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WO2009157628A1 - Composition pharmaceutique pour le traitement ou la prévention d’un cancer comprenant un composé de triazine comme ingrédient actif - Google Patents

Composition pharmaceutique pour le traitement ou la prévention d’un cancer comprenant un composé de triazine comme ingrédient actif

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Publication number
WO2009157628A1
WO2009157628A1 PCT/KR2008/007679 KR2008007679W WO2009157628A1 WO 2009157628 A1 WO2009157628 A1 WO 2009157628A1 KR 2008007679 W KR2008007679 W KR 2008007679W WO 2009157628 A1 WO2009157628 A1 WO 2009157628A1
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WO
WIPO (PCT)
Prior art keywords
cancer
alkyl
group
ring structure
substituted
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/KR2008/007679
Other languages
English (en)
Inventor
Da-Woon Jung
Jin Mi Kim
Zhong Min Che
Young-Tae Chang
Jin Kim
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Industry Academic Cooperation Foundation of Yonsei University
Original Assignee
Industry Academic Cooperation Foundation of Yonsei University
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from KR1020080127140A external-priority patent/KR101181910B1/ko
Application filed by Industry Academic Cooperation Foundation of Yonsei University filed Critical Industry Academic Cooperation Foundation of Yonsei University
Publication of WO2009157628A1 publication Critical patent/WO2009157628A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to a pharmaceutical composition for anti-cancer comprising a triazine compound as an active ingredient.
  • Mature cancer tissues have a characteristics to invade into adjacent tissues from a lesion developed and proliferate, called as invasion. Invasion and metastasis of cancer cells is an indispensible relationship and the invasion of cancer cells could be considered as an early stage of metastasis.
  • the metastasis of cancer cells is mainly composed of two processes: (a) degradation of extracellular matrix by overproduction of proteases; and (b) oriented migration of cancer cells.
  • a theory that the metastasis of cancer cells is occurred by induction of cells in an adjacent micro-environment, not cancer cell alone, has been commonly accepted.
  • a fibroblast is a representative stromal cell.
  • the experimental studies how fibroblasts influence on epithelia or epithelial carcinomas and on a novel cancer therapy targeting fibroblasts have been actively carried out.
  • the epithelial cells rapidly acquired the characteristics of cancer cells such as excessive cell proliferation, loss of cell suicide program or tissue invasion capability where fibroblasts are adjacent to epithelial cells initiating metastasis to cancer cells in breast cancer (Sadlonova et a/. 2005).
  • fibroblasts derived from prostate cancer promotes proliferation of prostate cancer cells and affects differentiation of cancer cells (Orimo et a/. 2005).
  • tumor cells were invaded into connective tissues only in the presence of fibroblast when oral squamous cell carcinoma (OSCC) cell line was cultured in a three-dimensional manner (Che et al, 2006).
  • OSCC oral squamous cell carcinoma
  • PCT Nos. WO 03/032903, WO 03/050237 and WO 04/099106 disclosed only a method for synthesizing a triazine compound library and an utility thereof as anti- tubulin agent, not a selection and use of a practical compound representing an activity to inhibit cancer cell invasion in the triazine compound library.
  • HTS high-throughput screening
  • a pharmaceutical composition for anti-cancer comprising a triazine compound as an active ingredient. It is another object of this invention to provide a method for preventing or treating a cancer which comprises administrating to a subject suffering from cancer a pharmaceutical composition comprising a triazine compound as an active ingredient. It is still another object of this invention to provide a use of a triazine compound to prepare a medicament for preventing or treating a cancer.
