JP2011184344A - p21 EXPRESSION PROMOTER - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide an expression promoter of p21 (Waf1/Cip1). <P>SOLUTION: The p21 expression promoter includes a compound expressed by formula (I) or its salt, or a quaternary ammonium salt expressed by formula (II). In formula (I), R<SB>1</SB>is a substitutable or non-substitutable 4-20C alkyl group, or a group expressed by formula (i) (not illustrated) or expressed by formula (ii) (not illustrated); X is -NH-CO- or -CO-O-; Y is a substitutable or non-substitutable 1-4C alkylene group; R<SB>2</SB>and R<SB>3</SB>are the same or different 1-4C alkyl groups. In formula (II), R<SB>1</SB>, X and Y represent the same meaning as above; R<SB>4</SB>, R<SB>5</SB>and R<SB>6</SB>are the same or different 1-4C alkyl groups; A<SP>-</SP>is a counter ion. <P>COPYRIGHT: (C)2011,JPO&INPIT

Description

  The present invention relates to a compound that promotes the expression of p21 (Waf1 / Cip1) and suppresses cell proliferation.

  Normal skin is formed under the control of normal cell growth, whereas in skin cancer, abnormal growth of skin cells is observed as one of the findings. Skin cancer occurs anywhere in the body, but about 80% occurs on the face, head, and neck, causing malformations and dangers in these areas. In addition to patient survival, QOL (quality of life) is also present. It is a threatened disease. It is thought that the main cause of skin cancer is ultraviolet rays. In recent years, an increase in skin cancer has been feared due to an increase in the amount of ultraviolet light that falls on the ground due to the destruction of the ozone layer. Therefore, there is a potential demand for the prevention and treatment of skin cancer.

  p21 (Waf1 / Cip1) is a protein having a molecular weight of 21 kDa that is localized in the cell nucleus and consists of 164 amino acids. The protein has a cyclin binding site in the N-terminal 16th to 24th amino acid region and a Cdk binding site in the 45th to 65th amino acids. In addition, a nuclear localization signal exists in the C-terminal amino acid region 140 to 156, and this region includes a PCNA binding site (142 to 164) and a second Cdk binding site (152 to 158). It overlaps. The p21 gene has a total length of 15 kb and is located at 6p21 of the human chromosome. The size of mRNA is 2.1 kb. It has been reported that p53-dependent or independent transcriptional activation elements are present in the promoter.

  P21 synthesized in the cell moves to the nucleus, cyclin (any of A, B, D, E) and Cdk (any of Cdk2, Cdk4, Cdc2) and PCNA in the S phase nucleus Combine to form a heterotetramer. Since the kinase activity of cyclin / Cdk complex bound to p21 is strongly inhibited, phosphorylation of RB protein, activation of E2F, and further DNA polymerase, thymidine kinase, DHFR, Myc Does not induce synthesis of Cdc2, cyclin A, etc. As a result, when p21 of a cell is overexpressed, the cell division stops and cell growth is suppressed.

The relationship between p21 expression and various diseases is known. Patent Document 1 describes a p21 inducer effective for the prevention and treatment of Sjogren's syndrome, autoimmune pancreatitis, systemic lupus erythematosus (SLE), and the like. Patent Document 2 describes a method in which one or more of ^{aclacinomycins} suppresses cell proliferation by inducing expression of p16 ^INK4 and / or p21 ^waf1 . Patent Document 3 describes a pharmaceutical composition for preventing or treating rheumatoid arthritis, which comprises a compound that promotes the expression of the p21 ^Cip1 gene as an active ingredient. It has been reported that p21 expression is also associated with pulmonary diseases (Non-Patent Documents 1 and 2), obesity (Non-Patent Documents 3 and 4), arthritis and rheumatoid arthritis (Non-Patent Documents 5 and 6). In addition, it has been reported that p21 knockout mice have high skin cell proliferation and skin cancers are easily formed (Non-Patent Documents 7 to 9).
A p21 expression promoter is considered useful for the prevention and treatment of various diseases including skin cancer.

  Patent Document 4 includes the following formula (I) and / or formula (II):

A skin external preparation composition for preventing or improving photoaging or preventing or improving wrinkles is disclosed, which contains a dialkylamino derivative represented by the formula (4) or a quaternary ammonium salt.
In Patent Document 5, the following formula (I) and / or formula (IV):

A hair suppressant containing a dialkylamino derivative or a quaternary ammonium salt represented by formula (1) as an active ingredient is disclosed.

