KR20210107294A - A near-infrared turn-on fluorescent sensor for sensitive and specific detection of albumin - Google Patents
A near-infrared turn-on fluorescent sensor for sensitive and specific detection of albumin Download PDFInfo
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- KR20210107294A KR20210107294A KR1020200022077A KR20200022077A KR20210107294A KR 20210107294 A KR20210107294 A KR 20210107294A KR 1020200022077 A KR1020200022077 A KR 1020200022077A KR 20200022077 A KR20200022077 A KR 20200022077A KR 20210107294 A KR20210107294 A KR 20210107294A
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- South Korea
- Prior art keywords
- formula
- compound represented
- albumin
- fluorescence
- pharmaceutically acceptable
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- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- G01N21/17—Systems in which incident light is modified in accordance with the properties of the material investigated
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- G01N21/35—Investigating relative effect of material at wavelengths characteristic of specific elements or molecules, e.g. atomic absorption spectrometry using infrared light
- G01N21/359—Investigating relative effect of material at wavelengths characteristic of specific elements or molecules, e.g. atomic absorption spectrometry using infrared light using near infrared light
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- G01N2333/76—Assays involving albumins other than in routine use for blocking surfaces or for anchoring haptens during immunisation
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Abstract
Description
본 발명은 알부민 정량을 위한 근적외선 형광 센서 및 이의 제조방법에 관한 것이다.The present invention relates to a near-infrared fluorescence sensor for quantifying albumin and a method for preparing the same.
인간 혈청 알부민(Human serum albumin; HSA, 67kDa)은 간에서 생성되며 혈장에서 가장 풍부한 단백질이다. 간에서 HSA가 생성됨에 따라 저 알부민 혈증은 간경화, 간암, 간염, 알코올 관련 간질환 및 지방간 질환을 포함한 간부전과 관련이 있다. 급성 심부전, 신장 손상, 단백질 손실 신장 병증, 장병증 및 영양실조를 가진 일부 사람들도 알부민 수치가 낮다. 반면, 혈액 내 알부민 농도가 증가된 고 알부민 혈증은 탈수와 고단백질 식이로 인해 발생한다. Human serum albumin (HSA, 67 kDa) is produced in the liver and is the most abundant protein in plasma. As the liver produces HSA, hypoalbuminemia is associated with liver failure, including cirrhosis, liver cancer, hepatitis, alcohol-related liver disease and fatty liver disease. Some people with acute heart failure, kidney damage, protein-loss nephropathy, enteropathy, and malnutrition also have low albumin levels. On the other hand, hyperalbuminemia with increased blood albumin concentration is caused by dehydration and a high-protein diet.
HSA는 또한 음으로 하전된 구형 표면에 위치한 여러 리간드 결합 부위를 사용하여 다양한 내인성 화합물에 대한 “택시” 역할을 한다. HSA는 갑상선 호르몬, 지용선 호르몬, 비접합 빌리루빈, 유리 지방산 및 2가 양이온(Ca2+, Mg2+)과 결합하여 운반한다. 마찬가지로, 많은 약물이 HSA에 결합하며, 이것은 HSA에 결합할 때 약물의 약물동태(pharmacokinetic) 특성 및 약력학적(pharmacodynamic) 특성 모두에 영향을 미치기 때문에 큰 관심을 갖는다.HSA also acts as a “taxi” for a variety of endogenous compounds by using multiple ligand binding sites located on negatively charged spherical surfaces. HSA binds and transports thyroid hormones, lipolytic hormone, unconjugated bilirubin, free fatty acids and divalent cations (Ca 2+ , Mg 2+ ). Likewise, many drugs bind to HSA, which is of great interest because it affects both the pharmacokinetic and pharmacodynamic properties of a drug when it binds to HSA.
이와 같이, HSA의 농도는 질병의 발병률 및 사망률의 예후 마커 및 약물동태 특성의 예측인자로서 작용할 수 있으며, 생물학적 샘플에서 HSA의 정량화를 위한 민감하고 선택적인 검출방법의 개발은 임상적으로 중요하다. As such, the concentration of HSA can serve as a prognostic marker of disease morbidity and mortality and a predictor of pharmacokinetic properties, and the development of a sensitive and selective detection method for quantification of HSA in biological samples is of clinical importance.
현재의 기술적 수준에서 소변의 알부민 정량에 활용될 수 있는 가장 정확한 방법은 알부민 항체를 이용하는 면역분석(immunoassay)이나, 이 방법은 항체를 활용해야 하므로, 고가이며, 많은 시간이 소요되고, 여러 단계에 의해 진행되는 단점을 가지고 있다. 이에 비해, 알부민 형광센서를 이용하는 형광진단법은 매우 경제적이며, 짧은 시간 내에 손쉽게 알부민 정량이 가능한 장점을 가지고 있다. 여러 가지 알부민 형광센서가 개발되어 있으나, 생체시료로부터 알부민을 정확하게 검증하기 위해서는 알부민 선택적 형광 방출능, 생체 기저 형광의 간섭을 피할 수 있도록 비교적 긴 파장, 즉 근적외선 영역에서의 형광 방출능 및 알부민과 결합하는 생체인자 및 약물과의 경쟁을 통한 형광강도의 왜곡을 피할 수 있도록 독특한 알부민 결합자리를 갖는 형광센서의 개발 등이 요구되지만, 이러한 조건을 모두 갖춘 형광센서는 개발된 바 없다.At the current technical level, the most accurate method that can be used for quantification of albumin in urine is an immunoassay using an albumin antibody, but this method is expensive, time consuming, and requires many steps because it requires the use of an antibody. It has disadvantages that are driven by In contrast, the fluorescence diagnostic method using an albumin fluorescence sensor is very economical and has the advantage of being able to easily quantify albumin within a short time. Various albumin fluorescence sensors have been developed, but in order to accurately verify albumin from biological samples, albumin-selective fluorescence emission ability, fluorescence emission ability in a relatively long wavelength, that is, near-infrared region, and binding with albumin to avoid interference with bio-basal fluorescence Although the development of a fluorescent sensor having a unique albumin binding site is required to avoid distortion of fluorescence intensity through competition with bio factors and drugs, a fluorescent sensor that satisfies all these conditions has not been developed.
이에 본 발명자들은 알부민 선택적 형광 방출능, 근적외선 영역에서의 형광방출능 및 알부민 적이적 결합을 갖는 근적외선 형광센서를 개발하고 본 발명을 완성하였다.Accordingly, the present inventors developed a near-infrared fluorescence sensor having albumin-selective fluorescence emitting ability, fluorescence emitting ability in the near-infrared region, and albumin-specific binding and completed the present invention.
본 발명의 목적은 하기 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용가능한 염을 제공하는 것이다.An object of the present invention is to provide a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof.
[화학식 1][Formula 1]
(상기 화학식 1에서,(In
n은 1 내지 10의 정수이다).n is an integer from 1 to 10).
본 발명의 다른 목적은 상기 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용가능한 염의 제조방법을 제공하는 것이다.Another object of the present invention is to provide a method for preparing a compound represented by Formula 1 or a pharmaceutically acceptable salt thereof.
본 발명의 또 다른 목적은 상기 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용가능한 염을 포함하는 근적외선 형광센서를 제공하는 것이다.Another object of the present invention is to provide a near-infrared fluorescent sensor comprising the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof.
본 발명의 다른 목적은 상기 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용가능한 염을 포함하는 알부민 검출용 조성물을 제공하는 것이다.Another object of the present invention is to provide a composition for detecting albumin comprising the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof.
본 발명의 또 다른 목적은 상기 알부민 검출용 조성물을 이용하여 검출 샘플로부터 알부민을 검출하는 방법을 제공하는 것이다.Another object of the present invention is to provide a method for detecting albumin from a detection sample using the composition for detecting albumin.
상기 목적을 달성하기 위하여,In order to achieve the above object,
본 발명은 하기 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용가능한 염을 제공한다.The present invention provides a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof.
[화학식 1][Formula 1]
(상기 화학식 1에서,(In
n은 1 내지 10의 정수이다).n is an integer from 1 to 10).
또한, 본 발명은 하기 반응식 1에 나타낸 바와 같이,In addition, the present invention, as shown in
화학식 2로 표시되는 화합물을 용매에 용해하고, 다이메틸아민을 첨가하여 친핵성 방향족고리 치환 반응시켜 화학식 3으로 표시되는 화합물을 합성하는 단계(단계 1);synthesizing the compound represented by Formula 3 by dissolving the compound represented by
상기 단계 1의 화학식 3으로 표시되는 화합물 및 메톡사이드 나트륨을 유기용매에서 촉매하에 알돌축합반응시켜 화학식 4로 표시되는 화합물을 합성하는 단계(단계 2);synthesizing the compound represented by Formula 4 by subjecting the compound represented by
상기 단계 2의 화학식 4로 표시되는 화합물 및 3-클로로벤조일아세토나이트릴을 유기용매에서 축합반응시켜 화학식 1로 표시되는 화합물을 합성하는 단계(단계 3);를 포함하고,Condensing the compound represented by Formula 4 of
상기 단계 2를 반복 실시하는 횟수는 하기 반응식 1에서 n의 정수값과 동일한 것을 특징으로 하는,The number of times of repeating
제1항의 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용가능한 염의 제조방법을 제공한다.It provides a method for preparing a compound represented by Formula 1 of
[반응식 1][Scheme 1]
(상기 반응식 1에서,(In
n은 1 내지 10의 정수이다).n is an integer from 1 to 10).