  • a pharmaceutical composition for anti-cancer comprising (a) a therapeutically effective amount of a triazine compound represented by a following formula I; and (b) a pharmaceutically acceptable carrier:
  • R 1 and R 2 independently represent H, -(CH 2 ) n -O-(CH 2 )n-0-(CH 2 )n-NH2, -(CH 2 ) n -O-(CH 2 ) n -0-(CH 2 ) n -NHBz, -(CH 2 ) n -O-(CH 2 ) n CH 3 , -(CH 2 ) n -O-(CH 2 ) n , -(CH 2 ) n - COOH, straight or branched Ci-C 10 alkyl, C 3 -C 15 cycloalkyl, C 4 -C 20 alkylcycloalkyl, C 2 - Cio alkenyl and Ci-Ci 0 alkylamine which may be optionally substituted with hydroxyl group, or Ri and R 2 may be linked to each other to form Ci-Ci 0 alkyl with a ring structure; wherein the Ci-Ci 0 alkyl with the
  • a method for preventing or treating a cancer which comprises administrating to a subject suffering from cancer a pharmaceutical composition comprising (a) a therapeutically effective amount of a triazine compound represented by the above-described formula I; and (b) a pharmaceutically acceptable carrier.
  • HTS high-throughput screening
  • Triazine compounds as an active ingredient of this invention is a compound having an anti-cancer activity selected from 1040 compounds of tagged triazine compound library using a screening system established by the present inventors.
  • a preparation method and use of the triazine compound library used in the present invention were disclosed in PCT/WO 03/032903 and PCT/WO 03/050237, which are incorporated herein by reference.
  • Ci-Ci 0 alkylamine in the formula 1 of the present invention refers to an amine having an alkyl group of a straight chain or a branched chain containing methylamine, ethylamine, n-propylamine, isopropylamine, n-butylarmine, sec- butylamine, tert-butylamine, n-amyl and tert-amyl.
  • CrCi 0 alkyl of a straight chain or a branched chain refers to an alkyl group of a straight chain or a branched chain containing methylamine, ethylamine, n-propylamine, isopropylamine, n-butylamine, sec-butylamine, tert-butylamine, n-amyl, tert-amyl or hexyl.
  • C 2 -Ci 0 alkenyl used in the present invention refers to an alkenyl of a straight chain or a branched chain having 2 to 10 carbon atoms containing one or more carbon-carbon double bonds.
  • C 2 -Ci 0 alkenyl includes, but not limited to, vinyl, allyl, 2-butenyl, 3-butenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4- hexenyl, 5-hexenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 5-heptenyl or 6-heptenyl.
  • C 4 -C 20 cycloalkyl used in the present invention refers to a saturated hydrocarbon with a mono- or multi-ring structure consisting of 3 to 15 carbon atoms.
  • C 3 -Ci 5 cycloalkyl includes, but not limited to, cyclopropyl ring, cyclobutyl ring, cyclohexyl ring or cycloheptyl ring.
  • C 4 -C 20 alkylcycloalkyl used in the present invention refers to an alkyl consisting of 4 to 20 carbon atoms, which is substituted with an alkyl in the above-described cycloalkyl.
  • C 7 -Ci 6 aralkyl used in the present invention refers to a Ci-Ci 0 alkyl substituted with one, or two or more phenyl rings in a random position, and for example, includes benzyl, 2-phenylethyl, 3-phenyl(n-prop-l-yl), 4-phenyl (hex-l-yl), 3-phenyl(n-am-2-yl) or 3,3-diphenylpropyl, but not limited to.
  • Ci-C 5 alkoxy used in the present invention, for example, includes methoxy, ethoxy or propoxy, but not limited to.
  • halogen used in the present invention includes F, Cl, Br and I.
  • R 1 and R 2 in the formula I of this invention may form a CrC 10 alkyl ring in which Ri and R 2 are linked to each other, wherein the CrCi 0 alkyl ring may comprise a hetero-atom of O, N or S, or may be substituted with Ci-Ci 0 alkyl.
  • R 2 and R 3 , or R 4 and R 5 in the formula I of this invention may be linked to form Ci-Ci 0 alkyl with a ring structure.