Japanese Patent Laid-Open No. 10-236953 JP 2002-326937 A International Publication No. WO01 / 021793 Pamphlet JP 2009-120515 A International Publication No. WO2010 / 0166606 Pamphlet

Inoshima I et al, Am J Physiol Lung Cell Mol Physiol, 286: 727-733, 2004 O'Reilly MA et al, Am J Respir Cell Mol Biol, 24: 703-710, 2001 Naaz A et al, FASEB J, 18: 1925-1927, 2004 Kim SH et al, Biochem Biophys Res Commun, 372: 108-113, 2008 Nasu K et al, J Immunol, 165: 7246-7252, 2000 Woods JM et al, Arthritis Res Ther, 8: R113, 2006 Philipp J et al, Oncogene, 18: 4689-4698, 1999 Weinberg WC et al, Cancer Res, 59: 2050-2054, 1999 Topley GI et al, Proc Natl Acad Sci U S A, 96: 9089-9094, 1999

  The present invention relates to providing a compound that can suppress cell proliferation by promoting the expression of p21, or is useful as a prophylactic or therapeutic agent for various diseases.

  The present inventors have found that a compound represented by the following formula (I) or (II) has an activity of promoting the expression of p21, and have completed the present invention.

That is, the present invention provides the following.
(1) The following formula (I):

[Where:
R ₁ is a substituted or unsubstituted C _4-20 -alkyl group or has the following formula (i):

(Where
R ₁ ′ is a substituted or unsubstituted C _2-20 -alkylene group, or — (CH ₂ ) _n —O— (CH ₂ ) _m —O— (CH ₂ ) _o —, where n, m and o are integers from 1 to 6,
X ′ is —CO—NH— or —O—CO—,
Y ′ is a substituted or unsubstituted C _1-4 -alkylene group,
R ₂ ′ and R ₃ ′ are the same or different C _1-4 -alkyl groups)
Or a group represented by the following formula (ii):

(Where
R ₁ ', X' and Y 'have the same meaning as above,
R ₄ ′, R ₅ ′ and R ₆ ′ are the same or different C _1-4 -alkyl groups,
A ^'- is a counterion)
A group represented by
X is -NH-CO- or -CO-O-
Y is a substituted or unsubstituted C _1-4 -alkylene group,
R ₂ and R ₃ are the same or different C _1-4 -alkyl groups]
Or a salt thereof, or
Formula (II):

(Where
R ₁ , X and Y have the same meaning as described above,
R ₄ , R ₅ and R ₆ are the same or different C _1-4 -alkyl groups,
A ^- is a counter ion)
A quaternary ammonium salt represented by
A p21 expression promoter comprising:
(2) The X is —NH—CO—, the Y is a methylene group or an ethylene group, the X ′ is —CO—NH—, and the Y ′ is a methylene group or an ethylene group. 1) The p21 expression promoter described in the above.
(3) The R ₁ is a substituted or unsubstituted C _4-20 -alkyl group, the X is —NH—CO—, and the Y is a methylene group or an ethylene group. p21 expression promoter.
(4) A cell growth inhibitor comprising the compound according to any one of (1) to (3) or a salt thereof or a quaternary ammonium salt.
(5) The cell growth inhibitor according to (4), wherein the cells are epithelial cells.
(6) An anticancer agent comprising the compound according to any one of (1) to (3) or a salt thereof or a quaternary ammonium salt.

Induction of p21 expression in HaCaT cells Inhibition of HaCaT cell proliferation Inhibition of HeLa cell proliferation

  In the present specification, p21 and p21 (Waf1 / Cip1) are used as names indicating the same thing. Details of p21 are described in <http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=116899>. In the present specification, “expression of p21” refers to any of p21 gene expression, p21 mRNA expression, and p21 protein expression. That is, “promotion of p21 expression” includes promotion of transcription from p21 gene to p21 mRNA, increase in p21 mRNA, promotion of translation from p21 mRNA to p21 protein, and increase in the amount of p21 protein.

  The present invention provides a p21 expression promoter containing a compound represented by the following formula (I) or a salt thereof, or a quaternary ammonium salt represented by the above formula (II).