나아가 본 발명은 상기 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용가능한 염을 포함하는 근적외선 형광센서를 제공한다.Furthermore, the present invention provides a near-infrared fluorescent sensor comprising the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof.
또한, 본 발명은 상기 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용가능한 염을 포함하는 알부민 검출용 조성물을 제공한다.In addition, the present invention provides a composition for detecting albumin comprising the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof.
더 나아가 본 발명은 상기 알부민 검출용 조성물을 이용하여 검출 샘플로부터 알부민을 검출하는 방법을 제공한다.Furthermore, the present invention provides a method for detecting albumin from a detection sample using the composition for detecting albumin.
본 발명에 따른 근적외선 형광 센서는 알부민에 대해 특이적이고 민감한 형광 방출능을 갖고, 근적외선 영역에서의 형광 방출능으로 인한 생체 기저 형광의 간섭을 회피할 수 있으며, 다른 기타 생체 물질 및 약물과 차별화되는 독특한 알부민 결합자리로 인한 형광강도의 왜곡을 회피할 수 있어, 짧은 시간 내에 경제적이고 또한, 손쉽게 검출 시료에서 알부민을 정량화할 수 있는 효과가 있다.The near-infrared fluorescence sensor according to the present invention has a specific and sensitive fluorescence emitting ability for albumin, can avoid interference of bio-basal fluorescence due to fluorescence emitting ability in the near-infrared region, and is uniquely differentiated from other biomaterials and drugs. It is possible to avoid distortion of the fluorescence intensity due to the albumin binding site, so it is economical and has the effect of quantifying albumin in a detection sample easily within a short time.
도 1(A)는 PBS 완충액에서 HSA(10μM)의 부재 및 존재하에 실시예 1의 DMAT-π-CAP의 형광을 측정한 결과이다(삽입된 그림 점선 부분; HSA 부재하에 형광).
도 1(B)는 DMAT-π-CAP의 HSA 선택성을 확인한 결과이다.
도 1(C)는 HSA 존재 하에 DMAT-π-CAP의 시간에 따른 형광 특성을 확인한 결과이다.
도 2(A)는 HSA에 농도에 따른 DMAT-π-CAP의 형광 특성을 확인한 결과이다.
도 2(B)는 DMAT-π-CAP의 HSA 의존적 형광 강도 변화를 확인한 결과이다.
도 3(A)는 DMAT-π-CAP 및 HSA간의 결합방식을 확인하기 위한 Job's 플롯 분석을 나타낸 것이다.
도 3(B)는 부위-특이적 마커(와파린, 이부프로펜 및 헤민)의 첨가시 DMAT-π-CAP 및 HSA의 혼합물로부터의 형광 강도 (λem = 730 nm)의 변화를 확인한 결과이다.
도 3(C)는 하트 모양의 HSA와 헤민의 공결정구조를 나타낸 것이다.
도 4(A) 내지 도 4(C)는 다양한 농도의 HSA로 스파이킹한 세가지 소변 샘플에서 DMAT-π-CAP의 형광 특성을 확인한 결과이다.
도 4(D)는 DMAT-π-CAP(Fluorometric)에 의해 측정된 소변 샘플에서 알부민 수준을 면역분석(Immunoassay)에 의해 수득된 것과 비교한 결과이다.1(A) is a result of measuring the fluorescence of DMAT-π-CAP of Example 1 in the absence and presence of HSA (10 μM) in PBS buffer (inset dotted line portion; fluorescence in the absence of HSA).
1(B) is a result confirming the HSA selectivity of DMAT-π-CAP.
1(C) is a result of confirming the fluorescence characteristics of DMAT-π-CAP over time in the presence of HSA.
2(A) is a result of confirming the fluorescence characteristics of DMAT-π-CAP according to the concentration of HSA.
2(B) is a result confirming the HSA-dependent fluorescence intensity change of DMAT-π-CAP.
Figure 3 (A) shows the analysis of Job's plot to confirm the binding method between DMAT-π-CAP and HSA.
3(B) is a result confirming the change in fluorescence intensity (λem = 730 nm) from a mixture of DMAT-π-CAP and HSA upon addition of site-specific markers (warfarin, ibuprofen and hemin).
3(C) shows the co-crystal structure of HSA and hemin in the shape of a heart.
4(A) to 4(C) are results of confirming the fluorescence properties of DMAT-π-CAP in three urine samples spiked with various concentrations of HSA.
4(D) is a result of comparing albumin levels in urine samples measured by DMAT-π-CAP (Fluorometric) with those obtained by immunoassay.
이하, 본 발명을 상세히 설명한다.Hereinafter, the present invention will be described in detail.
화합물 또는 이의 약학적으로 허용가능한 염compound or a pharmaceutically acceptable salt thereof
본 발명은 하기 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용가능한 염을 제공한다.The present invention provides a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof.
[화학식 1][Formula 1]
(상기 화학식 1에서,(In
n은 1 내지 10의 정수이다).n is an integer from 1 to 10).
본 발명의 일실시예에 있어서, 상기 n은 1 내지 5의 정수일 수 있고, 바람직하게 n은 1 내지 3의 정수일 수 있고, 보다 바람직하게 n은 2의 정수일 수 있다.In one embodiment of the present invention, n may be an integer of 1 to 5, preferably n may be an integer of 1 to 3, and more preferably n may be an integer of 2.
본 발명의 일실시예에 있어서, 상기 화학식 1로 표시되는 화합물은 (2E,4E,6E)-2-(3-클로로벤조일)-7-(5-(다이메틸아미노)티오펜-2-일)헵타-2,4,6-트라이엔나이트릴 일 수 있다.In one embodiment of the present invention, the compound represented by
본 발명의 상기 화학식 1로 표시되는 화합물은 약학적으로 허용 가능한 염의 형태로 사용할 수 있으며, 염으로는 약학적으로 허용가능한 유리산(free acid)에 의해 형성된 산부가염이 유용하다. 약학적으로 허용가능한 염이란 표현은 환자에게 비교적 비독성이고 무해한 유효작용을 갖는 농도로서 이 염에 기인한 부작용이 화학식 1의 염기 화합물의 이로운 효능을 떨어뜨리지 않는 화학식 1의 염기 화합물의 어떠한 유기 또는 무기 부가염을 의미한다. 이들 염은 유리산으로는 무기산과 유기산을 사용할 수 있으며, 무기산으로는 염산, 브롬산, 질산, 황산, 과염소산, 인산 등을 사용할 수 있고, 유기산으로는 구연산, 초산, 젖산, 말레산, 푸마린산, 글루콘산, 메탄설폰산, 글리콘산, 숙신산, 타타르산, 갈룩투론산, 엠본산, 글루탐산, 아스파르트산, 옥살산, (D) 또는 (L) 말산, 말레산, 메테인설폰산, 에테인설폰산, 4-톨루엔술폰산, 살리실산, 시트르산, 벤조산 또는 말론산 등을 사용할 수 있다. 또한, 이들 염은 알칼리 금속염(나트륨염, 칼륨염 등) 및 알칼리 토금속염(칼슘염, 마그네슘염 등) 등을 포함한다. 예를 들면, 산부가염으로는 아세테이트, 아스파테이트, 벤즈에이트, 베실레이트, 바이카보네이트/카보네이트, 바이설페이트/설페이트, 보레이트, 캄실레이트, 시트레이트, 에디실레이트, 에실레이트, 포메이트, 퓨마레이트, 글루셉테이트, 글루코네이트, 글루큐로네이트, 헥사플루오로포스페이트, 하이벤제이트, 하이드로클로라이드/클로라이드, 하이드로브로마이드/브로마이드, 하이드로요오디드/요오디드, 이세티오네이트, 락테이트, 말레이트, 말리에이트, 말로네이트, 메실레이트, 메틸설페이트, 나프틸레이트, 2-나프실레이트, 니코티네이트, 나이트레이트, 오로테이트, 옥살레이트, 팔미테이트, 파모에이트, 포스페이트/수소 포스페이트/이수소 포스페이트, 사카레이트, 스테아레이트, 석시네이트, 타르트레이트, 토실레이트, 트리플루오로아세테이트, 알루미늄, 알기닌, 벤자틴, 칼슘, 콜린, 디에틸아민, 디올아민, 글라이신, 라이신, 마그네슘, 메글루민, 올아민, 칼륨, 나트륨, 트로메타민, 아연염 등이 포함될 수 있으며, 이들 중 하이드로클로라이드 또는 트리플루오로아세테이트가 바람직하다.The compound represented by Formula 1 of the present invention may be used in the form of a pharmaceutically acceptable salt, and as the salt, an acid addition salt formed by a pharmaceutically acceptable free acid is useful. The expression pharmaceutically acceptable salt refers to any organic or organic compound of the basic compound of formula (1), in which the concentration has an effective action that is relatively non-toxic and harmless to the patient, and the side effects due to the salt do not reduce the beneficial efficacy of the basic compound of formula (1). means inorganic addition salts. For these salts, inorganic acids and organic acids can be used as free acids, and hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, perchloric acid, phosphoric acid, etc. can be used as inorganic acids, and citric acid, acetic acid, lactic acid, maleic acid, fumarin, etc. can be used as organic acids. Acid, gluconic acid, methanesulfonic acid, glycolic acid, succinic acid, tartaric acid, galacturonic acid, embonic acid, glutamic acid, aspartic acid, oxalic acid, (D) or (L) malic acid, maleic acid, methanesulfonic acid, ethanesulfonic acid Phonic acid, 4-toluenesulfonic acid, salicylic acid, citric acid, benzoic acid or malonic acid may be used. Further, these salts include alkali metal salts (sodium salt, potassium salt, etc.) and alkaline earth metal salt (calcium salt, magnesium salt, etc.) and the like. For example, acid addition salts include acetate, aspartate, benzate, besylate, bicarbonate/carbonate, bisulfate/sulfate, borate, camsylate, citrate, edisylate, esylate, formate, fumarate, Gluceptate, gluconate, glucuronate, hexafluorophosphate, hebenzate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, malate ate, malonate, mesylate, methylsulfate, naphthylate, 2-naphsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, saccharate Late, stearate, succinate, tartrate, tosylate, trifluoroacetate, aluminium, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, Potassium, sodium, tromethamine, zinc salt and the like may be included, of which hydrochloride or trifluoroacetate is preferable.