  • the compound of the formula I includes triazine compounds represented by the following formulae 1-10:
  • R 1 and R 2 independently represent H, -(CH 2 ) n -O-(CH 2 ) n -0-(CH 2 ) n -NH 2 , -(CH 2 ) n -O-(CH 2 ) n -0-(CH 2 ) n -NHBz, -(CH 2 ) n -O-(CH 2 ) n CH 3 , -(CH 2 ) n -O-(CH 2 ) n , -(CH 2 V COOH, straight or branched d-Cio alkyl, C 3 -C 15 cycloalkyl, C 4 -C 20 alkylcycloalkyl, C 2 - Cio alkenyl and Ci-Ci 0 alkylamine which may be optionally substituted with hydroxyl group, or Ri and R 2 may be linked to each other to form CrC 10 alkyl with a ring structure; wherein the Ci-Ci 0 alkyl
  • the -N RiR 2 group comprising Ri and R 2 groups in formulae 1-10 is any one of the following groups:
  • the triazine compound as an active ingredient of the pharmaceutical composition in the present invention is a compound represented by the formula 6.
  • the -N R 1 R 2 group comprising R 1 and R 2 groups in formula 6 is any one of the following groups:
  • the triazine compound as an active ingredient of the pharmaceutical composition in the present invention is a compound represented in formula 6.
  • the triazine compounds of the formula I as an active ingredient of the pharmaceutical composition in the present invention inhibit cancer cell invasion or have cytotoxicity to cancer cells.
  • the method to screen the triazine compound of this invention is based on the fact that carcinoma-associated fibroblasts (CAFs) induce cancer cell invasion by co- culturing CAF and cancer cells.
  • the screening method is a method to suitably modify a Boyden chamber assay or a transwell assay analyzing cell migration or invasion by a conventional chemotaxis using a multi-chamber.
  • the basic principle of the screening method is as follows: carcinoma-associated fibroblasts (CAF) are incubated in the lower chamber of transwell, and cancer cells are cultured in the upper chamber of transwell, so as to induce cancer cell invasion. It is analyzed whether a candidate compound added inhibits cancer cell invasion.
  • the triazine compounds represented by the formula I as an active ingredient of the present invention inhibit secretion of, or impede function of a cytokine or a chemokine inducing cancer cell invasion secreted from fibroblasts, or have a specific cytotoxicity to cancer cells per se.
  • the cancer capable of being treated or prevented by the pharmaceutical composition of the present invention includes, but not limited to, oral cancer, stomach cancer, lung cancer, breast cancer, ovarian cancer, liver cancer, bronchogenic cancer, nasopharyngeal cancer, laryngeal cancer, pancreatic cancer, bladder cancer, colon cancer, uterine cervical cancer, brain cancer, prostate cancer, bone cancer, skin cancer, thymus cancer, parathyroid cancer, renal cancer and ureteric cancer.
  • the cancer to which the pharmaceutical composition of the present invention may be applied is any one of cancers selected from the group consisting of oral cancer, colon cancer, lung cancer, breast cancer and prostate cancer.
  • the pharmaceutical composition of this invention includes a pharmaceutically acceptable carrier.
  • the pharmaceutically acceptable carrier contained in the pharmaceutical composition of the present invention which is commonly used in pharmaceutical formulations, but is not limited to, includes lactose, dextrose, sucrose, sorbitol, mannitol, starch, rubber arable, potassium phosphate, arginate, gelatin, potassium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrups, methylcellulose, methylhydroxy benzoate, propylhydroxy benzoate, talc, magnesium stearate and mineral oils.
  • the pharmaceutical composition according to the present invention may further include a lubricant, a humectant, a sweetener, a flavoring agent, an emulsifier, a suspending agent and a preservative. Details of suitable pharmaceutically acceptable carriers and formulations can be found in Remington's Pharmaceutical Sciences (19th ed., 1995), which is incorporated herein by reference.
  • a suitable dosage amount of the pharmaceutical composition of the present invention may vary depending on pharmaceutical formulation methods, administration methods, the patient's age, body weight, sex, pathogenic state, diet, administration time, administration route, an excretion rate and sensitivity for a used pharmaceutical composition.