In the above formula (I) or formula (II), the alkyl group having 4 to 20 carbon atoms represented by R ₁ is a linear or branched alkyl group having 4 to 20 carbon atoms, such as an n-butyl group. , I-butyl group, sec-butyl group, t-butyl group, n-pentyl group, n-hexyl group, 2-ethylhexyl group, n-heptyl group, n-octyl group, n-nonanyl group, n-decyl group , Trimethyldecyl group, n-undecyl group, n-dodecyl group, n-tridecyl group, n-tetradecyl group, n-pentadecyl group, n-hexadecyl group, n-heptadecyl group, n-octadecyl group, methylheptadecyl group ( Methyl-branched isostearyl group), n-nonadecyl group, n-icosyl group and the like. Among these, n-heptyl group, n-octyl group, n-nonanyl group, n-decyl group, trimethyldecyl group, n-undecyl group, n-dodecyl group, n-tridecyl group, n-tetradecyl group, n-pentadecyl group C _8-15 -alkyl groups such as groups are preferred.

Alternatively, R ₁ in the above formula (I) or formula (II) may be a group represented by the above formula (i) or formula (ii). In the above formula (i) or formula (ii), the alkylene group having 2 to 20 carbon atoms represented by R ₁ ′ is a linear or branched alkylene group having 2 to 20 carbon atoms, such as an ethylene group. , Trimethylene group, tetramethylene group, pentamethylene group, hexamethylene group, heptamethylene group, octamethylene group, nonamethylene group, decamethylene group, undecamethylene group, dodecamethylene group, tridecamethylene group, tetradecamethylene group, penta Examples include a tecamethylene group, a hexadecamethylene group, a heptacamethylene group, an octadecamethylene group, a nonadecamethylene group, an icosadecamethylene group, a methylethylene group, an ethylethylene group, a propylene group, and a propenylene group. Among these, ethylene group, trimethylene group, tetramethylene group, pentamethylene group, hexamethylene group, heptamethylene group, octamethylene group, nonamethylene group, decamethylene group, undecamethylene group, dodecamethylene group, tridecamethylene group, tetra C _2-16 -alkylene groups such as decamethylene group, pentatecamemethylene group, hexadecamethylene group, methylethylene group, ethylethylene group and propylene group are preferred. Alternatively, the group represented by R ₁ ′ in the above formula (i) or formula (ii) may be — (CH ₂ ) _n —O— (CH ₂ ) _m —O— (CH ₂ ) _o —. Here, n, m and o are integers of 1 to 6, preferably n, m and o are 2.

In the above formula (i) or formula (ii), the group represented by X ′ is —CO—NH— or —O—CO—. The group represented by Y ′ is a substituted or unsubstituted C _1-4 -alkylene group, preferably an unsubstituted C _1-4 -alkylene group, more preferably a methylene group or an ethylene group.

R ₂ ′ and R ₃ ′ in the above formula (i) are C _1-4 -alkyl groups, and R ₄ ′, R ₅ ′ and R ₆ ′ in the above formula (ii) are C _1-4 -alkyl. It is a group. Examples of the C _1-4 -alkyl group include a methyl group, an ethyl group, a propyl group, and a butyl group, and among them, a methyl group and an ethyl group are preferable. R ₂ ′ and R ₃ ′ may be the same group or different from each other, and the above R ₄ ′, R ₅ ′ and R ₆ ′ may be the same group or different from each other. Also good.

The group represented by X in the above formula (I) or formula (II) is —NH—CO— or —CO—O—. The group represented by Y is a substituted or unsubstituted C _1-4 -alkylene group, preferably an unsubstituted C _1-4 -alkylene group, more preferably a methylene group or an ethylene group.

R ₂ and R _{3 in} the above formula (I) are C _1-4 -alkyl groups, and R ₄ , R ₅ and R _{6 in the} above formula (II) are C _1-4 -alkyl groups. Examples of the C _1-4 -alkyl group include a methyl group, an ethyl group, a propyl group, and a butyl group, and among them, a methyl group and an ethyl group are preferable. R ₂ and R ₃ may be the same group or different from each other, and R ₄ , R ₅ and R ₆ may be the same group or different from each other.

Examples of the counter ion represented by A ^{− in the} above formula (II) or A ′ ⁻ in (ii) include halogen ions, carboxylate ions, sulfonate ions, sulfate ions, nitrate ions, and the like. Carboxylate ions are preferred. Examples of the halogen ion include fluorine ion, chlorine ion, bromine ion and iodine ion. Examples of the carboxylate ion include formate ion, acetate ion, propionate ion, fumarate ion, and malate ion.