본 발명에 따른 산 부가염은 통상의 방법, 예를 들면, 화학식 1로 표시되는 화합물을 유기용매, 예를 들면 메탄올, 에탄올, 아세톤, 메틸렌클로라이드, 아세토니트릴 등에 녹이고 유기산 또는 무기산을 가하여 생성된 침전물을 여과, 건조하여 제조되거나, 용매와 과량의 산을 감압 증류한 후 건조하거나 유기용매 하에서 결정화시켜셔 제조할 수 있다.The acid addition salt according to the present invention can be prepared by a conventional method, for example, by dissolving the compound represented by
또한, 염기를 사용하여 약학적으로 허용 가능한 금속염을 만들 수 있다. 알칼리 금속 또는 알칼리 토금속 염은 예를 들면 화합물을 과량의 알칼리 금속 수산화물 또는 알칼리 토금속 수산화물 용액 중에 용해하고, 비용해 화합물 염을 여과하고, 여액을 증발, 건조시켜 얻는다. 이때, 금속염으로는 나트륨, 칼륨 또는 칼슘염을 제조하는 것이 제약상 적합하다. 또한, 이에 대응하는 은 염은 알칼리 금속 또는 알칼리 토금속 염을 적당한 은 염(예, 질산은)과 반응시켜 얻는다.In addition, a pharmaceutically acceptable metal salt may be prepared using a base. The alkali metal or alkaline earth metal salt is obtained, for example, by dissolving the compound in an excess alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the undissolved compound salt, and evaporating and drying the filtrate. In this case, it is pharmaceutically suitable to prepare a sodium, potassium or calcium salt as the metal salt. The corresponding silver salt is also obtained by reacting an alkali metal or alkaline earth metal salt with a suitable silver salt (eg silver nitrate).
나아가, 본 발명은 상기 화학식 1의 화합물 및 이의 약학적으로 허용되는 염뿐만 아니라, 이로부터 제조될 수 있는 가능한 용매화물, 수화물, 이성질체, 광학 이성질체 등을 모두 포함한다.Furthermore, the present invention includes all possible solvates, hydrates, isomers, optical isomers, etc. that can be prepared therefrom, as well as the compound of
화합물 또는 이의 약학적으로 허용가능한 염의 제조방법Method for preparing a compound or a pharmaceutically acceptable salt thereof
본 발명은 하기 반응식 1에 나타낸 바와 같이,The present invention, as shown in
화학식 2로 표시되는 화합물을 용매에 용해하고, 다이메틸아민을 첨가하여 친핵성 방향족고리 치환 반응시켜 화학식 3으로 표시되는 화합물을 합성하는 단계(단계 1);synthesizing the compound represented by
상기 단계 1의 화학식 3으로 표시되는 화합물 및 메톡사이드 나트륨을 유기용매에서 촉매하에 알돌축합반응시켜 화학식 4로 표시되는 화합물을 합성하는 단계(단계 2);synthesizing the compound represented by Formula 4 by subjecting the compound represented by
상기 단계 2의 화학식 4로 표시되는 화합물 및 3-클로로벤조일아세토나이트릴을 유기용매에서 축합반응시켜 화학식 1로 표시되는 화합물을 합성하는 단계(단계 3);를 포함하고,Condensing the compound represented by Formula 4 of
상기 단계 2를 반복 실시하는 횟수는 하기 반응식 1에서 n의 정수값과 동일한 것을 특징으로 하는,The number of times of repeating
제1항의 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용가능한 염의 제조방법을 제공한다.It provides a method for preparing a compound represented by
[반응식 1][Scheme 1]
(상기 반응식 1에서,(In
n은 1 내지 10의 정수이다).n is an integer from 1 to 10).
본 발명의 제조방법에 있어서, 상기 단계 1의 용매는 물 또는 유기용매를 사용할 수 있고, 유기용매의 예로는 메탄올, 에탄올, 테트라하이드로퓨란(THF), 다이옥산, 다이클로로메탄(DCM), 1,2-다이메톡시에탄, 벤젠, 톨루엔, 자일렌, 다이메틸포름아미드(DMF), 다이메틸설폭사이드(DMSO) 또는 아세토나이트릴을 사용할 수 있다. In the preparation method of the present invention, water or an organic solvent may be used as the solvent in
본 발명의 제조방법에 있어서, 상기 단계 2 또는 단계 3의 유기용매의 예로는 메탄올, 에탄올, 테트라하이드로퓨란(THF), 다이옥산, 다이클로로메탄(DCM), 1,2-다이메톡시에탄, 벤젠, 톨루엔, 자일렌, 다이메틸포름아미드(DMF), 다이메틸설폭사이드(DMSO) 또는 아세토나이트릴을 사용할 수 있다.In the production method of the present invention, examples of the organic solvent of
본 발명의 제조방법에 있어서, 상기 단계 2를 2번 반복하여, 하기 실시예 1-3의 화합물 5인 (2E,4E)-5-(5-(다이메틸아미노)티오펜-2-일)펜타-2,4-다이에날을 제조하였다.In the preparation method of the present invention, by repeating
근적외선 형광센서Near-infrared fluorescence sensor
본 발명은 하기 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용가능한 염을 포함하는 근적외선 형광센서를 제공한다.The present invention provides a near-infrared fluorescent sensor comprising a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof.
[화학식 1][Formula 1]
(상기 화학식 1에서,(In
n은 1 내지 10의 정수이다).n is an integer from 1 to 10).
본 발명의 일실시예에 있어서, 본 발명의 근적외선 형광센서는 근적외선 영역에서 형광을 방출하고, 표적물질과 결합시, 자가 형광보다 약 730배 우수한 형광 강도를 나타낸다(도 1A 참조).In one embodiment of the present invention, the near-infrared fluorescent sensor of the present invention emits fluorescence in the near-infrared region, and exhibits a fluorescence intensity that is about 730 times superior to that of autofluorescence when combined with a target material (see FIG. 1A ).
알부민 검출용 조성물Composition for detecting albumin
본 발명은 하기 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용가능한 염을 포함하는 알부민 검출용 조성물을 제공한다.The present invention provides a composition for detecting albumin comprising a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof.
[화학식 1][Formula 1]
(상기 화학식 1에서,(In
n은 1 내지 10의 정수이다).n is an integer from 1 to 10).
본 발명의 일실시예에 있어서, 상기 알부민 검출용 조성물의 검출 샘플은 소변, 혈액, 눈물, 땀 또는 타액일 수 있고, 바람직하게 소변일 수 있다.In one embodiment of the present invention, the detection sample of the composition for detecting albumin may be urine, blood, tears, sweat or saliva, preferably urine.
본 발명의 일실시예에 있어서, 상기 알부민 검출용 조성물은 알부민에 대한 강한 선택성을 가지며(도 1B 참조), 또한, 알부민과 결합시 농도 의존적으로 형광의 세기가 강해지는 효과가 있다(도 2A 참조). In one embodiment of the present invention, the composition for detecting albumin has a strong selectivity for albumin (see FIG. 1B), and also has an effect of increasing the intensity of fluorescence in a concentration-dependent manner when combined with albumin (see FIG. 2A). ).