  • the pharmaceutical composition of the present invention may be administered with a daily dosage of 0.001-100 mg/kg (body weight).
  • the pharmaceutical composition according to the present invention may be administered orally or parenterally, and preferably, administered parenterally, e.g., by intravenous, subcutaneous, intramuscular, intra-abdominal or transdermal injection. It is preferable that the administration route is determined depending on a disease to which the pharmaceutical composition of the present invention may be applied.
  • concentration of triazine compounds represented as the formulae 1-10 included in the composition of the present invention may be determined depending on treatment's purpose, pathological condition of a subject or necessity period, and is not limited to a particular range of concentration.
  • the pharmaceutical composition according to the present invention may be formulated with pharmaceutically acceptable carrier and/or vehicle as described above, finally providing several forms including a unit dose form and a multi-dose form.
  • the formulations include, but not limited to, a solution, a suspension or an emulsion in oil or aqueous medium, an elixir, a powder, a granule, a tablet and a capsule, and may further comprise a dispersion agent or a stabilizer.
  • the triazine compound as an active ingredient of the pharmaceutical composition in the present invention has an inhibitory activity on cancer cell invasion or a specific cytotoxicity to cancer cells, enabling to be applied as an excellent anticancer drug.
  • Fig. 1 schematically represents a system to screen a molecule with a low molecular weight regulating tumor-stroma interactions.
  • a filter with a pore size of 8 ⁇ m was coated with collagen type I (45 g/30 L).
  • 2 x 10 4 OSCC cells were inoculated into an upper well of transwell having the porous filter, and each CAF of 2 x 10 4 , CAF-conditioned media (CM), or CCL7 was added to a lower well of transwell having the porous filter.
  • the cells passing the filter were immobilized and stained with 0.25% crystal violet. The cells were counted under a light microscope.
  • Fig. 2 is a schematic diagram representing that a compound (S06) screened according to the method of the present invention prevents invasion and proliferation of a CAF-induced oral cancer cell line (YD-IOB) and reduces secretion of CCL7 by CAF.
  • Cancer cell line (YD-IOB) was inoculated into an upper well of transwell having the porous filter (pore size; 8 ⁇ m), and CAF was added to a lower well of transwell. To measure cell invasion, the cells passing a collagen-coated transwell membrane were immobilized and stained. The cells were counted under a light microscope. Cell invasion was visualized using a light microscope (Fig. 2A (i)), and cells invaded were quantitated by a cell counting (Fig. 2A (H)).
  • a cell viability of the oral cancer cell line (YD-IOB) was measured for 48 hrs after adding the compound (S06) (Fig. 2B).
  • Figs. 3a-3c show graphs to test the sensitivity to cytotoxicity of the triazine compound (S06) in oral cancer cell lines (YDlOB, HSC-2, HSC-3 and Ca9.22) using the MTT assay.
  • Fig. 4 represents a result to test the sensitivity to cytotoxicity of the triazine compound (S06) in colon cancer cell lines (HCT-116, DLD-I and HT-29) using the MTT assay.
  • Fig. 5 represents a result to test the sensitivity to cytotoxicity of the triazine compound (S06) in lung cancer cell lines (A549, NCI-H596 and NCI-H460) using the MTT assay.
  • Fig. 6 represents a result to test the sensitivity to cytotoxicity of triazine compound (S06) in breast cancer cell lines (MDA-MB-231, MDA-MB-435 and MCF-7) using the MTT assay.
  • Fig. 7 shows graphs to test the sensitivity to cytotoxicity of the triazine compound (S06) in prostate cancer cell line (PC-3) using the MTT assay.
  • Hg. 8 is a histogram representing that the triazine compound (S06) has no influence on cell viability of CAF.
  • S06 triazine compound
  • Figs. 1Oa-IOe are results representing that derivatives (S06-1 to S06-5) of triazine compound (S06) have cytotoxity on oral cancer cells.
