KR20140044154A - Bischromenylchalcone or dimethoxyichromenylchalcone derivative and use in anti-cancer agent and preparing method of the same - Google Patents

Bischromenylchalcone or dimethoxyichromenylchalcone derivative and use in anti-cancer agent and preparing method of the same Download PDF

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KR20140044154A
KR20140044154A KR1020120110177A KR20120110177A KR20140044154A KR 20140044154 A KR20140044154 A KR 20140044154A KR 1020120110177 A KR1020120110177 A KR 1020120110177A KR 20120110177 A KR20120110177 A KR 20120110177A KR 20140044154 A KR20140044154 A KR 20140044154A
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derivative
methoxy
chromen
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임융호
이영한
고동수
신순영
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건국대학교 산학협력단
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/42—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms in positions 2 and 4
    • C07D311/44—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms in positions 2 and 4 with one hydrogen atom in position 3
    • C07D311/54—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms in positions 2 and 4 with one hydrogen atom in position 3 substituted in the carbocyclic ring
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
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    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
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    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
    • C07D407/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

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Abstract

The present invention relates to a method for manufacturing a bischromenylchalcone derivative or a dimethoxyichromenylchalcone derivative and an use of the same as an anti-cancer agent and, more specifically, to an anti-cancer pharmaceutical composition having an anti-cancer effect through an inhibitory effect on cell cycle in colon cancer cell strains of a bischromenylchalcone derivative or a dimethoxyichromenylchalcone derivative.

Description

비스크로메닐칼콘 또는 디메톡시크로메닐칼콘 유도체 및 그의 항암제로서의 용도 {Bischromenylchalcone or dimethoxyichromenylchalcone derivative and Use in anti-cancer agent and preparing method of the same}Biscromonomycalone or dimethoxy-chromenyl chalcone derivatives and their use as anticancer agents {Bischromenylchalcone or dimethoxyichromenylchalcone derivative and Use of the anti-cancer agent and preparing method of the same}

본 발명은 비스크로메닐칼콘 유도체 (bischromenylchalcone derivative) 또는 디메톡시크로메닐칼콘 유도체 (dimethoxyichromenylchalcone derivative)의 제법 및 항암제로서의 용도에 관한 것으로, 더욱 상세하게는 비스크로메닐칼콘 또는 디메톡시크로메닐칼콘 유도체의 대장암 세포주에서 세포주기 억제를 통한 항암 효과를 갖는 항암제용 약학조성물에 관한 것이다.The present invention relates to a bischromenylchalcone derivative or a dimethoxychromenylchalcone derivative and its use as an anticancer agent. More particularly, the present invention relates to a process for producing a bischromenylchalcone derivative or a dimethoxychromenylchalcone derivative, The present invention relates to a pharmaceutical composition for an anticancer drug having an anticancer effect through inhibition of cell cycle in a cancer cell line.

칼콘은 식물 유래 이차대사물의 일종으로 C6-C3-C6의 골격을 갖는 플라보노이드 계열에 속하는 화합물이다. 일반적으로 플라보노이드가 세 개의 ring으로 구성된 것과는 달리 칼콘은 두 개의 ring을 a,b-불포화 카르보닐기가 연결하는 구조이므로 플라보노이드보다는 조금 더 유동성이 큰 구조를 갖는다. 칼콘은 식물에서 페닐프로파노이드 생합성 경로를 통해서 만들어 지는데 다른 이차대사물과 마찬가지로 극소량만이 식물에서 자연상태로 발견되기 때문에 생물학적 실험을 수행하기에는 충분한 양의 확보가 필요하다. 칼콘은 또한 식물 유래 폴리페놀 화합물에 속하기 때문에 당양한 치환기를 가질 수 있는 구조를 가지기에 여러종류의 유도체들이 천연 상태에서 발견되고 인공적으로 합성될 수 있다. 플라보노이드의 일종인 플라본은 세 개의 ring을 가진 구조인데 이 유도체의 일종의 벤조플라본은 ring을 한 개 더 지닌 구조를 가지고 이들은 유방암 저항 단백질을 저해하는 것으로 알려져 있다. 따라서 본 발명자들은 항암 효과를 보이는 새로운 화합물을 찾고자 하던 중 칼콘이나 벤조플라본과 같이 항암효과를 보이는 천연물 유래 화합물로부터 새로운 구조를 갖는 화합물을 디자인하게 되었다. Chalcone is a plant-derived secondary metabolite and is a compound belonging to the flavonoid family having a C6-C3-C6 skeleton. Unlike flavonoids, which are generally composed of three rings, chalcone has a structure that is slightly more fluid than a flavonoid because the two rings are linked by a, b-unsaturated carbonyl groups. The chalcone is made through the phenylpropanoid biosynthetic pathway in plants. Like other secondary metabolites, only very small amounts are found in nature in plants, so it is necessary to secure sufficient quantities to carry out biological experiments. Since chalcone also belongs to plant-derived polyphenol compounds, various derivatives can be found in natural state and can be artificially synthesized since they have a structure capable of having substituted substituents. Flavone, a kind of flavonoid, is a structure with three rings. One kind of benzoflavone of this derivative has a structure with one ring, which is known to inhibit the breast cancer resistance protein. Therefore, while searching for a novel compound having an anticancer effect, the present inventors have designed a compound having a new structure from a compound derived from a natural product exhibiting anticancer effect such as chalcone or benzoflavone.

관련 선행 특허로 대한민국특허공개번호 제1020120050918호는 벤프로페린(benproperine) 유도체의 암 및 혈관신생-관련 질환의 예방 및 치료용 약학적 조성물에 관한 것이고,Korean Patent Publication No. 1020120050918 relates to a pharmaceutical composition for the prevention and treatment of cancer and angiogenesis-related diseases of benproperine derivatives,

다른 관련 선행 특허로 대한민국특허공개번호 제020070048798호는 퀴나졸리논 유도체 및 이것의 Ｂ-ＲＡＦ 억제제로서의 용도에 관하여 기재되어 있다.
As another related prior patent, Korean Patent Publication No. 020070048798 discloses a quinazolinone derivative and its use as a B-RAF inhibitor.

본 발명은 상기의 필요성에 의하여 안출된 것으로서 본 발명의 목적은 효과적인 항암제를 제공하는 것이다.The present invention has been made in view of the above needs, and an object of the present invention is to provide an effective anticancer agent.

상기 목적을 달성하기 위하여, 본 발명은 하기의 화학식 1로 표시되는 비스크로메닐칼콘 유도체를 제공한다.In order to accomplish the above object, the present invention provides a biscromethinyl chalcone derivative represented by the following formula (1).

Figure pat00001
Figure pat00001

[화학식 1][Chemical Formula 1]

또한, 본 발명은 상기 화학식 1의 비스크로메닐칼콘 유도체 또는 이의 약학적으로 허용되는 염을 포함하는 암 질환의 예방 및 치료를 위한 약학조성물을 제공한다.The present invention also provides a pharmaceutical composition for the prevention and treatment of cancer diseases, which comprises the biscromethinyl chalcone derivative of formula (I) or a pharmaceutically acceptable salt thereof.

또한 본 발명은 하기의 화학식 2로 표시되는 디메톡시크로메닐칼콘 유도체를 제공한다.The present invention also provides a dimethoxy-chromenyl chalcone derivative represented by the following formula (2).