또한, 본 발명의 일실시예에 있어서, 상기 알부민 검출용 조성물은 매우 독특한 HSA(인간 혈청 알부민; Human serum albumin) 결합자리를 가지며(도 3C 참조), 이로인해 다른 생체인자로부터의 간섭을 회피할 수 있는 장점이 있다.In addition, in one embodiment of the present invention, the composition for detecting albumin has a very unique HSA (Human serum albumin) binding site (see FIG. 3C ), thereby avoiding interference from other biological factors. There are advantages that can be
알부민을 검출하는 방법How to detect albumin
본 발명은 상기 알부민 검출용 조성물을 이용하여 검출 샘플로부터 알부민을 검출하는 방법을 제공한다.The present invention provides a method for detecting albumin from a detection sample using the composition for detecting albumin.
본 발명의 일실시예에 있어서, 상기 검출 샘플은 소변, 혈액, 눈물, 땀 또는 타액일 수 있고, 바람직하게 소변일 수 있다.In one embodiment of the present invention, the detection sample may be urine, blood, tears, sweat or saliva, preferably urine.
본 발명의 일실시예에 있어서, 상기 검출은 정량 또는 정성 검출일 수 있다.In one embodiment of the present invention, the detection may be quantitative or qualitative detection.
이하, 본 발명을 하기의 실시예에 의하여 더욱 상세하게 설명한다. 단, 하기의 실시예는 본 발명을 예시하는 것일 뿐, 본 발명의 내용이 하기의 실시예에 의해 한정되는 것은 아니다.Hereinafter, the present invention will be described in more detail with reference to the following examples. However, the following examples are merely illustrative of the present invention, and the content of the present invention is not limited by the following examples.
<준비예><Preparation example>
화학시약은 Sigma-Aldrich, TCI 또는 Alfa에서 구입하였다.Chemical reagents were purchased from Sigma-Aldrich, TCI or Alfa.
핵자기 공명 스펙트럼을 내부 표준으로서 테트라메틸실란을 사용하여 1H NMR에 대해 400 MHZ 및 13C NMR에 대해 100 MHZ에서 Bruker 400 AMX 분광계 (Karlsruhe, Germany)에 기록되었다. FAB 질량 분석 데이터 (FAB-MS)는 한국기초과학연구소(대한민국)에서 입수하여 m/z (intensity relative to base peak = 100)의 형태로 보고되었다. 최종 방법의 순도는 다음 방법을 사용하여 HPLC로 측정하였다 : Varian Polaris RP C18-A (250 mm × 4.6 mm, 5 μm particle size) 칼럼; 60분 동안 물에서 아세토니트릴 경사용리법(gradient elution) (0-8분간 5%, 5-15분간 5~10%, 15-30분동안 25%, 30-45분동안 25~60%, 45-55분동안 60~100% 및 55-60분동안 100%); 1 ㎖/min의 유속; 서로다른 두 파장(340nm 및 254nm)에서 검출.Nuclear magnetic resonance spectra were recorded on a
모든샘플에 대해, 0.1% 포름산을 물에 첨가하였다. 생물학적으로 시험된 모든 최종화합물을 HPLC로 판단하여 97%이상의 순도로 분리하였다. Cytation™5 (BioTek, USA)를 사용하여 흡광도 및 형광을 기록하였다. For all samples, 0.1% formic acid was added to the water. All of the biologically tested final compounds were isolated with a purity of 97% or more by HPLC. Absorbance and fluorescence were recorded using Cytation™5 (BioTek, USA).
<실시예 1> 소변 알부민 정량을 위한 근적외선 형광 센서(DMAT-π-CAP)의 합성<Example 1> Synthesis of near-infrared fluorescence sensor (DMAT-π-CAP) for quantification of urine albumin
<1-1> 5-(다이메틸아미노)티오펜-2-카르발데히드(5-(dimethylamino)thiophene-2-carbaldehyde)의 제조<1-1> Preparation of 5-(dimethylamino)thiophene-2-carbaldehyde (5-(dimethylamino)thiophene-2-carbaldehyde)
시판되는 5-브로모티오펜-2-카복스알데하이드(5-bromothiophene-2-carboxaldehyde, 2.62 mmol)을 H2O에 용해시켰다. 이 용액을 다이메틸아민(dimethylamine, 7.85 mmol)에 첨가하였다. 100℃에서 12시간동안 교반한 후, 반응 혼합물을 실온으로 냉각시켰다. 이어서, 혼합물을 물로 희석하고 EtOAc (3 x 50 ㎖)로 추출하였다. 합한 유기층을 염수로 세척하고 MgSO4상에서 건조하였다. 휘발물을 감압하에 제거한 후, 잔류물을 실리카겔상에서 컬럼크로마토그래피(용리액, 헥산:아세톤=4:1)에 의해 정제하여 92%의 수율로 목적생성물(화합물 3)을 황색 고체로서 수득하였다 :1H NMR (500 MHz, acetone-d6) δ9.49 (s, 1H), 7.60 (d, J = 4.5 Hz, 1H), 6.07 (d, J = 4.4 Hz, 1H), 3.11 (s, 6H).Commercially available 5-bromothiophene-2-carboxaldehyde (5-bromothiophene-2-carboxaldehyde, 2.62 mmol) was dissolved in H 2 O. This solution was added to dimethylamine (7.85 mmol). After stirring at 100° C. for 12 h, the reaction mixture was cooled to room temperature. The mixture was then diluted with water and extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine and dried over MgSO 4 . After the volatiles were removed under reduced pressure, the residue was purified by column chromatography on silica gel (eluent, hexane:acetone=4:1) to give the desired product (compound 3) as a yellow solid in a yield of 92%: 1 H NMR (500 MHz, acetone-d6) δ9.49 (s, 1H), 7.60 (d, J = 4.5 Hz, 1H), 6.07 (d, J = 4.4 Hz, 1H), 3.11 (s, 6H).
<1-2> (E)-3-(5-(다이메틸아미노)티오펜-2-일)아크릴알데하이드((E)-3-(5-(dimethylamino)thiophen-2-yl)acrylaldehyde)의 제조<1-2> (E)-3-(5-(dimethylamino)thiophen-2-yl)acrylaldehyde ((E)-3-(5-(dimethylamino)thiophen-2-yl)acrylaldehyde) Produce
메탄올 용매에 메톡사이드 나트륨(Sodium methoxide, 6.01 mmol)이 용해되어 있는 제1용액을, 질소분위기하에서 dry THF 용매에 상기 실시예 1-1의 화합물 3 (2.40 mmol) 및 (1,3-다이옥솔란-2-일메틸)트라이페닐포스포늄 브로마이드((1,3-dioxolan-2-ylmethyl)triphenylphosphonium bromide, 3.36 mmol)이 용해되어 있는 제2용액에 적가하였다. 반응 혼합물을 환류하에 18시간동안 교반한 다음 0℃로 냉각시켰다. 2 N HCl (30 ㎖)로 처리한 후, 반응 혼합물을 실온에서 20분동안 교반하였다. 그 후, 반응 혼합물을 2N NaOH로 중화시킨 뒤, 물로 희석하고, EtOAc (3 X 50 ㎖)로 추출하였다. 합한 유기층을 염수로 세척하고 MgSO4상에서 건조하였다. 휘발물을 감압하에 제거한 후, 잔류물을 실리가켈상에서 컬럼 크로마토그래피(용리액, 헥산:에틸아세테이트:아세톤=6:1:1에 의해 정제하여 원하는 생성물(화합물 4)을 34% 수율로 황색 고체로서 수득하였다: δ9.45 (d, J = 7.8 Hz, 1H), 7.59 (d, J = 15.1 Hz, 1H), 7.26 (d, J = 4.3 Hz, 1H), 6.00 (d, J = 4.3 Hz, 1H), 5.96 (dd, J = 7.9 Hz, 7.2 Hz, 1H), 3.09 (s, 6H).A first solution in which sodium methoxide (6.01 mmol) is dissolved in a methanol solvent, and the
<1-3> (2E,4E)-5-(5-(다이메틸아미노)티오펜-2-일)펜타-2,4-다이에날 ((2E,4E)-5-(5-(dimethylamino)thiophen-2-yl)penta-2,4-dienal)의 제조<1-3> (2E,4E)-5-(5-(dimethylamino)thiophen-2-yl)penta-2,4-dienal ((2E,4E)-5-(5-( Preparation of dimethylamino)thiophen-2-yl)penta-2,4-dienal)
메탄올 용매에 메톡사이드 나트륨 (Sodium methoxide, 2.03 mmol)이 용해되어 있는 제1용액을 질소분위기하에서 dry THF 용매에 상기 실시예 1-2의 화합물 4 (0.81 mmol) 및 (1,3-다이옥솔란-2-일메틸)트라이페닐포스포늄 브로마이드((1,3-dioxolan-2-ylmethyl)triphenylphosphonium bromide, 1.14 mmol)이 용해되어 있는 제2 용액에 적가하였다. 반응 혼합물을 환류하에 18시간 동안 교반한 다음, 0℃로 냉각시켰다. 2 N HCl (30 ㎖)로 처리한 후, 반응 혼합물을 실온에서 20분동안 교반하였다. 그 후, 반응 혼합물을 2N NaOH로 중화시킨 뒤, 물로 희석하고, EtOAc (3 X 50 ㎖)로 추출하였다. 합한 유기층을 염수로 세척하고 MgSO4상에서 건조하였다. 휘발물을 감압하에 제거한 후, 잔류물을 실리가켈상에서 컬럼 크로마토그래피(용리액, 헥산:에틸아세테이트:아세톤=6:1:1에 의해 정제하여 원하는 생성물(화합물 5)을 42% 수율로 적색 고체로서 수득하였다: 1H NMR (500 MHz, acetone-d6) : δ9.50 (d, J = 10.1 Hz, 1H), 7.32 (dd, J = 14.0 Hz, 4.7 Hz, 1H), 7.16 (d, J = 18.2 Hz, 1H), 7.03 (d, J = 5.1 Hz, 1H), 6.43 (dd, J = 14.0 Hz, 4.6 Hz, 1H), 6.06 (dd, J = 10.1 Hz, 8.6 Hz, 1H), 5.9 (d, J = 5.2 Hz, 1H), 3.03 (s, 6H).A first solution in which sodium methoxide (2.03 mmol) is dissolved in a methanol solvent was added to a dry THF solvent under a nitrogen atmosphere, with the compound 4 of Example 1-2 (0.81 mmol) and (1,3-dioxolane-) 2-ylmethyl)triphenylphosphonium bromide ((1,3-dioxolan-2-ylmethyl)triphenylphosphonium bromide, 1.14 mmol) was added dropwise to the dissolved second solution. The reaction mixture was stirred at reflux for 18 h and then cooled to 0 °C. After treatment with 2 N HCl (30 mL), the reaction mixture was stirred at room temperature for 20 min. The reaction mixture was then neutralized with 2N NaOH, diluted with water and extracted with EtOAc (3 X 50 mL). The combined organic layers were washed with brine and dried over MgSO 4 . After the volatiles were removed under reduced pressure, the residue was purified by column chromatography on silica gel (eluent, hexane:ethyl acetate:acetone=6:1:1) to give the desired product (compound 5) as a red solid in 42% yield. was obtained as: 1 H NMR (500 MHz, acetone-d6): δ9.50 (d, J = 10.1 Hz, 1H), 7.32 (dd, J = 14.0 Hz, 4.7 Hz, 1H), 7.16 (d, J) = 18.2 Hz, 1H), 7.03 (d, J = 5.1 Hz, 1H), 6.43 (dd, J = 14.0 Hz, 4.6 Hz, 1H), 6.06 (dd, J = 10.1 Hz, 8.6 Hz, 1H), 5.9 (d, J = 5.2 Hz, 1H), 3.03 (s, 6H).