Preferably, X in formula (I) is —NH—CO—, Y is a methylene group or ethylene group, X ′ is —CO—NH—, and Y ′ is a methylene group or ethylene group. Preferably, X in the formula (I) is —NH—CO—, Y is a methylene group or ethylene group, and R ₁ is a substituted or unsubstituted C _4-20 -alkyl group.

C _1-4 represented by an alkyl group and Y - - C _4-20 shown by R ₁ in the formula (I) or formula (II) R ₁ alkylene group, and the above formula (i) or formula (ii) The C _2-20 -alkylene group represented by “′ and the C _1-4 -alkylene group represented by Y ′ may be substituted with one or more substituents. Examples of the substituent include a halogen atom, a hydroxyl group, an alkoxyl group, an acyl group, an amino group that may be protected, a heterocyclic group, and the like. Here, examples of the halogen atom include a chlorine atom, a bromine atom, and an iodine atom. As an alkoxyl group, a C1-C12 alkoxyl group is preferable, for example, a methoxy group, an ethoxy group, an isopropoxy group etc. are mentioned. As an acyl group, a C1-C12 alkanoyl group is preferable, for example, a formyl group, an acetyl group, a propionyl group, a butyryl etc. are mentioned. Examples of the amino group that may be protected include an amino group, an acylamino group, an alkylamino group, and a dialkylamino group. As the heterocyclic group, for example, a 5- to 14-membered monocyclic or condensed ring group having 1 to 3 nitrogen atoms, oxygen atoms and / or sulfur atoms as heteroatoms is preferable, for example, pyridyl group, pyridazinyl group, Examples include a furyl group, a thienyl group, an indolyl group, a thiazolyl group, an imidazolyl group, a benzofuryl group, and a benzothienyl group.

Examples of the salt of the compound represented by the above formula (I) (excluding the case where R ₁ is a group represented by the formula (ii)) include, for example, hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid, iodination. Hydroacid, nitric acid, pyrosulfuric acid, inorganic acid such as metaphosphoric acid, citric acid, benzoic acid, acetic acid, propionic acid, fumaric acid, maleic acid, sulfonic acid (for example, methanesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid) And salts with amino acids such as glutamic acid and aspartic acid.

  Examples of the compound represented by the formula (I) or a salt thereof or the quaternary ammonium salt represented by the formula (II) include dodecanoic acid 2-dimethylamino-ethyl ester, dodecylcarbamoylmethyltrimethylammonium chloride, 2- (dodeca Noyloxy) -N, N, N-trimethylethanaminium, 2-dimethylamino-N- (2- [2- [2- (2-dimethylamino-acetylamino) -ethoxy] -ethoxy] -ethyl)- Acetamide, 2-dimethylamino-N- [8- (2-dimethylamino-acetylamino) -octyl] -acetamide, 2-dimethylamino-N- [12- (2-dimethylamino-acetylamino) -dodecyl]- Acetamide, 2-dimethylamino-N- [4- (2-dimethylamino-acetamino) -butyl] -acetamide is preferred.

  The compound represented by the above formula (I) or a salt thereof and the quaternary ammonium salt represented by the formula (II) are, for example, Izv. Vyssh. Ucheb. Zaved., Khim. Khim. Tekhnol., 14 (9), 1369 (1971) and the like, for example, can be produced by reacting choline chloride and fatty acid chloride under a nitrogen stream. Alternatively, the preparation procedure of the compound represented by the above formula (I) or a salt thereof and the quaternary ammonium salt represented by the formula (II) is described in International Publication No. WO2010 / 0166606.

  As shown in the examples described later, the compound represented by the above formula (I) or a salt thereof and the quaternary ammonium salt represented by the formula (II) strongly induce the expression of p21 in cells, and Depresses the growth of Therefore, these compounds or salts thereof and quaternary ammonium salts are useful as cell p21 expression promoters and cell growth inhibitors. The cell type to which the cell growth inhibitor of the present invention is applied is not particularly limited, but epithelial cells are preferable, epidermal cells are more preferable, and human epidermal cells are still more preferable.