Figure pat00002
Figure pat00002

[화학식 2] (2)

또한, 본 발명은 상기 화학식 2의 디메톡시크로메닐칼콘 유도체 또는 이의 약학적으로 허용되는 염을 포함하는 암 질환의 예방 및 치료를 위한 약학조성물을 제공한다. The present invention also provides a pharmaceutical composition for the prevention and treatment of cancer diseases, which comprises the dimethoxycromonyl chalcone derivative of formula (2) or a pharmaceutically acceptable salt thereof.

또 본 발명은 1-(6-메톡시-2H-크로멘-3-일)에타논 및 6-메톡시-2H-크로멘-3-카바알데히드를 녹인 후에 염기를 가하는 단계를 포함하는 하기 화학식 1의 화합물의 제조방법을 제공한다.The present invention also relates to a process for the preparation of 1- (6-methoxy-2H-chromen-3-yl) ethanone and 6-methoxy-2H-chromen-3-carbaldehyde, 1 < / RTI >

Figure pat00003
Figure pat00003

[화학식 1][Chemical Formula 1]

또 본 발명은 1-(6-메톡시-2H-크로멘-3-일)에타논 및 7-메톡시-2H-크로멘-3-카바알데히드를 녹인 후에 염기를 가하는 단계를 포함하는 하기 화학식 2의 화합물의 제조방법을 제공한다.The present invention also relates to a process for the preparation of 1- (6-methoxy-2H-chromen-3-yl) ethanone and 7-methoxy-2H-chromen- 2 < / RTI >

Figure pat00004
Figure pat00004

[화학식 2] (2)

본 발명의 조성물에 의해 예방 또는 치료될 수 있는 암 질환은 대장암인 것이 바람직하나, 자궁경부암, 폐암, 췌장암, 비소세포성폐암, 간암, 골암, 피부암, 두부암, 경부암, 피부 흑색종, 안구내 흑색종, 자궁암, 난소암, 뇌종양, 방광암, 혈액암, 위암, 항문부근암, 유방암, 나팔관암종, 자궁내막암종, 질암, 음문암종, 호지킨병(Hodgkin's disease), 식도암, 소장암, 내분비선암, 갑상선암, 부갑상선암, 부신암, 연조직 육종, 요도암, 음경암, 전립선암, 신장암, 수뇨관암, 신장세포 암종, 신장골반 암종, 중추신경계(CNS central nervoussystem) 종양, 1차 CNS 림프종, 척수 종양, 뇌간 신경교종, 뇌하수체 선종 등을 포함한다.Cancer diseases that can be prevented or treated by the composition of the present invention are preferably colon cancer, but it is preferable that the cancer is cervical cancer, lung cancer, pancreatic cancer, non-small cell lung cancer, liver cancer, bone cancer, skin cancer, head cancer, Endometrial carcinoma, vaginal cancer, vulvar carcinoma, Hodgkin's disease, esophageal cancer, small bowel cancer, endocrine cancer, endometrial cancer, endometrial cancer, endometrial cancer, endometrial cancer, endometrial cancer, endometrial cancer, endometrial cancer, endometrial cancer, Renal cell carcinoma, renal pelvic carcinoma, CNS central nervous system tumor, primary CNS lymphoma, renal cell carcinoma, renal cell carcinoma, renal cell carcinoma, renal pelvic carcinoma, Spinal cord tumor, brainstem glioma, pituitary adenoma, and the like.

본 발명의 조성물은 각각의 사용 목적에 맞게 통상의 방법에 따라 산제, 과립제, 정제, 캡슐제, 현탁제,에멀젼, 시럽, 에어로졸 등의 경구 제형, 멸균 주사용액의 주사제 등 다양한 형태로 제형화하여 사용할 수 있으며, 경구 투여하거나 정맥내, 복강내, 피하, 직장, 국소 투여 등을 포함한 다양한 경로를 통해 투여될 수 있다.The composition of the present invention may be formulated into various forms such as powders, granules, tablets, capsules, oral formulations such as suspensions, emulsions, syrups and aerosols, injections of sterilized injection solutions, and the like, And can be administered via various routes including oral administration or intravenous, intraperitoneal, subcutaneous, rectal, topical administration, and the like.

이러한 조성물에 포함될 수 있는 적합한 담체, 부형제 또는 희석제의 예로는 락토오스, 덱스트로스, 수크로스,솔비톨, 만니톨, 자일리톨, 에리쓰리톨, 말티톨, 전분, 아카시아 고무, 알지네이트, 젤라틴, 칼슘 포스페이트,칼슘 실리케이트, 셀룰로스, 메틸 셀룰로스, 비정질 셀룰로스, 폴리비닐 피롤리돈, 물, 메틸하이드록시벤조에이트, 프로필하이드록시벤조에이트, 탈크, 마그네슘 스테아레이트 및 광물유 등을 들 수 있다. 본 발명의 조성물은 충전제, 항응집제, 윤활제, 습윤제, 향료, 유화제, 방부제 등을 추가로 포함할 수 있다.Examples of suitable carriers, excipients or diluents that may be included in such compositions include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate, Cellulose, methylcellulose, amorphous cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil. The composition of the present invention may further comprise a filler, an anti-coagulant, a lubricant, a wetting agent, a flavoring agent, an emulsifier, an antiseptic, and the like.

경구 투여를 위한 고형 제제에는 정제, 환제, 산제, 과립제, 캡슐제 등이 포함되며, 이러한 고형 제제는 상기 조성물에 적어도 하나 이상의 부형제, 예를 들면 전분, 탄산칼슘, 수크로스, 락토오스, 젤라틴 등을 혼합하여 제형화한다. 또한, 단순한 부형제 이외에 마그네슘 스테아레이트, 탈크와 같은 윤활제가 사용될 수 있다.Solid formulations for oral administration include tablets, pills, powders, granules, capsules and the like, which may contain at least one excipient such as starch, calcium carbonate, sucrose, lactose, gelatin, Mix and formulate. In addition to simple excipients, lubricants such as magnesium stearate and talc may also be used.

경구용 액상 제제로는 현탁제, 내용액제, 유제, 시럽제 등이 예시될 수 있으며, 흔히 사용되는 단순 희석제인 물, 액체 파라핀 이외에 여러 가지 부형제, 예를 들면 습윤제, 감미제, 방향제, 보존제 등이 포함될 수 있다.Examples of the oral liquid preparation include suspensions, solutions, emulsions and syrups. In addition to water and liquid paraffin which are commonly used simple diluents, various excipients such as wetting agents, sweeteners, fragrances, preservatives and the like are included .

비경구 투여를 위한 제제에는 멸균된 수용액제, 비수성용제, 현탁제, 유제, 동결건조제, 좌제 등을 예시할 수 있다. 비수성용제, 현탁제에는 프로필렌글리콜, 폴리에틸렌글리콜, 올리브 오일과 같은 식물성 기름, 에틸올레이트와 같은 주사 가능한 에스테르 등이 포함될 수 있다. 주사제에는 용해제, 등장화제, 현탁화제, 유화제, 안정화제, 방부제 등과 같은 종래의 첨가제가 포함될 수 있다.Examples of preparations for parenteral administration include sterilized aqueous solutions, non-aqueous solvents, suspensions, emulsions, freeze-dried agents, suppositories, and the like. Examples of the non-aqueous solvent and suspending agent include propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate, and the like. Injectables may include conventional additives such as solubilizers, isotonic agents, suspending agents, emulsifiers, stabilizers, preservatives, and the like.