<1-4> (2E,4E,6E)-2-(3-클로로벤조일)-7-(5-(다이메틸아미노)티오펜-2-일)헵타-2,4,6-트라이엔나이트릴 ((2E,4E,6E)-2-(3-chlorobenzoyl)-7-(5-(dimethylamino)thiophen-2-yl)hepta-2,4,6-trienenitrile)의 제조<1-4> (2E,4E,6E)-2-(3-chlorobenzoyl)-7-(5-(dimethylamino)thiophen-2-yl)hepta-2,4,6-trienite Preparation of Lil ((2E,4E,6E)-2-(3-chlorobenzoyl)-7-(5-(dimethylamino)thiophen-2-yl)hepta-2,4,6-trienenitrile)
Dry THF(5ml)에 용해된 상기 실시예 1-3의 화합물 5 (83 mg, 0.32 mmol)의 용액에 이미다졸(imidazole) (33 mg, 0.49 mmol) 및 3-클로로벤조일아세토나이트릴(3-chlorobenzoylacetonitrile) (87 mg, 0.49 mmol)을 첨가하고, 생성된 혼합물을 60℃에서 18시간동안 질소하에서 교반하였다 그 후, 실온으로 냉각한 후, 반응혼합물을 감압하에 농축하고, 잔류물을 실리카겔 상에서 컬럼크로마토그래피(용리액, 헥산:디클로로메탄:에틸아세테이트=6:1:1)로 정제하여 원하는 화학식 1로 표시되는 화합물 1(64.9mg, 0.18mmol)을 55%의 수율로 청색 고체로서 수득하였다: 1H NMR (500 MHz, CDCl3) : δ7.87 (d, J = 12.3 Hz, 1H), 7.78 (s, 1H), 7.73 (d, J = 6.4 Hz, 1H), 7.52 (d, J = 6.2 Hz, 1H), 7.42 (t, J = 6.8 Hz, 1H), 7.27 (s, 1H), 7.11 (t, J = 12.5 Hz, 1H), 7.05 (d, J = 12.6 Hz, 1H), 7.03 (s, 1H), 6.77 (t, J = 12.7 Hz, 1H), 6.41 (t, J = 12.8 Hz, 1H), 3.10 (s, 6H); 13C NMR (125 MHz, CDCl3): δ187.4, 164.2, 157.0, 153.3, 139.3, 138.9, 136.0, 134.6, 132.2, 129.7, 128.7, 126.8, 125.8, 123.0, 120.5, 117.6, 104.1, 103.8, 42.3; FAB-MS calcd for C20H18ClN2OS [M+H]+ 369.0823, found 369.0828.In a solution of the compound 5 (83 mg, 0.32 mmol) of Example 1-3 dissolved in dry THF (5 ml), imidazole (33 mg, 0.49 mmol) and 3-chlorobenzoylacetonitrile (3- chlorobenzoylacetonitrile) (87 mg, 0.49 mmol) was added, and the resulting mixture was stirred at 60° C. under nitrogen for 18 h. Then, after cooling to room temperature, the reaction mixture was concentrated under reduced pressure, and the residue was columnar on silica gel. Purification by chromatography (eluent, hexane:dichloromethane:ethyl acetate=6:1:1) gave the desired compound 1 (64.9 mg, 0.18 mmol) represented by
<실험예 1> PBS 완충액(pH 7.4)에서 DMAT-π-CAP의 형광 특성 확인<Experimental Example 1> Confirmation of fluorescence properties of DMAT-π-CAP in PBS buffer (pH 7.4)
DMAT-π-CAP의 형광특성을 PBS 완충액에서 확인하기 위해, 구체적으로 DMAT-π-CAP(DMSO에 용해시켜 500μM로 제조) 및 HSA(pH7.4 PBS에 용해시켜 1mM로 제조)의 스톡 솔루션을 제조하였다. 실온에서, 1μL의 HSA 및 1μL의 DMAT-π-CAP 스톡 솔루션을 98μL의 PBS(pH 7.4)와 혼합하였다. 그 후, 3분동안 인큐베이션 한 뒤, 혼합물을 96-웰 플레이트에 옮기고 Cytation™5 (BioTek, USA)에 의해 형광을 측정하였다(λex= 600, λem = 730 nm). 모든 측정은 3회 수행되었다. To confirm the fluorescence properties of DMAT-π-CAP in PBS buffer, specifically, stock solutions of DMAT-π-CAP (dissolved in DMSO to prepare 500 μM) and HSA (pH 7.4 to prepare 1 mM by dissolving in PBS) were used. prepared. At room temperature, 1 μL of HSA and 1 μL of DMAT-π-CAP stock solution were mixed with 98 μL of PBS, pH 7.4. After incubation for 3 minutes, the mixture was transferred to a 96-well plate and fluorescence was measured by Cytation™5 (BioTek, USA) (λ ex = 600, λ em = 730 nm). All measurements were performed in triplicate.
HSA(인간 혈청 알부민; Human serum albumin) 첨가하기 전, 상기 실시예 1의 DMAT-π-CAP의 형광을 측정한 결과, 도 1(A)에 나타낸 바와 같이, 형광이 거의 관찰되지 않았으나(아래 그림 점선, 삽입부분), HSA를 처리한 후 형광을 관찰한 결과, 약 730배 증가된 형광이 관찰되었다(turn-on fluorescene, 실선 부분).As a result of measuring the fluorescence of DMAT-π-CAP of Example 1 before adding HSA (Human serum albumin), as shown in FIG. 1(A), almost no fluorescence was observed (Fig. As a result of observing fluorescence after HSA treatment, about 730-fold increase in fluorescence was observed (turn-on fluorescene, solid line).
<실험예 2> DMAT-π-CAP의 알부민 선택성 형광 특성 확인<Experimental Example 2> Confirmation of albumin-selective fluorescence properties of DMAT-π-CAP
DMAT-π-CAP의 알부민 선택성을 확인하기 위해 BSA(bovine serum albumin), 다양한 이온, 유기 소분자, 단백질 및 핵산 등이 포함된 시료에서 확인하였다. 보다 구체적으로, 1μL의 DMAT-π-CAP 스톡 솔루션(500μM) 및 1μL의 다양한 바이오 분석물[BSA(200μM)을 제외한 나머지는 1mM]을 포함하는 혼합물을 PBS(pH7.4)에 용해시키고, 실온에서 3분 동안 인큐베이션하였다. 그 후, 96-웰 플레이트로 옮긴 후, Cytation™5 (BioTek, USA)에 의해 형광을 측정하였다(λex=600nm, λem= 730 nm). 모든 측정은 3회 수행하였다. 또한, 시간 의존적 형광 특성을 확인하기 위해 3분동안 매초마다 형광을 측정하였다. To confirm the albumin selectivity of DMAT-π-CAP, it was confirmed in samples containing bovine serum albumin (BSA), various ions, small organic molecules, proteins, and nucleic acids. More specifically, a mixture containing 1 μL of DMAT-π-CAP stock solution (500 μM) and 1 μL of various bioanalytes [1 mM except for BSA (200 μM)] was dissolved in PBS (pH 7.4), and room temperature incubated for 3 min. Thereafter, after transfer to a 96-well plate, fluorescence was measured by Cytation™5 (BioTek, USA) (λ ex =600 nm, λ em = 730 nm). All measurements were performed in triplicate. In addition, in order to confirm the time-dependent fluorescence characteristics, fluorescence was measured every second for 3 minutes.