  • Figs. 1 Ia-I If is results measuring an activity to inhibit oral cancer cell invasion by representative compounds (B50, H39, G35, G14, J49, S14, M17, S17 or S20) represented by formulae 1-5 and 7-10 using the method of the present invention. Accordingly, it could be demonstrated that these compounds have inhibitory activities on oral cancer cell invasion.
  • Fig. 12 shows a histogram adding conditioned media recovered from YD-IOB cell line into CAF culture in a 24-well plate in the presence or absence of the triazine compound (S06; 1 ⁇ M, 2.5 ⁇ M or 5 ⁇ M) to induce CCL7 secretion.
  • Fig. 13 shows a histogram adding conditioned media recovered from YD-IOB cell line into CAF culture in a 24-well plate in the presence or absence of the triazine compound (S06; 1 ⁇ M, 2.5 ⁇ M or 5 ⁇ M) to induce CXCL7 secretion.
  • Fig. 13 shows a histogram adding conditioned media recovered from YD-IOB cell line into CAF culture in a 24-well plate in the presence or absence of the triazine compound (S06; 1 ⁇ M, 2.5 ⁇ M or 5 ⁇ M) to induce CXCL7 secretion.
  • Fig. 15 is a photograph representing that apoptosis of oral cancer cells is induced by S06 treatment.
  • the compound S06 with a final concentration of 10 ⁇ M was added to oral cancer cell line (YD-IOB). After incubating for 12 hrs, cells were stained using an annexin V/carboxyfluorescein diacetate staining kit to detect apoptosis.
  • CDF Carboxyfluorescein diacetate.
  • Triazine Library Compounds 1040 compounds from a tagged triazine library were dissolved in DMSO (dimethyl sulfoxide) at a concentration of 5 mM. Tagged triazine library compounds and preparation method thereof are described in a conventional reference (Facilitated forward chemical genetics using tagged triazine library and zebrafish embryo screening, Khersonsky, S. M; Jung, D. W.; Kang, T. W.; Walsh, D. P.; Moon, H. S.; Jo, H.; Jacobson,E. M.; Shetty, V.; Neubert, T. A.; Chang, Y. T; J. Am. Chem. Soc. 2003, 125, 11804-11805). For a transwell invasion assay, an anti- invasive effect was measured by treating a candidate triazine compound with a final concentration of 5 ⁇ M.
  • OSCC Oral Squamous Cell Carcinoma
  • YD-IOB cell line (Lee EJ et a/. Exp MoI Med 2005, 37:379-90) registered in Korean Cell Line Bank
  • HSC-2, HSC-3 and Ca9.22 cell lines registered in Japanese Cell Line Bank were used as oral squamous cell carcinoma (OSCC) cells in the experiments.
  • HSC-2, HSC-3 or Ca9.22 cell line was incubated at 37°C incubator maintaining 5% CO 2 in DMEM:Hams-F12 (3: 1) supplemented with 1% penicillin/streptomycin and 10% FBS (fetal bovine serum).
  • YD-IOB cell line was cultured in media with the above composition supplemented with cholera toxin (0.1 ⁇ g/ml, Sigma), hydrocortisone (0.4 ⁇ g/ml, Sigma), insulin (5 ⁇ g/ml, Sigma), apo- transferrin (5 ⁇ g/ml, Sigma) and 3,3',5-triiodo-l-thyronine (2 ⁇ g/ml, Sigma) additionally.
  • HT-29 and DLD-I cell lines were incubated in RPMI 1640 supplemented with 1% penicillin/streptomycin and 10% FBS.
  • HCT-116 cell line was incubated in DMEM supplemented with 1% penicillin/streptomycin and 10% FBS.
  • NCI-H596, NCI-H460 and A549 cell lines were kindly provided from Yonsei Cancer Research Institute. NCI-H596 and NCI-H460 cell lines were incubated in
  • RPMI 1640 supplemented with 1% penicillin/streptomycin and 10% FBS.
