effect on leukemia P388-transplanted mice, and thus are anticancer agents for mammals including humans. Can be used as

Examples of the dosage form include oral administration by tablets, capsules, granules, syrups, etc., parenteral administration by injections (intravenous, intramuscular, subcutaneous), suppositories, etc. These preparations can be prepared according to a conventional method by using a known active agent that is usually used in the technical field of known pharmaceutical preparations such as an excipient, a disintegrating agent, a solubilizing agent, and a coating agent as a main ingredient. The amount used will vary depending on symptoms, age, weight, administration method, dosage form, etc., but usually 0.1 mg-100 mg per day for an adult
It is desirable to administer in single or divided doses.

[0034]

EXAMPLES Hereinafter, the present invention will be described in more detail with reference to examples, but the present invention is not limited thereto.

Example 1. Hyrt collected in Amami Oshima
Ios erecta (113.6 kg) was crushed in a blender while frozen, and then extracted with methanol (total 435 liters) 4 to 5 times. The extract was filtered over Celite, and the solvent was evaporated under reduced pressure. The obtained residue was redissolved in ethyl acetate. Ethyl acetate was distilled off from the ethyl acetate layer under reduced pressure, and the obtained residue was partitioned between hexane and 90% water-containing methanol.

Using the mouse leukemia P388 strain growth inhibitory activity as an index, a substance having the inhibitory activity was extracted and purified.

The solvent was distilled off from the active 90% water-containing methanol layer under reduced pressure to obtain a 90% water-containing methanol extract (91.82 g). Dissolve 90% hydrous methanol extract in a small amount of acetone, and divide it in half into HP twice.
It was applied to a -20 column (2,500 ml). Elution was carried out using a solvent (1 L each) in which the amount of acetone was sequentially increased in increments of 10% from water, an active 60-80% hydrous acetone fraction (11 L) was fractionated, and the solvent was distilled off under reduced pressure. The same operation was repeated twice to obtain 9.96 g of a 60-80% hydrous acetone fraction.

This fraction was subjected to silica gel chromatography (300 g of silica gel) and chloroform as a solvent.
Sequentially elute with a linear concentration gradient using 30% methanol and chloroform to collect 2 to 2.5 methanol / chloroform fraction (1 L), and distill under reduced pressure to extract 2 to 2.5% methanol / chloroform fraction. Minute (3.00g)
I got

When this was dissolved in chloroform, a precipitate was produced. The precipitate separated by filtration was recrystallized from methanol to obtain compound 3 (411.1 mg).

The chloroform-soluble portion (2.55 g) obtained by concentrating the filtrate was used as a column for system 500 P _REP PAK.
500 / C ₁₈ (50φ × 300 mm: manufactured by Waters), and 50% hydrous acetonitrile (flow rate 108)
(ml / min).

Fraction A eluted at 20-27 minutes (190
mg) and the B fraction (104 m) eluted at 27-30 minutes.
Activity was observed in g).

The fraction A was applied to an ODS-H column (Senshu Kagaku Co., Ltd.) and eluted with 70% water-containing methanol (flow rate 9.5 ml / min). C eluted at 50 to 55 minutes
The fraction and the D fraction eluted at 55 to 60 minutes were collected. Each of them was distilled off under reduced pressure to obtain a C fraction of 47.7 mg and a D fraction of 46.5 mg.

The solid precipitated from the D fraction was filtered off and recrystallized from methanol to give compound 1 (6.7 mg).

The filtrate was combined with the C fraction (89.5 mg).
Further purification was performed. That is, this was chromatographed on silica gel chromatography (10 g of silica gel) with chloroform (2
80 ml), 2% methanol / chloroform (67 m
l), 2.5% methanol / chloroform (84 ml)
The mixture was sequentially eluted with, and 67 ml of a 2% methanol / chloroform eluate was collected to obtain an E fraction (46.6 mg). The solid precipitated from the E fraction was recrystallized from methanol to give compound 1
Was obtained (17.0 mg), and the filtrate was further applied to a Rover column (RP-18: A size manufactured by Merck). Elution with 80% hydrous methanol (flow rate 10 ml / min)
An eluate of 10 to 15 minutes was collected.

Compound 1 was recrystallized from methanol.
(6.4 mg) was obtained. Finally, the total amount of compound 1 is 3
0.1 mg was obtained.

The above-mentioned B fraction (104 mg) was further purified as follows. That is, it was eluted with 2% methanol / chloroform on silica gel chromatography (silica gel 10 g). The eluate was collected in 10 ml fractions, and the 5th to 9th fractions were collected using a fraction collector. The eluted fraction was again eluted on silica gel chromatography (silica gel 10 g) with 66% ethyl acetate / hexane. Separate the eluate by 9 ml, and
The 7th to 7th fractions (36 ml) were collected and concentrated under reduced pressure.
Compound 2 (32.9 mg) was obtained as a colorless amorphous.

[0047]

【The invention's effect】

Test Example 1. Measurement of cell growth inhibitory effect Various cells [1.4 × 10 ³ cells / 1 in 96 well culture plate
00 μl medium (mouse leukemia P388 strain), 5 ×
10 ^3/100 [mu] l medium (human gastric cancer MKN-1
Cells) 10 ³ cells / 100 μl medium (human gastric cancer M
KN-7 cells), 10 ³ cells / 100 μl medium (human gastric cancer MKN-74 cells)] were seeded. This at 37 ℃,
The cells were cultured under 5% CO ₂ for 24 hours. A solution (1) prepared by dissolving the compound of the present invention in medium and adjusting the concentration to
00 μl) was added, and the mixture was cultured at 37 ° C. under 5% CO ₂ for 48 hours. Here, the medium having the composition shown in Table 1 below was used for each cell.