또한, 상기 바이오 분석물에는 HSA, BSA, Na+, K+, Ca2+, Mg2+, NH4+, PO4 3-, 우레아(urea), 요산(uric acid), 포도당(glucose), 글리신(glycine), 류신(leucine), 이소류신(isoleucine), 리도카인(lidocaine), 빌리루빈(bilirubin), γ-글로불린(γ-globulins), 크레아티닌(creatinine), 펩신(pepsin), 트랜스페린(transferrin), 인간 IgG(human IgG), 파파인(papain), 키오트립시노겐 A(chymotrypsinogen A), 트립신(trypsin), 및 DNA를 포함한다. In addition, the bio-analyte includes HSA, BSA, Na + , K + , Ca 2+ , Mg 2+ , NH 4+ , PO 4 3- , urea, uric acid, glucose, Glycine, leucine, isoleucine, lidocaine, bilirubin, γ-globulins, creatinine, pepsin, transferrin, human IgG (human IgG), papain, chymotrypsinogen A, trypsin, and DNA.
DMAT-π-CAP의 알부민 선택성을 확인한 결과, 도 1(B)에 나타낸 바와 같이, DMAT-π-CAP는 알부민에 대한 강한 선택성을 갖는 것을 확인할 수 있었다. 또한, 도 1(C)에 나타낸 바와 같이, DMAT-π-CAP로부터의 형광신호는 HSA와의 인큐베이션 후 3초 내에 안정되는 것을 확인하였다. As a result of confirming the albumin selectivity of DMAT-π-CAP, as shown in FIG. 1(B), it was confirmed that DMAT-π-CAP has strong selectivity for albumin. In addition, as shown in FIG. 1(C), it was confirmed that the fluorescence signal from DMAT-π-CAP was stabilized within 3 seconds after incubation with HSA.
따라서, 상기 결과로 인해 DMAT-π-CAP의 HSA의 선택적 결합 및 신속한 결합으로 인해 근적외선 영역에서 형광 특성을 나타내는 것을 확인할 수 있다. Therefore, due to the above results, it can be confirmed that DMAT-π-CAP exhibits fluorescence properties in the near-infrared region due to the selective and rapid binding of HSA.
<실험예 3> DMAT-π-CAP의 알부민 농도의존적 형광 특성 확인<Experimental Example 3> Confirmation of albumin concentration-dependent fluorescence characteristics of DMAT-π-CAP
DMAT-π-CAP의 알부민 농도의존적 형광 특성 확인하기 위해, HSA 스톡 솔루션(10mM)을 PBS(pH7.4)로 연속 희석하여 다양한 농도(10, 9, 8, 7, 6, 5, 4, 3, 2, 1, 0.5, 0.25, 0.125 mM)의 HSA 용액으로 만들었다. 그 후, DMAT-π-CAP(1μL, DMSO 중 500μM)를 98μL의 PBS(pH 7.4)에서 1μL의 각 HSA 용액과 혼합하고, 96-웰 플레이트로 옮긴 후, Cytation™5 (BioTek, USA)로 형광을 측정하였다(λex=600nm, λem= 730 nm). 모든 측정은 3회 수행하였다.To confirm the albumin concentration-dependent fluorescence properties of DMAT-π-CAP, HSA stock solution (10 mM) was serially diluted with PBS (pH 7.4) to various concentrations (10, 9, 8, 7, 6, 5, 4, 3). , 2, 1, 0.5, 0.25, 0.125 mM) of HSA solution. Then, DMAT-π-CAP (1 μL, 500 μM in DMSO) was mixed with 1 μL of each HSA solution in 98 μL of PBS (pH 7.4), transferred to a 96-well plate, and then into Cytation™5 (BioTek, USA). Fluorescence was measured (λ ex =600 nm, λ em = 730 nm). All measurements were performed in triplicate.
그 결과, 도 2(A)에 나타낸 바와 같이, DMAT-π-CAP는 알부민과 결합시 농도의존적으로 형광의 세기가 강해진 것을 확인하였다. As a result, as shown in FIG. 2(A), it was confirmed that the intensity of fluorescence was increased in a concentration-dependent manner when DMAT-π-CAP was combined with albumin.
<실험예 4> DMAT-π-CAP의 검출한계 및 해리상수(Kd) 측정<Experimental Example 4> Measurement of detection limit and dissociation constant (Kd) of DMAT-π-CAP
DMAT-π-CAP의 검출한계(LOD, limit of detection)는 하기 식을 사용하여 계산하였다. The limit of detection (LOD) of DMAT-π-CAP was calculated using the following equation.
[식 1][Equation 1]
Detection limit (LOD) = 3σ/kDetection limit (LOD) = 3σ/k
σ가 blank 측정의 표준편차인 경우, k는 730nm에서의 형광강도 대 HSA 농도 사이의 기울기이다. Where σ is the standard deviation of the blank measurement, k is the slope between the fluorescence intensity at 730 nm versus the HSA concentration.
따라서, DMAT-π-CAP(5μM)의 형광 방출 스펙트럼을 PBS(pH7.4)에서 5회 측정하여 블랭크 측정의 표준편차(σ)를 제공하였다. 기울기(k)를 얻기 위해, 730nm에서의 형광강도를 상이한 농도의 HSA에 대해 플롯팅 하였다. Therefore, the fluorescence emission spectrum of DMAT-π-CAP (5 μM) was measured 5 times in PBS (pH 7.4) to provide the standard deviation (σ) of the blank measurement. To obtain the slope (k), the fluorescence intensity at 730 nm was plotted for different concentrations of HSA.
또한, 다양한 농도의 HSA와 함께 인큐베이션된 DMAT-π-CAP(5μM)로부터 형광강도를 얻고, 비선형 Langmuir 등온선을 사용하여 데이터를 분석 하였다 :In addition, fluorescence intensities were obtained from DMAT-π-CAP (5 μM) incubated with various concentrations of HSA, and the data were analyzed using nonlinear Langmuir isotherms:
Δr = Δrmax * P/(K d +P)Δr = Δr max * P/( K d +P)
여기서, here,
Δr는 농도[P]에서 단백질의 존재 및 부재하에서 형광 이방성(비등방성, anisotropy)의 차이이고, Δr is the difference in fluorescence anisotropy (anisotropy) in the presence and absence of the protein at concentration [P],
Δrmax 는 형광 이방성의 최대 가능한 변화이고, Δr max is the maximum possible change in fluorescence anisotropy,
K d 는 결합 해리 상수이다. K d is the bond dissociation constant.
비선형 방정식은 Graphpad Prism 5를 사용하여 데이터에 피팅되었다. Nonlinear equations were fitted to the data using
그 결과, 도 2(B)에 나타낸 바와 같이, HSA의 낮은 농도에서 급격히 증가하는 형광의 세기는 HSA 농도가 증가하면서 서서히 포화되는 경향을 보이며, 이 그래프를 분석한 결과, DMAT-π-CAP과 HSA사이에 상당한 결합력이 있음을 확인하였다(해리상수 K d = 15.4 μM). 이 때 HSA 농도 0~10 μM 구간에서 HSA 농도와 DMAT-π-CAP에 의한 형광 세기간에 선형응답(linear response)이 성립됨을 확인할 수 있으며 (도 2(B) 삽입), 이로부터 LOD(limit of detection)은 10.9 nM (0.72 mg/ℓ)로 관찰되었다. 이는 이 농도 구간에서 DMAT-π-CAP에 의한 형광 측정에 의해 HSA의 농도 예측이 가능함을 의미하는데, 대부분의 경우 사람의 소변에서 HSA 농도는 이 구간 내에 존재하므로, 결국 DMAT-π-CAP를 이용하여 사람의 소변 샘플로부터 알부민 농도를 측정할 수 있음을 의미한다. As a result, as shown in FIG. 2(B), the intensity of fluorescence that rapidly increases at a low concentration of HSA shows a tendency to gradually saturate as the concentration of HSA increases. As a result of analyzing this graph, DMAT-π-CAP and It was confirmed that there is a significant binding force between HSA (dissociation constant K d = 15.4 μM). At this time, it can be confirmed that a linear response is established between the HSA concentration and the fluorescence intensity by DMAT-π-CAP in the HSA concentration range of 0 to 10 μM (Fig. 2(B) inset), from which the LOD (limit of detection) was observed at 10.9 nM (0.72 mg/L). This means that the concentration of HSA can be predicted by fluorescence measurement by DMAT-π-CAP in this concentration range. In most cases, since the concentration of HSA in human urine is within this range, DMAT-π-CAP is used in the end. This means that albumin concentrations can be measured from human urine samples.