본 발명의 조성물은 약제학적으로 유효한 양으로 투여한다. 본 발명에서, "약제학적으로 유효한 양"은 의학적 치료에 적용 가능한 합리적인 수혜/위험 비율로 질환을 치료하기에 충분한 양을 의미하며, 유효 용량 수준은 환자의 질환의 종류, 중증도, 약물의 활성, 약물에 대한 민감도, 투여 시간, 투여 경로 및 배출 비율, 치료 기간,동시 사용되는 약물을 포함한 요소 및 기타 의학 분야에 잘 알려진 요소에 따라 결정될 수 있다. 본 발명의 조성물은 개별 치료제로 투여하거나 다른 치료제와 병용하여 투여될 수 있고, 종래의 치료제와 순차적으로 또는 동시에 투여될 수 있으며, 단일 또는 다중 투여될 수 있다. 상기한 요소들을 모두 고려하여 부작용 없이 최소한의 양으로 최대 효과를 얻을 수 있는 양을 투여하는 것이 중요하며, 이는 당업자에 의해 용이하게 결정될 수 있다.The composition of the present invention is administered in a pharmaceutically effective amount. In the present invention, "pharmaceutically effective amount" means an amount sufficient to treat a disease at a reasonable benefit / risk ratio applicable to medical treatment, and the effective dose level will depend on the type of disease, severity, The sensitivity to the drug, the time of administration, the route of administration and the rate of release, the duration of the treatment, factors including co-administered drugs, and other factors well known in the medical arts. The composition of the present invention may be administered as an individual therapeutic agent or in combination with other therapeutic agents, and may be administered sequentially or simultaneously with conventional therapeutic agents, and may be administered singly or multiply. It is important to take into account all of the above factors and to administer the amount in which the maximum effect can be obtained in a minimal amount without side effects, which can be easily determined by those skilled in the art.

구체적으로, 본 발명의 조성물에서 화합물의 유효량은 환자의 나이, 성별, 체중에 따라 달라질 수 있으며, 일반적으로는 체중 ㎏ 당 0.01 내지 100 mg, 바람직하게는 0.1 내지 10 mg을 매일 또는 격일 투여하거나 1일 1 내지 3회로 나누어 투여할 수 있다. 그러나, 투여 경로, 질병의 중증도, 성별, 체중, 연령 등에 따라서 증감될 수 있으므로 상기 투여량이 어떠한 방법으로도 본 발명의 범위를 한정하는 것은 아니다.Specifically, the effective amount of the compound in the composition of the present invention may vary depending on the age, sex and body weight of the patient, and is generally 0.01 to 100 mg, preferably 0.1 to 10 mg per kg of body weight, It may be administered one to three times a day. However, the dosage may not be limited in any way because it may be increased or decreased depending on route of administration, severity of disease, sex, weight, age, and the like.

본 발명의 조성물은 쥐, 생쥐, 가축, 인간 등의 포유동물에 다양한 경로로 투여될 수 있다. 투여의 모든 방식은 예상될 수 있는데, 예를 들면, 경구, 직장 또는 정맥, 근육, 피하, 자궁내 경막 또는 뇌혈관내(intracerebroventricular) 주사에 의해 투여될 수 있다.The composition of the present invention may be administered to mammals such as rats, mice, livestock, humans, and the like in various routes. All modes of administration may be expected, for example, by oral, rectal or intravenous, intramuscular, subcutaneous, intra-uterine or intracerebroventricular injections.

본 발명에서 "투여"는 임의의 적절한 방법으로 환자에게 소정의 물질을 제공하는 것을 의미하며, 본 발명의 조성물의 투여 경로는 목적 조직에 도달할 수 있는 한 일반적인 모든 경로를 통하여 경구 또는 비경구 투여될 수 있다. 또한, 본 발명의 조성물은 유효성분을 표적 세포로 전달할 수 있는 임의의 장치를 이용해 투여될 수 있다.In the present invention, "administration" means providing a predetermined substance to a patient in any appropriate manner, and the administration route of the composition of the present invention may be administered orally or parenterally . In addition, the composition of the present invention can be administered using any device capable of delivering an effective ingredient to a target cell.

본 발명에서 "대상"은 인간, 원숭이, 소, 말, 양, 돼지, 닭, 칠면조, 메추라기, 고양이, 개, 마우스, 쥐, 또끼 또는 기니아 피그를 포함하나 이에 한정되지 아니하는 동물을 의미하고, 일 실시예에서는 포유류를, 또 다른 실시예에서는 인간을 의미한다.The term "subject" in the present invention means an animal including, but not limited to, a human, a monkey, a cow, a horse, a sheep, a pig, a chicken, a turkey, a quail, a cat, a dog, a mouse, a rat, Mammal in one embodiment, and human in another embodiment.

본 발명에서 유효성분과 결합하여 사용된 "치료학적으로 유효한 양"이란 용어는 대상 질환을 치료 또는 예방하는데 유효한 벤프로페린, 그의 약학적으로 허용가능한 염 또는 그의 유도체의 양을 의미한다.The term "therapeutically effective amount " used in connection with the active ingredient in the present invention means the amount of benperin, its pharmaceutically acceptable salt or derivative thereof, which is effective in treating or preventing a subject disease.

본 발명의 약학적 조성물은 유효성분으로서 상가 본 발명의 유도체 화합물 또는 그의 약학적으로 허용가능한 염 이외에 공지된 항암제 또는 혈관신생 저해제를 추가로 포함할 수 있고, 이들 질환의 치료를 위해 공지된 다른 치료와 병용될 수 있다. 다른 치료에는 화학요법, 방사선 치료, 호르몬 치료, 골수 이식, 줄기-세포 대체 치료, 다른 생물학적 치료, 면역치료 등이 포함되지만, 이에 한정되는 것은 아니다.The pharmaceutical composition of the present invention may further comprise a known anticancer agent or angiogenesis inhibitor in addition to the derivative compound of the present invention or a pharmaceutically acceptable salt thereof as an active ingredient and may further include other known treatments for the treatment of these diseases ≪ / RTI > Other treatments include, but are not limited to, chemotherapy, radiation therapy, hormone therapy, bone marrow transplantation, stem cell replacement therapy, other biological therapies, immunotherapy, and the like.