  Furthermore, the p21 expression promoter of the present invention containing the compound represented by the above formula (I) or a salt thereof, or the quaternary ammonium salt represented by the formula (II) has various symptoms that develop as the expression of p21 increases. Diseases such as Sjogren's syndrome, autoimmune pancreatitis, systemic lupus erythematosus (SLE), rheumatoid arthritis, autoimmune diseases such as pulmonary fibrosis, obesity, arthritis, rheumatoid arthritis, cancer, other cell proliferation It is useful as a drug for preventing or treating diseases. Therefore, the present invention provides a prophylactic / therapeutic agent for the above-mentioned diseases comprising a compound represented by the above formula (I) or a salt thereof or a quaternary ammonium salt represented by the formula (II) as an active ingredient. The disease to be prevented or treated is preferably cancer, more preferably epithelial tumor, and still more preferably skin cancer. Therefore, the present invention also provides an anticancer agent containing the compound represented by the above formula (I) or a salt thereof or a quaternary ammonium salt represented by the formula (II) as an active ingredient.

  The p21 expression promoter, cell growth inhibitor or disease preventive / therapeutic agent (anticancer agent etc.) according to the present invention can be administered to humans or animals as pharmaceuticals, quasi drugs or cosmetics. When used as a pharmaceutical or quasi-drug, the p21 expression promoter, cell growth inhibitor or disease preventive / therapeutic agent (anticancer agent, etc.) of the present invention may be used alone, or pharmaceutically or cosmetically. May be used in combination with an acceptable carrier. Examples of such carriers include excipients, binders, chelating agents, disintegrating agents, lubricants, surfactants, diluents, osmotic pressure adjusting agents, pH adjusting agents, emulsifiers, preservatives, stabilizers, and oxidation agents. Examples include inhibitors, colorants, ultraviolet absorbers, humectants, thickeners, brighteners, activity enhancers, anti-inflammatory agents, powders, keratolytic agents, bactericides, corrigents, and flavoring agents.

  There are no particular limitations on the route of administration of pharmaceuticals and quasi-drugs, and examples include oral and parenteral administration. The dosage form for administration is not particularly limited, and for example, forms for oral administration include solid preparations such as tablets, coated tablets, granules, powders, capsules, and elixirol, syrups and suspensions. Examples of forms for parenteral administration include injection, infusion, transdermal, transmucosal, nasal, enteral, inhalation, suppository, bolus and the like. The form of the cosmetic is not particularly limited, and examples thereof include lotion, emulsion, suspension, cream, ointment, paste, powder, cake, stick, sheet, patch and the like.

  The compounding amount of the quaternary ammonium salt of the formula (I) and / or the formula (II) in the pharmaceutical, quasi-drug, or cosmetic may be in the range of 0.0001 to 20% by mass, Preferably 0.001-5 mass% is preferable.

  The drug or quasi-drug is 0.001 to 1200 mg, preferably 0.01 to 300 mg once a day as the mass of the compound of formula (I) and / or the quaternary ammonium salt of formula (II). The dose may be divided into several doses, but the dose may be appropriately adjusted based on the patient's age, sex, weight, condition, etc., as judged by a medical professional.

  The anticancer agent of the present invention can be administered in combination with other drugs, for example, other anticancer agents, other drugs, radiation and the like. The administration regimen is appropriately determined based on the judgment of a medical professional based on the age, sex, weight, condition, etc. of the patient.

  Hereinafter, the present invention will be described in more detail based on examples.

Example 1 Evaluation of p21 expression promoting effect Methods The established human epidermal cells (HaCaT cells) (Boukamp P, et al. J Cell Biol. 106: 761-771, 1988) were treated with 10 vol% non-immobilized FBS (Gibco), 1 vol% penicillin / streptomycin (Gibco). ) -Containing DMEM medium (Gibco) at 37 ° C. under 5% CO ₂ .
HaCaT cells were seeded at a rate of 1.5 × 10 ⁵ cells / dish in 3 mL each in a 6 cm dish, and replaced with 3 mL of DMEM medium containing compound 2 or 6 shown in Table 1 below after 24 hours. Further, after 48 hours, HaCaT cells were collected, and protein extraction was performed using Cell Lysis Buffer (Cell Signaling Technology). In the protein extraction, Complete Protease Inhibitor Cocktail Tablets (Roche) was used. The extracted protein was quantified by BCA Protein Assay Kit (Thermo Scientific) and the concentration was adjusted. Thereafter, the protein was diluted with Lane Marker Sample Buffer (Thermo Scientific), treated at 99 ° C. for 5 minutes, and then loaded with 4-20% gradient gel (TEFCO) at 15 μg / lane for electrophoresis. .