<실험예 5> DMAT-π-CAP와 HSA간의 결합방식 확인(Job's plot analysis)<Experimental Example 5> Confirmation of binding method between DMAT-π-CAP and HSA (Job's plot analysis)
DMAT-π-CAP와 HSA간의 결합방식을 확인하기 위해, 총 농도 (DMAT-π-CAP+HSA)를 10μM로 유지하면서 DMAT-π-CAP의 몰분율이 0에서 1이 되도록 DMAT-π-CAP과 HSA를 혼합한 시료를 준비하고 각 몰분율에서 DMAT-π-CAP의 형광을 측정하였다. In order to confirm the binding method between DMAT-π-CAP and HSA, while maintaining the total concentration (DMAT-π-CAP+HSA) at 10 μM, DMAT-π-CAP and DMAT-π-CAP and A sample mixed with HSA was prepared, and the fluorescence of DMAT-π-CAP was measured at each mole fraction.
그 결과, 도 3(A)에 나타낸 바와 같이, 몰분율 0.5에서 형광이 최대로 관찰되었으며, 이는 DMAT-π-CAP과 HSA가 1:1 복합체(complex)를 형성하며 또한 DMAT-π-CAP는 HSA에 단일한 결합자리를 가지는 것을 의미한다(Job's plot analysis).As a result, as shown in FIG. 3(A), fluorescence was maximally observed at a mole fraction of 0.5, which is that DMAT-π-CAP and HSA form a 1:1 complex, and DMAT-π-CAP is HSA It means having a single binding site in (Job's plot analysis).
<실험예 6> DMAT-π-CAP와 HSA간의 결합위치 확인<Experimental Example 6> Confirmation of binding position between DMAT-π-CAP and HSA
DMAT-π-CAP와 HSA간의 결합위치를 확인하기 위해 도 3(C)에 나타낸 바와 같이, 이미 결합자리가 알려져 있는 세 가지 물질과의 경쟁법(competition assay)을 진행하였다. 즉, HSA가 가지고 있는 약물 결합 부위(drug binding site) 중에 서들러 사이트 I(Sudlow's site 1)에 결합하는 와파린(약물 결합 부위 I, 서브도메인 IIA) 및 서들러 사이트 II(Sudlow's site 2)에 결합하는 이부프로펜(약물 결합부위 II, 서브도메인 IIIA), 그리고 서들러 사이트(Sudlow's site) 1 및 2에 관계없는 자리에 결합하는 헤민(서브도메인 IB) 등이 포함된 시료에 DMAT-π-CAP를 가하고, 형광강도의 변화를 관찰하였다. In order to confirm the binding position between DMAT-π-CAP and HSA, as shown in FIG. 3(C) , a competition assay with three substances with known binding sites was performed. That is, it binds to warfarin (drug binding site I, subdomain IIA) that binds to Sudlow's
그 결과, 도 3(B)에 나타낸 바와 같이, 와파린(warfarin) 및 이부프로펜(ibuprofen)은 농도를 증가시켜도 DMAT-π-CAP에 의한 형광의 세기에 아무런 변화를 관찰할 수 없었으나, 헤민(hemin)의 경우에는 농도가 증가함에 따라 DMAT-π-CAP의 형광이 급격하게 감소함을 관찰할 수 있었다. As a result, as shown in FIG. 3(B), no change was observed in the intensity of fluorescence by DMAT-π-CAP even when the concentrations of warfarin and ibuprofen were increased, but hemin (hemin) ), it was observed that the fluorescence of DMAT-π-CAP rapidly decreased as the concentration increased.
따라서, DMAT-π-CAP는 헤민(hemin)과 경쟁적으로 HSA에 결합하며 헤민(hemin)과 같은 결합자리를 가지고 있음을 알 수 있었다. 지금까지 헤민(hemin) 결합자리에 결합하는 것으로 알려진 HSA 센서는 알려진 바 없다. Therefore, it was found that DMAT-π-CAP binds to HSA competitively with hemin and has the same binding site as hemin. So far, there is no known HSA sensor known to bind to a hemin binding site.
그러므로, DMAT-π-CAP는 매우 독특한 HSA 결합자리를 가지며 그로 인해 다른 생체인자로부터의 간섭을 회피할 수 있는 장점을 가진다.Therefore, DMAT-π-CAP has a very unique HSA binding site and thereby has the advantage of avoiding interference from other biological factors.
<실험예 7> DMAT-π-CAP를 이용한 소변 알부민의 형광 분석<Experimental Example 7> Fluorescence analysis of urine albumin using DMAT-π-CAP
상기 실험예 1 내지 6의 결과에 나타낸 바와 같이, DMAT-π-CAP은 HSA에 대한 선택적 형광능, 근적외선 영역에서의 형광능, 그리고 다른 물질들과 차별화된 결합자리 등을 가지고 있어, 간섭이 최소화된 형광을 발산하며, 따라서 DMAT-π-CAP가 포함된 시료의 형광 측정으로부터 HSA의 농도를 매우 정확하게 예측할 수 있는 장점을 가지고 있다. 이를 확인하기 위해, 세 가지 사람의 소변 샘플에 DMAT-π-CAP (5 μM)을 가하고 HSA를 일정 농도 간격(0.2-2.0 μM; 13.3-133.0 mg/ℓ)으로 스파이킹(spiking)하고 형광을 관찰하였다. 보다 구체적으로, DMAT-π-CAP를 DMSO에 용해시켜 500 μM 스톡 솔루션을 수득 하였다. 건강한 여성 공여자로부터 소변 샘플을 수집하고 4 ℃, 1000g에서 10분 동안 원심 분리한 ,후 같은 날에 사용하였다. As shown in the results of Experimental Examples 1 to 6, DMAT-π-CAP has a selective fluorescence ability for HSA, a fluorescence ability in the near-infrared region, and a binding site differentiated from other materials, so that interference is minimized It has the advantage of being able to predict the concentration of HSA very accurately from the fluorescence measurement of the sample containing DMAT-π-CAP. To confirm this, DMAT-π-CAP (5 μM) was added to three human urine samples and HSA was spiked at constant concentration intervals (0.2-2.0 μM; 13.3-133.0 mg/L) and fluorescence was measured. observed. More specifically, DMAT-π-CAP was dissolved in DMSO to obtain a 500 μM stock solution. Urine samples were collected from healthy female donors and centrifuged at 4 °C and 1000 g for 10 min, and then used on the same day.
소변 (98 ~ 99 ㎕)에서 DMAT-π-CAP(500 μM, 1 ㎕) 및 다양한 농도의 HSA (0, 2, 4, 6, 8, 10 μM; 1 ㎕)를 96- 웰 플레이트에서 3분 동안 배양하고, 형광 방출은 Cytation ™5 (BioTek, USA)에 의해 측정되었다 (λex=600nm, λem= 730 nm). 모든 측정은 3 회 수행되었다.DMAT-π-CAP (500 μM, 1 μL) and various concentrations of HSA (0, 2, 4, 6, 8, 10 μM; 1 μL) in urine (98-99 μL) in 96-well plates for 3 min During incubation, fluorescence emission was measured by Cytation ™5 (BioTek, USA) (λ ex =600 nm, λ em = 730 nm). All measurements were performed in triplicate.
그 결과, 도 4에 나타낸 바와 같이, 스파이킹(spiking)한 HSA의 농도에 비례하여 DMAT-π-CAP에 의한 형광이 증가하는 것을 세 가지 소변 샘플(도 4(A), 도 4(B) 및 도 4(C))에서 모두 확인할 수 있었으며, 이로부터 소변에 포함된 HSA의 농도를 결정할 수 있었다(4.8 mg/ℓ, 7.6 mg/ℓ 그리고 22.7 mg/ℓ). As a result, as shown in FIG. 4, the fluorescence by DMAT-π-CAP increased in proportion to the spiking HSA concentration in three urine samples (FIG. 4(A), FIG. 4(B)) and FIG. 4(C)), from which it was possible to determine the concentration of HSA contained in urine (4.8 mg/L, 7.6 mg/L and 22.7 mg/L).
한편, 같은 소변 샘플을 HSA 항체를 이용한 인간 알부민 ELISA 키트 (Cell Biolabs, Inc. STA-383-Human Albumin ELISA kit)를 제조사의 프로토콜에 따라 사용하였다. 분석 완충액에 용해된 인간 HSA 표준을 사용하여 얻은 보정 곡선을 사용하여 소변 샘플에서 HSA 농도를 추정하였다.Meanwhile, for the same urine sample, a human albumin ELISA kit (Cell Biolabs, Inc. STA-383-Human Albumin ELISA kit) using an HSA antibody was used according to the manufacturer's protocol. A calibration curve obtained using human HSA standards dissolved in assay buffer was used to estimate HSA concentrations in urine samples.