본 발명의 약학적 조성물에 포함될 수 있는 항암제의 예시에는 DNA 알킬화제(DNA alkylating [0060] agents)로 메클로에타민(mechloethamine), 클로람부칠(chlorambucil), 페닐알라닌(phenylalanine), 무스타드(mustard), 사이클로포스파미드(cyclophosphamide), 이포스파미드(ifosfamide), 카르무스틴(carmustine: BCNU), 로무스틴(lomustine: CCNU), 스트렙토조토신(streptozotocin), 부설판(busulfan), 티오테파(thiotepa), 시스플라틴(cisplatin) 및 카보플라틴(carboplatin); 항암 항생제(anti-cancer antibiotics)로 닥티노마이신Examples of anticancer agents that may be included in the pharmaceutical composition of the present invention include DNA alkylating agents such as mechloethamine, chlorambucil, phenylalanine, mustard, But are not limited to, cyclophosphamide, ifosfamide, carmustine (BCNU), lomustine (CCNU), streptozotocin, busulfan, thiotepa, , Cisplatin and carboplatin; Antitumor antibiotics (anti-cancer antibiotics)

(dactinomycin: actinomycin D), 독소루비신(doxorubicin: adriamycin), 다우노루비신(daunorubicin), 이다루비신(idarubicin), 미토크산트론(mitoxantrone), 플리카마이신(plicamycin), 마이토마이신(mitomycin) 및 C 브레오마이신(C Bleomycin); 및 식물 알카로이드(plant alkaloids)로 빈크리스틴(vincristine), 빈블라스틴(vinblastine), 파클리탁셀(paclitaxel), 도세탁셀(docetaxel), 에토포사이드(etoposide), 테니포사이드(teniposide), 토포테칸(topotecan) 및 이리도테칸(iridotecan) 등이 포함되지만, 이에 한정되는 것은 아니다.but are not limited to, dactinomycin: actinomycin D, doxorubicin: adriamycin, daunorubicin, idarubicin, mitoxantrone, plicamycin, mitomycin, C Bleomycin; And plant alkaloids such as vincristine, vinblastine, paclitaxel, docetaxel, etoposide, teniposide, topotecan, and iridotecan, Iridotecan, and the like, but are not limited thereto.

본 발명의 비스크로메닐칼콘 또는 디메톡시크로메닐칼콘 유도체는 대장암 세포주의 세포주기 진행 억제 및 세포사멸 유도 효과를 보임으로써 암 질환의 예방 및 치료를 위한 약학조성물로 유용하게 이용될 수 있다.
The biscrometholactone or dimethoxycromonyl chalcone derivative of the present invention exhibits cell cycle progression inhibition and cell death-inducing effect of a colon cancer cell line, and thus can be usefully used as a pharmaceutical composition for prevention and treatment of cancer diseases.

도 1은 비스크로메닐칼콘 유도체 (E)-1,3-bis(6-methoxy-2H-chromen-3-yl)prop-2-en-1-one 화합물의 수소핵자기공명분광스펙트럼이다. (400MHz 브루커 핵자기공명분광기기 사용)
도 2는 비스크로메닐칼콘 유도체 (E)-1,3-bis(6-methoxy-2H-chromen-3-yl)prop-2-en-1-one 화합물의 탄소핵자기공명분광스펙트럼이다. (100MHz 브루커 핵자기공명분광기기 사용)
도 3은 비스크로메닐칼콘 유도체 (E)-1,3-bis(6-methoxy-2H-chromen-3-yl)prop-2-en-1-one 화합물의 고분해능질량분석 스펙트럼이다. (제올사 (Jeol Ltd., Tokyo, Japan)의 JMS700 HREIMS (high-resolution electron impact ionization mass spectrometer) 기기 사용)
도 4는 비스크로메닐칼콘 유도체 (E)-1,3-bis(6-methoxy-2H-chromen-3-yl)prop-2-en-1-one의 대장암 세포의 세포주기 진행 억제 효과이다. HCT116 대장암 세포에 용매인 DMSO만 처리한 경우 (왼쪽 그림)와 비스크로메닐칼콘 유도체를 20uM 농도로 처리하여 (오른쪽 그림) 24시간 경과한 후 세포주기 진행 상태를 관찰한 결과이다. sub-G1 세포양은 apoptosis를 통한 세포사멸이 진행되고 있음을 의미한다. 2N, diploid; 4N, tetraploid; M1, sub-G1기; M2, G1기; M3, S기; M4, G2/M기
도 5는 디메톡시크로메닐칼콘 유도체 (E)-1-(6-methoxy-2H-chromen-3-yl)-3-(7-methoxy-2H-chromen-3-yl)prop-2-en-1-one 화합물의 수소핵자기공명분광스펙트럼이다. (400MHz 브루커 핵자기공명분광기기 사용)
도 6은 디메톡시크로메닐칼콘 유도체 (E)-1-(6-methoxy-2H-chromen-3-yl)-3-(7-methoxy-2H-chromen-3-yl)prop-2-en-1-one 화합물의 탄소핵자기공명분광스펙트럼이다. (100MHz 브루커 핵자기공명분광기기 사용)
도 7은 디메톡시크로메닐칼콘 유도체 (E)-1-(6-methoxy-2H-chromen-3-yl)-3-(7-methoxy-2H-chromen-3-yl)prop-2-en-1-one 화합물의 고분해능질량분석 스펙트럼이다. (제올사 (Jeol Ltd., Tokyo, Japan)의 JMS700 HREIMS (high-resolution electron impact ionization mass spectrometer) 기기 사용)
도 8은 디메톡시크로메닐칼콘 유도체 (E)-1-(6-methoxy-2H-chromen-3-yl)-3-(7-methoxy-2H-chromen-3-yl)prop-2-en-1-one의 대장암 세포의 세포주기 진행 억제 효과이다. 대장암 세포에 용매인 DMSO만 처리한 경우 (왼쪽 그림)와 디메톡시크로메닐칼콘 유도체 (DMCC)를 20uM 농도로 처리하여 (오른쪽 그림) 24시간 경과한 후 세포주기 진행 상태를 관찰한 결과이다. sub-G1 세포양은 apoptosis를 통한 세포사멸이 진행되고 있음을 의미한다. 2N, diploid; 4N, tetraploid; M1, sub-G1기; M2, G1기; M3, S기; M4, G2/M기BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 is a hydrogen nuclear magnetic resonance spectroscopy spectrum of a bis-cyclomethylacetone derivative (E) -1,3-bis (6-methoxy-2H-chromen-3-yl) prop-2-en-1-one. (Using a 400 MHz Bruker nuclear magnetic resonance spectrometer)
FIG. 2 is a carbon nuclear magnetic resonance spectroscopy spectrum of a bis-cresylmethyla chalcon derivative (E) -1,3-bis (6-methoxy-2H-chromen-3-yl) prop-2-en-1-one. (Using a 100 MHz Bruker nuclear magnetic resonance spectrometer)
FIG. 3 is a high-resolution mass spectrometry spectrum of a bis-cresylmethyla chalcon derivative (E) -1,3-bis (6-methoxy-2H-chromen-3-yl) prop-2-en-1-one. (Using a JMS700 HREIMS (high-resolution electron impact ionization mass spectrometer) instrument from Jeol Ltd., Tokyo, Japan)
4 is an effect of suppressing cell cycle progression of colorectal cancer cells of biscromethanyl chalcone derivative (E) -1,3-bis (6-methoxy-2H-chromen-3-yl) prop-2-en- . HCT116 colon cancer cells were treated with the solvent DMSO only (left) and bismuthromethylacetone derivative at 20 uM concentration (right). After 24 hours, cell cycle progression was observed. The amount of sub-G1 cells indicates apoptosis-mediated apoptosis. 2N, diploid; 4N, tetraploid; M1, sub-G1 group; M2, G1 group; M3, S group; M4, G2 / M machine
FIG. 5 is a graph showing the effect of the dimethoxy chromenyl chalcone derivative (E) -1- (6-methoxy-2H-chromen-3-yl) -3- 1-one < / RTI > compound. (Using a 400 MHz Bruker nuclear magnetic resonance spectrometer)
FIG. 6 is a graph showing the molecular weight distribution of a dimethoxy chromenyl chalcone derivative (E) -1- (6-methoxy-2H-chromen-3-yl) -3- 1-one < / RTI > compound. (Using a 100 MHz Bruker nuclear magnetic resonance spectrometer)
FIG. 7 is a graph showing the effect of the dimethoxy chromenyl chalcone derivative (E) -1- (6-methoxy-2H-chromen-3-yl) -3- 1-one. ≪ / RTI > (Using a JMS700 HREIMS (high-resolution electron impact ionization mass spectrometer) instrument from Jeol Ltd., Tokyo, Japan)
FIG. 8 is a graph showing the effect of the dimethoxy chromenyl chalcone derivative (E) -1- (6-methoxy-2H-chromen-3-yl) -3- 1-one inhibits cell cycle progression of colorectal cancer cells. Colorectal cancer cells were treated with DMSO (left) and dimethoxychromenylacetone derivative (DMCC) at 20 uM concentration (right) for 24 h and observed cell cycle progression. The amount of sub-G1 cells indicates apoptosis-mediated apoptosis. 2N, diploid; 4N, tetraploid; M1, sub-G1 group; M2, G1 group; M3, S group; M4, G2 / M machine