  • A549 cell line was incubated in DMEM supplemented with 1% penicillin/streptomycin and
  • MCF-7, MDA-MB-231 and MDA-MB-435 cell lines were purchased from ATCC (American Type Culture Collection) and incubated in DMEM supplemented with 1% penicillin/streptomycin and 10% FBS.
  • PC-3 cell line kindly provided from Yonsei Cancer Research Institute was incubated in Hams-F12 supplemented with 1% penicillin/streptomycin and 10% FBS.
  • a method to screen an inhibitor of cancer cell invasion was performed according to suitable modifications of a transwell assay.
  • the invasion of cancer cells was measured in a 24-transwell plate (Corning Inc.)-
  • a filter with a pore diameter of 8 ⁇ m was coated with collagen type I, and CAF (carcinoma-associated fibroblasts) were seeded into a lower well beneath the porous filter at a density of 2.1 x 10 4 cells/well.
  • media were replaced with serum- free media and 2 x 10 4 cancer cells diluted in serum-free media were loaded on an upper well above the filter coated with collagen.
  • a triazine compound to be screened was added to the upper side of the filter.
  • cells passing the porous filter were immobilized with 10% formalin and stained with 0.25% crystal violet. The number of cells was counted under a microscope.
  • MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide) assay was carried out.
  • the cells were seeded in 96-well plate at a density of 8 x 10 3 cells/well. After culturing overnight, a triazine compound as a candidate to be screened was added to the plate and further incubated for 24 hrs or 48 hrs. Media were replaced with serum-free media containing MTT reagents and further incubated for 3 hrs. The culture solution was removed and DMSO was added. Formazan crystal formed was dissolved and the absorbance was measured at 540 nm.
  • CCL7 ELISA The amount of CCL7 secreted into cell culture media was measured using a
  • the amount of CXCL7 secreted into cell culture media was measured using a Human CCL7 ELISA kit (R&D Systems).
  • the method to harvest cell culture media was carried out according to the method as same as the above-described CCL7 ELISA.
  • the amount of IL-8 secreted into cell culture media was measured using a Human CCL7 ELISA kit (R&D Systems).
  • the method to harvest cell culture media was carried out according to the method as same as the above-described CCL7 ELISA.
  • the screening method used for selection was as follows: CAF were cultured in a lower well of a transwell and OSCC cells as cancer cell were incubated in an upper well of a transwell. OSCC cell invasion was induced to investigate whether a candidate compound added inhibit cell invasion (Hg. 1). After cancer cells passing a collagen-coated filter located between the upper and lower compartment of transwell were fixed and stained, the extent to invasion of cancer cells was judged by measuring the number of stained cells. In addition, MTT assay of candidate compounds for CAF as well as measurement of the invasion-inhibitory activity described above were carried out to exclude selection of candidate compounds having an inhibitory activity caused from non-specific cytotoxicity. The compounds representing cytotoxicity to carcinoma-associated fibroblasts by MTT assay was kept out.
  • the compound S06 (the compound of formula 6) among ten compounds selected not only has a specific cytotoxicity to cancer cells but also inhibits secretion of MCP-3/CCL7 known to have a chemostaxis to cancer cells as a cytokine secreted from fibroblasts (Fig. 2).
  • CCL7 (Chemokine C-C motif ligand 7) is a cytokine known as a CC chemokine that was previously called monocyte-specific chemokine 3 (MCP3).
  • CCL7 specifically attracts chemotaxis of monocytes, and regulates macrophage function. It is produced by certain tumor cell lines and by macrophages. The secretion of CCL7 was enhanced by tumor stimulation in carcinoma-associated fibroblast used in the present invention. It is thought that CCL7 secreted improves migration of cancer cells, accelerating cancer cell invasion.
  • CXCLl (Chemokine C-X-C motif ligand 1) is a small cytokine belonging to the CXC chemokine family that was previously called GROl oncogene, Neutrophil- activating protein 3 (NAP-3) and melanoma growth stimulating activity, alpha (MSGA- ⁇ ).
  • CXCLl is secreted by human melanoma cells, has mitogenic properties and is implicated in melanoma pathogenesis.