면역분석(immunoassay)을 이용하여 분석한 결과, 도 4(D)에 나타낸 바와 같이, HSA의 농도는 1.6 mg/ℓ, 4.6 mg/ℓ 그리고 21.4 mg/ℓ로 결정되었다. 형광에 의해 분석된 HSA 농도(Fluorometric)와 면역분석에 의해 분석된 농도(immunoassay)를 비교한 결과, 매우 유사한 것을 확인하였다. As a result of analysis using an immunoassay, as shown in FIG. 4(D), the concentrations of HSA were determined to be 1.6 mg/L, 4.6 mg/L, and 21.4 mg/L. As a result of comparing the HSA concentration analyzed by fluorescence (Fluorometric) and the concentration analyzed by immunoassay (immunoassay), it was confirmed that they were very similar.
이제까지 본 발명에 대하여 그 바람직한 실시예들을 중심으로 살펴보았다. 본 발명이 속하는 기술 분야에서 통상의 지식을 가진 자는 본 발명이 본 발명의 본질적인 특성에서 벗어나지 않는 범위에서 변형된 형태로 구현될 수 있음을 이해할 수 있을 것이다. 그러므로 개시된 실시예들은 한정적인 관점이 아니라 설명적인 관점에서 고려되어야 한다. 본 발명의 범위는 전술한 설명이 아니라 특히 청구범위에 나타나 있으며, 그와 동등한 범위내에 있는 모든 차이점은 본 발명에 포함된 것으로 해석되어야 할 것이다.So far, with respect to the present invention, the preferred embodiments have been looked at. Those of ordinary skill in the art to which the present invention pertains will understand that the present invention can be implemented in modified forms without departing from the essential characteristics of the present invention. Therefore, the disclosed embodiments are to be considered in an illustrative rather than a restrictive sense. The scope of the present invention is not shown in the foregoing description, but particularly in the claims, and all differences within an equivalent scope should be construed as being included in the present invention.
Claims (13)
[화학식 1]
(상기 화학식 1에서,
n은 1 내지 10의 정수이다).A compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof:
[Formula 1]
(In Formula 1,
n is an integer from 1 to 10).
상기 n은 1 내지 5의 정수인 것을 특징으로 하는 화합물 또는 이의 약학적으로 허용가능한 염.According to claim 1,
Wherein n is an integer of 1 to 5, or a pharmaceutically acceptable salt thereof.
상기 n은 1 내지 3의 정수인 것을 특징으로 하는 화합물 또는 이의 약학적으로 허용가능한 염.According to claim 1,
Wherein n is an integer of 1 to 3, or a pharmaceutically acceptable salt thereof.
상기 화학식 1로 표시되는 화합물은
(2E,4E,6E)-2-(3-클로로벤조일)-7-(5-(다이메틸아미노)티오펜-2-일)헵타-2,4,6-트라이엔나이트릴인 것을 특징으로 하는 화합물 또는 이의 약학적으로 허용가능한 염.According to claim 1,
The compound represented by Formula 1 is
(2E,4E,6E)-2-(3-chlorobenzoyl)-7-(5-(dimethylamino)thiophen-2-yl)hepta-2,4,6-triennitrile A compound or a pharmaceutically acceptable salt thereof.
화학식 2로 표시되는 화합물을 용매에 용해하고, 다이메틸아민을 첨가하여 친핵성 방향족고리 치환 반응시켜 화학식 3으로 표시되는 화합물을 합성하는 단계(단계 1);
상기 단계 1의 화학식 3으로 표시되는 화합물 및 메톡사이드 나트륨을 유기용매에서 촉매하에 알돌축합반응시켜 화학식 4로 표시되는 화합물을 합성하는 단계(단계 2);
상기 단계 2의 화학식 4로 표시되는 화합물 및 3-클로로벤조일아세토나이트릴을 유기용매에서 축합반응시켜 화학식 1로 표시되는 화합물을 합성하는 단계(단계 3);를 포함하고,
상기 단계 2를 반복 실시하는 횟수는 하기 반응식 1에서 n의 정수값과 동일한 것을 특징으로 하는,
제1항의 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용가능한 염의 제조방법:
[반응식 1]
(상기 반응식 1에서,
n은 1 내지 10의 정수이다).As shown in Scheme 1 below,
synthesizing the compound represented by Formula 3 by dissolving the compound represented by Formula 2 in a solvent, adding dimethylamine to perform a nucleophilic aromatic ring substitution reaction (step 1);
synthesizing the compound represented by Formula 4 by subjecting the compound represented by Formula 3 of Step 1 and sodium methoxide to an aldol condensation reaction in an organic solvent under a catalyst (step 2);
Condensing the compound represented by Formula 4 of Step 2 and 3-chlorobenzoylacetonitrile in an organic solvent to synthesize the compound represented by Formula 1 (step 3);
The number of times of repeating step 2 is the same as the integer value of n in Scheme 1 below,
A method for preparing a compound represented by Formula 1 of claim 1 or a pharmaceutically acceptable salt thereof:
[Scheme 1]
(In Scheme 1,
n is an integer from 1 to 10).
상기 단계 1의 용매는 물 또는 유기용매이고,
상기 유기용매는 메탄올, 에탄올, 테트라하이드로퓨란(THF), 다이옥산, 다이클로로메탄(DCM), 1,2-다이메톡시에탄, 벤젠, 톨루엔, 자일렌, 다이메틸포름아미드(DMF), 다이메틸설폭사이드(DMSO), 및 아세토나이트릴로 이루어지는 군으로부터 선택되는 1종 이상인 것을 특징으로 하는 제조방법.6. The method of claim 5,
The solvent of step 1 is water or an organic solvent,
The organic solvent is methanol, ethanol, tetrahydrofuran (THF), dioxane, dichloromethane (DCM), 1,2-dimethoxyethane, benzene, toluene, xylene, dimethylformamide (DMF), dimethyl A manufacturing method, characterized in that at least one selected from the group consisting of sulfoxide (DMSO), and acetonitrile.
상기 단계 2 또는 단계 3의 유기용매는 메탄올, 에탄올, 테트라하이드로퓨란(THF), 다이옥산, 다이클로로메탄(DCM), 1,2-다이메톡시에탄, 벤젠, 톨루엔, 자일렌, 다이메틸포름아미드(DMF), 다이메틸설폭사이드(DMSO), 및 아세토나이트릴로 이루어지는 군으로부터 선택되는 1종 이상인 것을 특징으로 하는 제조방법.6. The method of claim 5,
The organic solvent of step 2 or step 3 is methanol, ethanol, tetrahydrofuran (THF), dioxane, dichloromethane (DCM), 1,2-dimethoxyethane, benzene, toluene, xylene, dimethylformamide (DMF), dimethyl sulfoxide (DMSO), and a production method, characterized in that at least one selected from the group consisting of acetonitrile.
상기 알부민 검출용 조성물의 검출 샘플은 소변, 혈액, 눈물, 땀 또는 타액인 것을 특징으로 하는 알부민 검출용 조성물.10. The method of claim 9,
The detection sample of the composition for detecting albumin is urine, blood, tears, sweat or saliva.
상기 알부민 검출용 조성물의 검출 샘플은 소변, 혈액, 눈물, 땀 또는 타액인 것을 특징으로 하는 알부민을 검출하는 방법.12. The method of claim 11,
The detection sample of the composition for detecting albumin is a method for detecting albumin, characterized in that urine, blood, tears, sweat or saliva.
상기 검출은 정량 또는 정성 검출인 것을 특징으로 하는 알부민을 검출하는 방법.12. The method of claim 11,
The detection is a method for detecting albumin, characterized in that quantitative or qualitative detection.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2013027694A1 (en) * | 2011-08-24 | 2013-02-28 | 国立大学法人京都大学 | Molecular imaging probes for diagnosing conformation disease |
| KR20170011148A (en) * | 2015-07-21 | 2017-02-02 | 건국대학교 산학협력단 | Curcumin-based near infrared fluorescence (NIRF) probes for detection of tau fibril and use of the same |
| KR20170135370A (en) | 2016-05-31 | 2017-12-08 | 순천향대학교 산학협력단 | Carbon nanotube field-effect transistor modified with bromocresol green and determination of human serum albumin using the same |
| KR20180022399A (en) * | 2016-08-24 | 2018-03-06 | 건국대학교 산학협력단 | Near-infrared fluorescence smart probe for detecting tau protein for the early diagnosis of Alzheimer's disease |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2013027694A1 (en) * | 2011-08-24 | 2013-02-28 | 国立大学法人京都大学 | Molecular imaging probes for diagnosing conformation disease |
| KR20170011148A (en) * | 2015-07-21 | 2017-02-02 | 건국대학교 산학협력단 | Curcumin-based near infrared fluorescence (NIRF) probes for detection of tau fibril and use of the same |
| KR20170135370A (en) | 2016-05-31 | 2017-12-08 | 순천향대학교 산학협력단 | Carbon nanotube field-effect transistor modified with bromocresol green and determination of human serum albumin using the same |
| KR20180022399A (en) * | 2016-08-24 | 2018-03-06 | 건국대학교 산학협력단 | Near-infrared fluorescence smart probe for detecting tau protein for the early diagnosis of Alzheimer's disease |
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| KR102302318B1 (en) | 2021-09-14 |
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