이하, 실시예를 통하여 본 발명을 더욱 상세히 설명하고자 한다. 이들 실시예는 오로지 본 발명을 예시하기 위한 것으로서, 본 발명의 범위가 이들 실시예에 의해 제한되는 것으로 해석되지는 않는 것은 당업계에서 통상의 지식을 가진 자에게 있어서 자명할 것이다.
Hereinafter, the present invention will be described in more detail with reference to Examples. It is to be understood by those skilled in the art that these examples are for illustrative purposes only and that the scope of the present invention is not construed as being limited by these examples.

실시예Example 1.  One. 비스크로메닐칼콘Biscoromenylcalcone 유도체의 합성 Synthesis of derivatives

본 발명에서는 화학식 1로 표시되는 비스크로메닐칼콘 유도체를 아래 반응식에 나타낸 방법을 사용하여 다음과 같이 합성하였다.In the present invention, the biscromethalicolone derivative represented by formula (1) was synthesized as follows using the method shown in the following reaction formula.

Figure pat00005

Figure pat00005

출발물질로 사용된 1-(6-methoxy-2H-chromen-3-yl)ethanone (I)은 2-hydroxy-5-methoxybenzaldehyde와 methylvinylketone을 K2CO3 염기 존재 하에서 문헌 방법 [ European Journal of Medicinal Chemistry, 2010, 1424-1429]에 따라 반응시켜 얻었다. 같은 방법으로 2-hydroxy-5-methoxybenzaldehyde를 K2CO3염기 존재하에서 acrolein과 반응시켜 또 다른 출발물질인 6-methoxy-2H-chromene-3-carbaldehyde (II) 를 얻었다. 6-methoxy-2H-chromene-3-carbaldehyde (II , 190 mg, 1 mmol)와 1-(6-methoxy-2H-chromen-3-yl)ethanone (I, 204 mg, 1 mmol)을 10 mL 에탄올에 녹인 후에 혼합물의 온도를 얼음 수조를 이용하여 5℃까지 낮춘다. 위의 냉각 용액에 50% KOH 용액 2 mL를 천천히 가하고 상온에서 약 30시간 교반한다. 반응 혼합물을 약 100 mL의 얼음물에 넣고, 6N HCl 가하여 pH를 약 3으로 조절한다. 위의 용액을 CH2Cl2 50 mL를 사용하여 두 번 추출하고, 추출된 유기용매층을 MgSO4 건조제를 사용하여 건조한다. 건조제를 감압여과하여 제거하고 여액을 회전증발기을 사용하여 용매를 제거한다. 잔사를 관 크로마토그라피를 (전개용매; 에틸아세테이트 : 헥산 = 1 : 5) 통해 정제하여 (E)-1,3-bis(6-methoxy-2H-chromen-3-yl)prop-2-en-1-one을 얻었다.
1- (6-methoxy- 2H- chromen-3-yl) ethanone ( I ) used as a starting material was prepared by reacting 2-hydroxy-5-methoxybenzaldehyde with methylvinylketone in the presence of K2CO3 base [European Journal of Medicinal Chemistry, 2010 , 1424-1429]. In the same manner, 2-hydroxy-5-methoxybenzaldehyde was reacted with acrolein in the presence of K2CO3 base to obtain another starting material, 6-methoxy-2H-chromene-3-carbaldehyde ( II ). 6-methoxy-2H-chromene- 3-carbaldehyde (II, 190 mg, 1 mmol) and 1- (6-methoxy- 2H -chromen- 3-yl) ethanone (I, 204 mg, 1 mmol) to 10 mL of ethanol And the temperature of the mixture is lowered to 5 캜 by using an ice water bath. Add 2 mL of 50% KOH solution slowly to the above cooling solution, and stir at room temperature for about 30 hours. The reaction mixture is poured into about 100 mL of ice water and the pH is adjusted to about 3 by addition of 6N HCl. The above solution is extracted twice with 50 mL of CH2Cl2, and the extracted organic solvent layer is dried using an MgSO4 desiccant. The desiccant is removed by filtration under reduced pressure, and the solvent is removed using a rotary evaporator. The residue was purified by column chromatography (eluent: ethyl acetate: hexane = 1: 5) to give (E) -1,3-bis (6-methoxy-2H- chromen- 1-one.

최종산물의 확인을 위해 핵자기공명분광 실험을 수행하였다. 사용한 기기는 브루커사 400MHz 기기였다. 또한 핵자기공명분광법으로 확인한 유도체의 구조를 재확인하기 위하여 고분해능질량분석법을 이용하였다. 사용한 기기는 제올사 (Jeol Ltd., Tokyo, Japan)의 JMS700 HREIMS (high-resolution electron impact ionization mass spectrometer) 였다.
Nuclear magnetic resonance spectroscopy experiments were performed to confirm the final product. The device used was a Bruscia 400MHz device. High resolution mass spectrometry was also used to confirm the structure of the derivatives identified by nuclear magnetic resonance spectroscopy. The instrument used was JMS700 HREIMS (high-resolution electron impact ionization mass spectrometer) from Jeol Ltd., Tokyo, Japan.

비스크로메닐칼콘 유도체 (E)-1,3-bis(6-methoxy-2H-chromen-3-yl)prop-2-en-1-one의 수소핵자기공명분광스펙트럼과 탄소핵자기공명스펙트럼은 각각 [도 1]과 [도 2]에 나타낸 바와 같고 화학적이동도는 아래와 같다.
Hydrogen Nuclear Magnetic Resonance Spectroscopy and Carbon Nuclear Magnetic Resonance Spectra of (E) -1,3-bis (6-methoxy-2H-chromen-3-yl) prop-2-en- The chemical mobility is as shown in Fig. 1 and Fig. 2, respectively.