  • CXCLl is a cytokine having various activities such as angiogenesis, inflammation, wound healing, and tumorigenesis. In addtion, CXCLl is secreted by fibroblasts used in the present invention and is accelerated by cancer cell stimulation. It is thought that CXCLl plays a function in enhancing invasion and proliferation of cancer cells.
  • anexin V is a calcium-dependent phospholipid binding protein which has a high binding affinity with a phosphatidylserine (PS).
  • PS phosphatidylserine
  • Apoptosis in cells could be verified by Annexin V bound to PS exposed. As a experimental result, it could be appreciated that apoptosis in cancer cells is induced by treatment of the compound S06 (Rg. 15).
  • the compounds of formulae 1-10 screened in the present invention inhibit cancer cell invasion and have not only a selective cytotoxicity to cancer cells by apoptosis but also an activity to inhibit secretion of cytokines from fibroblasts which promote cancer cell invasion, thereby providing much more remarkable treatment efficacy on cancer.

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Abstract

La présente invention concerne une composition pharmaceutique pour combattre un cancer, laquelle comprend l'un quelconque des composés de triazine représentés par la formule I comme ingrédient actif. Le composé de triazine comme ingrédient actif de la composition pharmaceutique dans la présente invention présente une activité inhibitrice sur l’invasion de cellules cancéreuses ou une cytotoxicité spécifique aux cellules cancéreuses, permettant son utilisation comme un médicament anticancéreux efficace.
PCT/KR2008/007679 2008-06-23 2008-12-24 Composition pharmaceutique pour le traitement ou la prévention d’un cancer comprenant un composé de triazine comme ingrédient actif Ceased WO2009157628A1 (fr)

Applications Claiming Priority (4)

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KR20080059264 2008-06-23
KR10-2008-0059264 2008-06-23
KR1020080127140A KR101181910B1 (ko) 2008-06-23 2008-12-15 트리아진계 화합물을 유효성분으로 포함하는 항암용 약제학적 조성물
KR10-2008-0127140 2008-12-15

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US20150110742A1 (en) * 2012-05-02 2015-04-23 Yale University Tlr-agonist-conjugated antibody recruiting molecules (tlr-arms)
CN104739838A (zh) * 2014-09-30 2015-07-01 三峡大学 小分子抑制剂及在抑制鸟氨酸脱羧酶(odc)上的应用
EP3381909A1 (fr) * 2017-03-29 2018-10-03 Universite de Nantes Nouvelle substance de triazine à utiliser dans le traitement du cancer, en particulier pour le traitement d'un cancer à grandes cellules et composition pharmaceutique contenant ladite substance

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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20150110742A1 (en) * 2012-05-02 2015-04-23 Yale University Tlr-agonist-conjugated antibody recruiting molecules (tlr-arms)
US9556167B2 (en) * 2012-05-02 2017-01-31 Yale University TLR-agonist-conjugated antibody recruiting molecules (TLR-ARMs)
US10016412B2 (en) 2012-05-02 2018-07-10 Yale University TLR-agonist-conjugated antibody recruiting molecules (TLR-ARMs)
CN104739838A (zh) * 2014-09-30 2015-07-01 三峡大学 小分子抑制剂及在抑制鸟氨酸脱羧酶(odc)上的应用
CN104739838B (zh) * 2014-09-30 2017-07-14 三峡大学 小分子抑制剂及在抑制鸟氨酸脱羧酶(odc)上的应用
EP3381909A1 (fr) * 2017-03-29 2018-10-03 Universite de Nantes Nouvelle substance de triazine à utiliser dans le traitement du cancer, en particulier pour le traitement d'un cancer à grandes cellules et composition pharmaceutique contenant ladite substance
WO2018177784A1 (fr) * 2017-03-29 2018-10-04 Universite De Nantes Nouvelle substance triazinique destinée à être utilisée dans le traitement du cancer, plus précisément dans le traitement du cancer non à petites cellules

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