[0048]

[Table 1] For P388 cell line MNK For each cell line RPMI-1640 454.5 ml 437 ml FCS 5% (25 ml) 10% (50 ml) Streptomycin 2.5 ml (100 U / ml) 2.5 ml (100 U / ml) Penicillin 100 μg / ml 100 μg / ml HEDS 0.05 mM 0.05 mM 7.5% NaHCO ₃ 13 ml 13 ml ─────────────────────────────── -------------- Total volume 500 ml After completion of the culture, the cells were washed 3 times with 200 μl of medium to remove the compound from the culture solution. In addition, 37
The cells were cultured at 5 ° C. and 5% CO ₂ for 96 hours. After that, 50 μl of MTT (1 μg / μl medium) was added to this culture medium, and further cultured at 37 ° C. under 5% CO ₂ for 4 hours. The medium was removed, DMSO (150 μl) was added, the generated formazan was dissolved, and the absorbance (OD) at 540 nm was measured. The OD value at each compound concentration was measured, and the IC ₅₀ calculated from the inhibition curve is shown in Table 2.

[0049]

[Table 2] Cell growth inhibitory effect of sucaralan derivative (48-hour contact) ────────────────────────────── Compound # Cancer cell line Inhibitory activity (ng / ml) ───────────────────────────── 1 P388 14.5 MKN-1 57.7 MKN-7 56.0 MKN-74 36.8 2 P388 250.0 3 P388 505.0 ───────────────────────────── Test Example 2 Measurement of survival effect on leukemia P388 strain transplanted mouse 1 A group of 6 CDF1 mice (purchased from Charles River Japan, female, 7-week-old, weight 20-24 g) were intraperitoneally transplanted with mouse leukemia cells P388 at a rate of 10 ⁶ / mouse as the number of viable cells. The transplantation was performed by using a 27G injection needle at 0.1 ml / mouse of a cancer cell suspension of 10 ⁷ cells / ml. The test compound is dissolved in a small amount of dimethylacetamide, and 10% polyoxyethylate is added to this solution.
d vegetable oil (Emulphor
(Registered trademark))-physiological saline was added to form a suspension. This sample solution was intraperitoneally administered three times on the first day, the fifth day, and the ninth day of cancer cell transplantation, and then the survival days of the mice were observed. As a control mouse, a mouse to which neither the test compound nor vehicle was administered was used.

The antitumor activity was evaluated by the life extension rate [ILS (%): Increase in Life] calculated from the following formula.
-Span, R .; I. Geran et al, Can
cer Chemother. Rept. , 3,197
2].

Life prolongation rate = (A / B-1) × 100 A = weighted median of survival days of sample-administered group B = weighted median of survival days of administered group The life-prolonging effect thus determined The results are shown in Table 3.

[0052]

[Table 3] Life-prolonging effect on leukemia-P388-transplanted mice ────────────────────────────────── Weight change Mean survival days ILS (mg / kg) (%) Weighted median (days) (%) ─────────────────────────── ───────── Control ＋1.3 8.6 -1 8.0 ＋0.4 15.0 74.4 4.0 ＋0.9 13.0 51.2 2.0 ＋2.4 11.3 31.4 1.0 ＋2.6 11.4 32.6 0.5 ＋3.0 10.7 24.4 ──── ────────────────────────────── As described above, the novel squalane derivative of the present invention has a strong antitumor activity and thus is an anticancer agent. Can be used as

 ─────────────────────────────────────────────────── ─── Continuation of front page (72) Inventor Tadashi Hata 1-2-58 Hiromachi, Shinagawa-ku, Tokyo Sankyo Co., Ltd. (72) Inventor Kazuhiko Sasakawa 1-2-58 Hiromachi, Shinagawa-ku, Tokyo Sankyo Co., Ltd. (72) Inventor Tomio Kobayashi 1-258 Hiromachi, Shinagawa-ku, Tokyo Sankyo Co., Ltd.

Claims (10)

[Claims] 1. A compound represented by the following formula (I): 2. A compound represented by the following formula (II): 3. A compound represented by the following formula (III): 4. A compound represented by the formula (I) is extracted and purified from a sponge belonging to the genus Hyrtios having the ability to produce the compound represented by the formula (I) according to claim 1. A method for producing a compound represented by the formula (I). 5. A compound represented by the formula (II) is extracted and purified from a sponge belonging to the genus Hyrtios having the ability to produce the compound represented by the formula (II) according to claim 2. A method for producing a compound represented by the formula (II). 6. A compound represented by the formula (III) is extracted and purified from a sponge belonging to the genus Hyrtios having the ability to produce the compound represented by the formula (III) according to claim 3. A method for producing a compound represented by the formula (III). 7. A compound represented by the formula (I) according to claim 1, a compound represented by the formula (II) according to claim 2, and / or
Alternatively, a sponge Hyrtios erector capable of producing the compound represented by (III) according to claim 3.
cta). 8. An anticancer agent comprising the compound represented by formula (I) according to claim 1 as an active ingredient. 9. An anticancer agent comprising the compound represented by the formula (II) according to claim 2 as an active ingredient. 10. An anticancer agent comprising the compound represented by the formula (III) according to claim 3 as an active ingredient.