1H NMR (400MHz, DMSO-d6) δ 7.96 (s, 1H, H-4), 7.33 (d, 1H, H-β, J = 15.5 Hz), 7.15 (d, 1H, H-α, J = 15.5 Hz), 7.07 (s, 1H, H-4’), 6.93 (d, 1H, H-5), 6.92 (m, 1H, H-7), 6.84 (m, 1H, H-8), 6.81 (m, 1H, H-7’), 6.81 (m, 1H, H-8’), 6.80 (s, 1H, H-5’), 5.06 (s, 2H, H-2’), 4.93(s, 2H, H-2), 3.74 (s, 3H, 6 - OCH3), 3.71 (s, 3H, 6’ - OCH3) 1 H NMR (400MHz, DMSO- d 6) δ 7.96 (s, 1H, H-4), 7.33 (d, 1H, H-β, J = 15.5 Hz), 7.15 (d, 1H, H-α, J 1H), 6.84 (m, 1H, H-4), 6.93 (d, H-5 '), 5.06 (s, 2H, H-2'), 4.93 (m, 3H, 6'-OCH3), 3.71 (s, 3H, 6'-OCH3)

13C NMR (100MHz, DMSO-d6) δ 186.2 (C=O), 154.0 (C-6), 153.9 (C-6’), 148.8 (C-9), 139.2 (C-β), 133.8 (C-4), 131.8 (C-3), 131.5 (C-4’), 130.4 (C-3’), 122.7 (C-10’), 121.6 (C-10), 120.2 (C-α), 118.5 (C-7), 116.6 (C-8), 116.5 (C-7’), 116.2 (C-8’), 113.2 (C-5), 112.2 (C-5’), 64.7 (C-2’), 63.8 (C-2), 55.4 (6 - OCH3), 55.4 (6’ - OCH3)
 13 C NMR (100 MHz, DMSO-d 6 )? 186.2 (C = O), 154.0 (C-6), 153.9 (C-6 '), 148.8 C-4), 131.8 (C-3), 131.5 (C-4 '), 130.4 (C-3'), 122.7 C-8), 116.2 (C-8), 116.2 (C-8), 116.2 '), 63.8 (C-2), 55.4 (6-OCH3), 55.4 (6'

크로메닐칼콘 유도체 (E)-1,3-bis(6-methoxy-2H-chromen-3-yl)prop-2-en-1-one는 현재까지 보고되지 않은 새로운 물질로서 C23H20O5의 분자식을 갖는다. 핵자기공명분광법으로 확인한 이 화합물의 구조를 확증하기 위하여 고분해능질량분석법을 이용하였고, 이론적인 분자량이 376.1311이었고 실험으로 얻은 분자량은 376.1309이었기 때문에 이 화합물은 (E)-1,3-비스(6-메톡시-2H-크로멘-3-일)프로프-2-엔-1-온 ((E)-1,3-bis(6-methoxy-2H-chromen-3-yl)prop-2-en-1-one)로 확인되었다. 비스크로메닐칼콘 유도체의 고분해능질량분석 스펙트럼은 [도 3]과 같다.
(E) -1,3-bis (6-methoxy-2H-chromen-3-yl) prop-2-en-1-one has a molecular formula of C23H20O5 as a new substance not reported to date. ( E ) -l, 3-bis (6- (3-methyl-l, 3-dihydroxy-phenyl) -methanesulfonamide was used because of its high molecular weight of 376.1311 and the molecular weight of 376.1309. methoxy -2 H - chromen-3-yl) prop-2-en-1-one ((E) -1,3-bis ( 6-methoxy-2 H -chromen-3-yl) prop-2 -en-1-one). A high-resolution mass spectrometry spectrum of the bisracymenylacetonate derivative is shown in Fig.

실시예Example 2.  2. 비스크로메닐칼콘Biscoromenylcalcone 유도체의 대장암 세포의 세포주기 진행 억제 및 세포사멸 유도 효과 Inhibits cell cycle progression and induces apoptosis of colorectal cancer cells

HCT116 대장암세포에 비스크로메닐칼콘 유도체 (BCC)를 처리하고 1일후 1% 트립신-EDTA 용액을 첨가해 배양 용기에 부착되어 있던 세포를 떼어내어 세포를 수확한 후, 70% 에탄올을 첨가해 세포를 고정시켰다. PI (Propidium Iodide)를 첨가해 세포의 DNA를 염색한 다음 유세포 분리측정기(Fluorescent Activating Cell Sorting; FACS, BD Science, 미국)를 이용하여 세포의 DNA 함량을 측정하였다. 통상적으로 DNA 함량이 이배체 (diplod; 2N)인 경우 G1 기, 사배체 (tetraploid; 4N)이면 G2/M, 2N과 4N 사이의 세포는 S기로 간주하며, G1 주기 세포의 2N DNA 함량보다 적은 양의 DNA를 함유하는 세포 (sub-G1)는 세포사멸 (apoptosis)이 진행되고 있음을 의미한다.HCT116 Colon cancer cells were treated with biscatorimethyla chalcone derivative (BCC), and after 1 day, 1% trypsin-EDTA solution was added to remove the cells attached to the culture vessel to harvest the cells, and then 70% Lt; / RTI > The DNA of the cells was stained with PI (Propidium Iodide) and the DNA content of the cells was measured using Fluorescent Activating Cell Sorting (FACS, BD Science, USA). Cells between G2 / M and 2N and 4N are regarded as S groups when the DNA content is diplodate (2N) and less than the 2N DNA content of G1 periodic cells when tetraploid (4N) The DNA-containing cell (sub-G1) means that apoptosis is underway.

[도 4]에 나타낸 바와 같이, 정상적으로 성장하고 있는 HCT116 대장암세포에 비스크로메닐칼콘 유도체 (BCC)를 24 시간 처리하면 sub-G1기 세포는 1.08%에서 6.2%로 증가한 반면, G1 주기세포는 57.74%에서 33.09%로, S 주기 세포는 12.84%에서 3.97%로 감소되었으나, G2/M 주기를 가지는 세포는 27.10%에서 55.59%로 증가하였다. 이상의 결과로부터, 본 발명의 비스크로메닐칼콘 유도체는 HCT116 대장암 세포의 G2/M 세포주기 진행을 억제시키고 세포사멸을 유도시킨다는 사실을 확인할 수 있었다.As shown in FIG. 4, when the normal growth of HCT116 colorectal cancer cells was treated with biscatoriminal chalcone derivative (BCC) for 24 hours, sub-G1 phase cells increased from 1.08% to 6.2%, while G1 phase cells increased to 57.74 % To 33.09%, S periodic cells decreased from 12.84% to 3.97%, while those with G2 / M cycles increased from 27.10% to 55.59%. From the above results, it was confirmed that the bisracimemal chalcone derivative of the present invention inhibits G2 / M cell cycle progression of HCT116 colorectal cancer cells and induces apoptosis.

실시예Example 3.  3. 디메톡시크로메닐칼콘Dimethoxycromonyl chalcone 유도체의 합성 Synthesis of derivatives

본 발명에서는 화학식 2로 표시되는 디메톡시크로메닐칼콘 유도체를 아래 반응식에 나타낸 방법을 사용하여 다음과 같이 합성하였다.In the present invention, the dimethoxycromonyl chalcone derivative represented by formula (2) was synthesized as follows using the method shown in the following reaction formula.