P21 and actin (control) were detected from the migrated proteins. Proteins from the gel were transferred to Hybond-P membrane (Amersham), blocked with 5 wt% skim milk for 30 minutes at room temperature, and reacted with primary antibody overnight at 4 ° C. Primary antibodies include p21: p21 Waf1 / Cip1 (DCS60) mouse monoclonal antibody (Cell Signaling Technology, # 2946; 1 / 2000-fold dilution), or Actin: Actin (I-19) goat polyclonal antibody (Santa Cruz Biotechnology, sc -1616; 1 / 1000-fold dilution). Thereafter, the membrane was washed with TBS-tween, and the secondary antibody reaction was performed for 1 hour at room temperature. Secondary antibodies include mouse: ECL ^™ anti-mouse IgG, HRP-linked whole antibody (from sheep) (Amersham, NA931-100UL; diluted 1/5000) or goat: anti-goat IgG-HRP (Santa Cruz Biotechnology 1 / 5000-fold dilution) was used. Subsequently, the membrane was washed again, and a band was detected by LumiGLO Reagent (registered trademark) and Peroxide (Cell Signaling Technology) or Amersham ^™ ECL Plus Western Blotting Detection System (GE healthcare).

2. Results The results are shown in FIG. Compounds 2 and 6 increased p21 protein expression in a concentration-dependent manner.

Example 2 Evaluation of Cell Growth Inhibitory Effect Method HaCaT cells were diluted with DMEM medium to 3 × 10 ³ / well, and each 100 μl was spread in a 96-well plate. After overnight incubation, 100 μl of DMEM medium containing any of compounds 1-7 listed in Table 1 was replaced. 72 hours later, 10 μl of Cell Counting Kit-8 solution (DOJINDO) was added to each well and incubated at 37 ° C. for 3 hours. Next, the absorbance at 450 nm was measured with a microplate reader. The measurement time was 0.5 seconds per well.

2. Results The results are shown in FIG. Compounds 1-7 suppressed the proliferation of HaCaT cells.

Example 3 Evaluation of tumor cell growth inhibitory effect Method HeLa cells (human cervical cancer cells) were diluted with DMEM medium to 1 × 10 ³ / well, and 100 μl each was spread in a 96-well plate. After overnight incubation, 100 μl of DMEM medium containing Compound 2 was replaced. 72 hours later, 10 μl of Cell Counting Kit-8 solution (DOJINDO) was added to each well and incubated at 37 ° C. for 3 hours. Next, the absorbance at 450 nm was measured with a microplate reader. The measurement time was 0.5 seconds per well.

2. Results The results are shown in FIG. Compound 2 inhibited tumor cell growth.

Claims (6)

Formula (I):
[Where:
R ₁ is a substituted or unsubstituted C _4-20 -alkyl group or has the following formula (i):
(Where
R ₁ ′ is a substituted or unsubstituted C _2-20 -alkylene group, or — (CH ₂ ) _n —O— (CH ₂ ) _m —O— (CH ₂ ) _o —, where n, m and o are integers from 1 to 6,
X ′ is —CO—NH— or —O—CO—,
Y ′ is a substituted or unsubstituted C _1-4 -alkylene group,
R ₂ 'and R ₃ ' are the same or different C _1-4 -alkyl groups)
Or a group represented by the following formula (ii):
(Where
R ₁ ', X' and Y 'have the same meaning as above,
R ₄ ′, R ₅ ′ and R ₆ ′ are the same or different C _1-4 -alkyl groups,
A ^'- is a counterion)
A group represented by
X is -NH-CO- or -CO-O-
Y is a substituted or unsubstituted C _1-4 -alkylene group,
R ₂ and R ₃ are the same or different C _1-4 -alkyl groups]
Or a salt thereof, or
Formula (II):
(Where
R ₁ , X and Y have the same meaning as described above,
R ₄ , R ₅ and R ₆ are the same or different C _1-4 -alkyl groups,
A ^- is a counter ion)
A quaternary ammonium salt represented by
A p21 expression promoter comprising:   The X is —NH—CO—, the Y is a methylene group or an ethylene group, the X ′ is —CO—NH—, and the Y ′ is a methylene group or an ethylene group. P21 expression promoter. The p21 expression promotion according to claim 1, wherein R ₁ is a substituted or unsubstituted C _4-20 -alkyl group, the X is -NH-CO-, and the Y is a methylene group or an ethylene group. Agent.   The cell growth inhibitor containing the compound of any one of Claims 1-3, its salt, or a quaternary ammonium salt.   The cell growth inhibitor according to claim 4, wherein the cells are epithelial cells.   The anticancer agent containing the compound of any one of Claims 1-3, its salt, or a quaternary ammonium salt.