Figure pat00006

Figure pat00006

출발물질로 사용된 1-(6-methoxy-2H-chromen-3-yl)ethanone (I)은 2-hydroxy-5-methoxybenzaldehyde와 methylvinylketone을 K2CO3 염기 존재 하에서 문헌 방법 [ European Journal of Medicinal Chemistry, 2010, 1424-1429]에 따라 반응시켜 얻었다. 같은 방법으로 2-hydroxy-4-methoxybenzaldehyde를 K2CO3염기 존재하에서 acrolein과 반응시켜 또 다른 출발물질인 7-methoxy-2H-chromene-3-carbaldehyde (II) 를 얻었다. 7-methoxy-2H-chromene-3-carbaldehyde (II, 190 mg, 1 mmol)와 1-(6-methoxy-2H-chromen-3-yl)ethanone (I, 204 mg, 1 mmol)을 10 mL 에탄올에 녹인 후에 혼합물의 온도를 얼음 수조를 이용하여 5℃까지 낮춘다. 위의 냉각 용액에 50% KOH 용액 2 mL를 천천히 가하고 상온에서 약 30시간 교반한다. 반응 혼합물을 약 100 mL의 얼음물에 넣고, 6N HCl 가하여 pH를 약 3으로 조절한다. 위의 용액을 CH2Cl2 50 mL를 사용하여 두 번 추출하고, 추출된 유기용매층을 MgSO4 건조제를 사용하여 건조한다. 건조제를 감압여과하여 제거하고 여액을 회전증발기을 사용하여 용매를 제거한다. 잔사를 관 크로마토그라피를 (전개용매; 에틸아세테이트 : 헥산 = 1 : 5) 통해 정제하여 (E)-1-(6-methoxy-2H-chromen-3-yl)-3-(7-methoxy-2H-chromen-3-yl)prop-2-en-1-one을 얻었다.
1- (6-methoxy- 2H- chromen-3-yl) ethanone ( I ) used as a starting material was prepared by reacting 2-hydroxy-5-methoxybenzaldehyde with methylvinylketone in the presence of K2CO3 base [European Journal of Medicinal Chemistry, 2010 , 1424-1429]. In the same manner, 2-hydroxy-4-methoxybenzaldehyde was reacted with acrolein in the presence of K2CO3 base to obtain another starting material, 7-methoxy-2H-chromene-3-carbaldehyde ( II ). 7-methoxy-2H-chromene- 3-carbaldehyde (II, 190 mg, 1 mmol) and 1- (6-methoxy- 2H -chromen- 3-yl) ethanone (I, 204 mg, 1 mmol) to 10 mL of ethanol And the temperature of the mixture is lowered to 5 캜 by using an ice water bath. Add 2 mL of 50% KOH solution slowly to the above cooling solution, and stir at room temperature for about 30 hours. The reaction mixture is poured into about 100 mL of ice water and the pH is adjusted to about 3 by addition of 6N HCl. The above solution is extracted twice with 50 mL of CH2Cl2, and the extracted organic solvent layer is dried using an MgSO4 desiccant. The desiccant is removed by filtration under reduced pressure, and the solvent is removed using a rotary evaporator. The residue was purified by column chromatography (eluting solvent; ethyl acetate: hexane = 1: 5) to give (E) -1- (6-methoxy- 2H-chromen- -chromen-3-yl) prop-2-en-1-one.

최종산물의 확인을 위해 핵자기공명분광 실험을 수행하였다. 사용한 기기는 브루커사 400MHz 기기였다. 또한 핵자기공명분광법으로 확인한 유도체의 구조를 재확인하기 위하여 고분해능질량분석법을 이용하였다. 사용한 기기는 제올사 (Jeol Ltd., Tokyo, Japan)의 JMS700 HREIMS (high-resolution electron impact ionization mass spectrometer) 였다.
Nuclear magnetic resonance spectroscopy experiments were performed to confirm the final product. The device used was a Bruscia 400MHz device. High resolution mass spectrometry was also used to confirm the structure of the derivatives identified by nuclear magnetic resonance spectroscopy. The instrument used was JMS700 HREIMS (high-resolution electron impact ionization mass spectrometer) from Jeol Ltd., Tokyo, Japan.

디메톡시크로메닐칼콘 유도체 (E)-1-(6-methoxy-2H-chromen-3-yl)-3-(7-methoxy-2H-chromen-3-yl)prop-2-en-1-one의 수소핵자기공명분광스펙트럼과 탄소핵자기공명스펙트럼은 각각 [도 5]와 [도 6]에 나타낸 바와 같고 화학적이동도는 아래와 같다.
3-yl) prop-2-en-1-one (E) -1- (6-methoxy-2H-chromen- The hydrogen nuclear magnetic resonance spectroscopy and the carbon nuclear magnetic resonance spectrum are shown in FIG. 5 and FIG. 6, respectively, and the chemical mobility thereof is as follows.

1H NMR (400MHz, DMSO-d6) δ 7.93 (s, 1H, H-4), 7.33 (d, 1H, H-β, J = 15.4 Hz), 7.13 (d, 1H, H-5’, J = 8.4 Hz), 7.07 (s, 1H, H-4’), 7.05 (d, 1H, H-α, J = 15.4 Hz), 6.93 (s, 1H, H-5), 6.90 (m, 1H, H-7), 6.83 (m, 1H, H-8), 6.55 (d, 1H, H-6’, J = 8.4 Hz), 6.49 (s, 1H, H-8’), 5.11 (s, 2H, H-2’), 4.93(s, 2H, H-2), 3.77 (s, 3H, 7’ - OCH3), 3.75 (s, 3H, 6 - OCH3) 1 H NMR (400MHz, DMSO- d 6) δ 7.93 (s, 1H, H-4), 7.33 (d, 1H, H-β, J = 15.4 Hz), 7.13 (d, 1H, H-5 ', J = 8.4 Hz), 7.07 ( s, 1H, H-4 '), 7.05 (d, 1H, H-α, J = 15.4 Hz), 6.93 (s, 1H, H-5), 6.90 (m, 1H 1H, H-7), 6.83 (m, 1H, H-8), 6.55 (d, 1H, H-6 ', J = 8.4 Hz), 6.49 3H, 7'-OCH3), 3.75 (s, 3H, 6-OCH3)

13C NMR (100MHz, DMSO-d6) δ 186.1 (C=O), 161.8 (C-7’), 155.7 (C-9’), 153.9 (C-6), 148.8 (C-9), 139.7 (C-β), 133.4 (C-4), 131.9 (C-3), 131.7 (C-4’), 129.2 (C-5’), 126.5 (C-3’), 121.6 (C-10), 118.5 (C-α), 118.3 (C-7), 116.6 (C-8), 115.3 (C-10’), 113.1 (C-5), 108.1 (C-6’), 101.2 (C-8’), 64.9 (C-2’), 63.9 (C-2), 55.4 (6 - OCH3), 55.4 (7’ - OCH3)
 13 C NMR (100MHz, DMSO- d 6) δ 186.1 (C = O), 161.8 (C-7 '), 155.7 (C-9'), 153.9 (C-6), 148.8 (C-9), 139.7 (C-3), 131.7 (C-4 '), 129.2 (C-5'), 126.5 , 118.5 (C-α), 118.3 (C-7), 116.6 (C-8), 115.3 ), 64.9 (C-2 '), 63.9 (C-2), 55.4 (6-OCH3), 55.4

디메톡시크로메닐칼콘 유도체 (E)-1-(6-methoxy-2H-chromen-3-yl)-3-(7-methoxy-2H-chromen-3-yl)prop-2-en-1-one은 현재까지 보고되지 않은 새로운 물질로서 C23H20O5의 분자식을 갖는다. 핵자기공명분광법으로 확인한 이 화합물의 구조를 확증하기 위하여 고분해능질량분석법을 이용하였고, 이론적인 분자량이 376.1311이었고 실험으로 얻은 분자량은 376.1308이었기 때문에 이 화합물은 (E)-1-(6-메톡시-2H-크로멘-3-일)-3-(7-메톡시-2H-크로멘-3-일)프로프-2-엔-1-온 ((E)-1-(6-methoxy-2H-chromen-3-yl)-3-(7-methoxy-2H-chromen-3-yl)prop-2-en-1-one)로 확인되었다. 디메톡시크로메닐칼콘 유도체 (E)-1-(6-methoxy-2H-chromen-3-yl)-3-(7-methoxy-2H-chromen-3-yl)prop-2-en-1-one의 고분해능질량분석 스펙트럼은 [도 7]과 같다.
3-yl) prop-2-en-1-one (E) -1- (6-methoxy-2H-chromen- Has a molecular formula of C23H20O5 as a new substance not reported to date. ( E ) -1- (6-methoxy-pyridin-2-yl) -ethanone was used because it had a theoretical molecular weight of 376.1311 and an experimental molecular weight of 376.1308. 2 H - chromen-3-yl) -3- (7-methoxy -2 H - chromen-3-yl) prop-2-en-1-one ((E) -1- (6- methoxy was found to be -2 H -chromen-3-yl) -3- (7-methoxy-2 H -chromen-3-yl) prop-2-en-1-one). 3-yl) prop-2-en-1-one (E) -1- (6-methoxy-2H-chromen- The high-resolution mass spectrometry spectrum of which is shown in Fig.

실시예Example 4.  4. 디메톡시크로메닐칼콘Dimethoxycromonyl chalcone 유도체의 대장암 세포주의 세포주기 진행 억제 및 세포사멸 유도 효과 Inhibits cell cycle progression and induces apoptosis of colon cancer cell line

HCT116 대장암세포에 디메톡시크로메닐칼콘 유도체 (DMCC)를 처리하고 1일후 1% 트립신-EDTA 용액을 첨가해 배양 용기에 부착되어 있던 세포를 떼어내어 세포를 수확한 후, 70% 에탄올을 첨가해 세포를 고정시켰다. PI (Propidium Iodide)를 첨가해 세포의 DNA를 염색한 다음 유세포 분리측정기(Fluorescent Activating Cell Sorting; FACS, BD Science, 미국)를 이용하여 세포의 DNA 함량을 측정하였다. 통상적으로 DNA 함량이 이배체 (diplod; 2N)인 경우 G1 기, 사배체 (tetraploid; 4N)이면 G2/M, 2N과 4N 사이의 세포는 S기로 간주하며, G1 주기 세포의 2N DNA 함량보다 적은 양의 DNA를 함유하는 세포 (sub-G1)는 세포사멸 (apoptosis)이 진행되고 있음을 의미한다.HCT116 Colorectal cancer cells were treated with dimethoxycromonyl chalcone derivative (DMCC), and after 1 day, 1% trypsin-EDTA solution was added to remove the cells attached to the culture container to harvest the cells, and then 70% . The DNA of the cells was stained with PI (Propidium Iodide) and the DNA content of the cells was measured using Fluorescent Activating Cell Sorting (FACS, BD Science, USA). Cells between G2 / M and 2N and 4N are regarded as S groups when the DNA content is diplodate (2N) and less than the 2N DNA content of G1 periodic cells when tetraploid (4N) The DNA-containing cell (sub-G1) means that apoptosis is underway.

[도 8]에 나타낸 바와 같이, 정상적으로 성장하고 있는 HCT116 대장암세포에 디메톡시크로메닐칼콘 유도체를 24 시간 처리하면 sub-G1기 세포는 1.67%에서 5.63%로 증가한 반면, G1 주기세포는 54.87%에서 24.56%로, S 주기 세포는 10.22%에서 4.62%로 감소되었으나, G2/M 주기를 가지는 세포는 29.04%에서 62.69%로 증가하였다. 이상의 결과로부터, 본 발명의 디메톡시크로메닐칼콘 유도체는 HCT116 대장암 세포의 G2/M 세포주기 진행을 억제시키고 세포사멸을 유도시킨다는 사실을 확인할 수 있었다.As shown in FIG. 8, when the normal-growing HCT116 colorectal cancer cells were treated with dimethoxycromonyl chalcone derivative for 24 hours, sub-G1 period cells increased from 1.67% to 5.63%, while G1 period cells increased to 54.87% 24.56%, S periodic cells were decreased from 10.22% to 4.62%, while those with G2 / M cycles increased from 29.04% to 62.69%. From the above results, it was confirmed that the dimethoxycromonyl chalcone derivative of the present invention inhibits G2 / M cell cycle progression of HCT116 colon cancer cells and induces apoptosis.

이상, 본 발명의 내용의 특정한 부분을 상세히 기술하였는바, 당업계의 통상의 지식을 가진 자에게 있어서, 이러한 구체적인 기술은 단지 바람직한 구현 예일 뿐이며, 이에 의해 본 발명의 범위가 제한되는 것이 아닌 점은 명백할 것이다. 따라서, 본 발명의 실질적인 범위는 첨부된 청구항들과 그것들의 등가물에 의하여 정의된다고 할 것이다.
Having described specific portions of the present invention in detail, it will be apparent to those skilled in the art that this specific description is only a preferred embodiment and that the scope of the present invention is not limited thereby. It will be obvious. Accordingly, the actual scope of the present invention will be defined by the appended claims and their equivalents.

Claims (6)

하기의 화학식 1 및 2로 표시되는 화합물로 구성된 군으로부터 선택된 화합물.
Figure pat00007

[화학식 1]
Figure pat00008

[화학식 2] 1. A compound selected from the group consisting of compounds represented by the following formulas (1) and (2).
Figure pat00007

[Chemical Formula 1]
Figure pat00008

(2) 제 1항의 화합물을 유효성분으로 포함하는 조성물.A composition comprising the compound of claim 1 as an active ingredient. 제 1항의 화합물 및 그의 약학적으로 허용가능한 염을 유효성분으로 포함하는 항암용 약학 조성물.An anticancer pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable salt thereof as an active ingredient. 제 3항에 있어서, 상기 조성물은 대장암에 대하여 항암활성을 가지는 것을 특징으로 하는 약학 조성물. The pharmaceutical composition according to claim 3, wherein the composition has anticancer activity against colon cancer. 1-(6-메톡시-2H-크로멘-3-일)에타논 및 6-메톡시-2H-크로멘-3-카바알데히드를 녹인 후에 염기를 가하는 단계를 포함하는 하기 화학식 1의 화합물의 제조방법.
Figure pat00009

[화학식 1](1), comprising dissolving 1- (6-methoxy-2H-chromen-3-yl) ethanone and 6-methoxy-2H-chromen- Gt;
Figure pat00009

[Chemical Formula 1] 1-(6-메톡시-2H-크로멘-3-일)에타논 및 7-메톡시-2H-크로멘-3-카바알데히드를 녹인 후에 염기를 가하는 단계를 포함하는 하기 화학식 2의 화합물의 제조방법.

Figure pat00010

[화학식 2]
(2), which comprises dissolving 1- (6-methoxy-2H-chromen-3-yl) ethanone and 7-methoxy-2H-chromen- Gt;

Figure pat00010

(2)
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