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Part 1. Design, synthesis and biological evaluation of novel biaryl amide compounds as analgesics

Part 1. Design, synthesis and biological evaluation of novel biaryl amide compounds as analgesics
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대학원 생명·약학부약학전공
이화여자대학교 대학원
본 논문은 두 가지 내용을 포함하고 있다. 첫 번째 부분에서는 통증 치료제 개발을 위한 새로운 물질의 디자인, 합성 및 활성을 평가한 내용을 다루었다. 통증은 사회적으로 심각한 문제이며 현재 시판중인 약물을 통한 통증 조절에는 어려움이 따르고 있다. 따라서 약효를 증가시키면서 독성을 낮추는 치료제 개발을 위한 새로운 분자 타겟의 발굴에 대한 중요성이 강조되어 왔다. 본 연구에서는 통증 조절을 위한 여러 타겟들 가운데 브라디키닌 수용체와 T-타입 칼슘 채널 및 나트륨 채널을 대상으로 새로운 물질을 개발하였다. 브라디키닌은 여러가지 생리학적인 과정에 관여하는데, 이는 염증 반응, 통증, 부종 등을 포함한다. 따라서 브라디키닌 차단제는 통증 및 염증 치료제로 각광받고 있다. 본 연구에서는 27 종의 새로운 시리즈의 비펩타이드성 biaryl diamide 물질을 디자인 및 합성하고 기니아 피그 적출 회장을 사용하여 브라디키닌 차단 작용을 확인하였다. 최종 물질 중 (Z)-4-(4-(bis(4-fluorophenyl)methyl)piperazin-1-yl)-4-oxo-N-(4-phenyl-butan-2-yl)but-2-enamide (물질 35) 의 브라디키닌 차단 작용이 가장 뛰어났으며 (1 μM 에서 87% 억제), rat model 에서 염증성 및 신경병성 통증에 효과를 나타냈다. 또한 T-타입 칼슘 채널이 통증에 관여하는 것에 기인하여, 새로운 diphenylpiperazine 유도체를 디자인 및 합성하고, patch-clamp assay 방법을 이용하여 T-타입 칼슘 채널 차단 효과를 확인하였다. 총 10 종의 물질 중 물질 40 (1-(4-((4-chlorophenyl)(phenyl)methyl)piperazin-1-yl)-4-(ethylami-no)butan-1-one, IC_(50) = 0.42 μM for Ca_(V)3.1) 과 물질 43 (1-(4-((4-chlorophenyl)(phenyl)methyl)piperazin-1-yl)-4-(cyclohexyl-methylamino)butan-1-one, IC_(50) = 0.19 μM for Ca_(V)3.1) 은 rat formalin test 에서 염증성 통증에 대한 진통 효과를 나타냈다. 또한, 물질 43에 대하여 신경병성 통증 억제 효과 실험에서 진통 효과를 확인하였다. 마지막으로 통증 치료제 개발을 위한 나트륨 채널 차단 효과를 기대하는 20 종의 새로운 biaryl propanamide 와 monoamide 유도체를 디자인 및 합성하였다. 최종 물질 중 물질 39 (4-amino-1-(4-((4-chlorophenyl)(phenyl)methyl)piperazin-1-yl)butan-1-one, rat sodium channel site 2 에 대하여 10 μM 에서 90% 억제) 는 in vivo 동물 모델에서 염증성 및 신경병성 통증에 대하여 진통 효과를 나타냈다. 두번째 분야는 한국의 남부 및 중국과 일본에서 서식하는 상록수인 Actinodaphne lancifolia (육박나무)의 줄기에서 추출한 isolancifolide의 전합성에 관한 내용이다. A. lancifolia 추출물 중 isolancifolide 와 lancifolide 는 in vitro 시험 및 in vivo 마우스 모델을 사용한 실험에서 종양 세포 성장 억제에 효과가 있는 것으로 나타났다. 본 연구에서는 총 5단계를 거쳐 isolancifolide 를 전합성하여 isolancifolide-s ((S,E)-3-decylidene-dihydro-4-hydroxy-5-methylenefuran-2(3H)-one) 라고 명명하였으며, isolancifolide-s 의 유도체인 HEP-1 ((S,E)-dihydro-4-hydroxy-5-methylene-3-(pent-4-enylidene)furan-2(3H)-one) 도 같은 방법으로 합성하였다. 본 연구를 통하여 isolancifolide-s 의 항염 및 항암 작용에 대한 연구뿐 아니라, 유도체 HEP-1 의 합성으로 변화된 구조에 따른 약리 활성을 확인하는 데 기여할 수 있을 것이라고 기대한다.;In the first part, design, synthesis and biological evaluation of novel biaryl amide compounds targeting bradykinin receptor, T-type calcium channel and sodium channel were reported for the discovery of new analgesics. In order to satisfy the necessity for more effective and less toxic pain therapies, the identification of novel molecular targets have been emphasized. One of the promising targets is the bradykinin receptors. Bradykinin is involved in a variety of physiological and pathophysiological processes and bradykinin contributes to the inflammatory response, producing pain, swelling, redness and heat. Bradykinin antagonists, therefore, are considered as potential drugs in pain and inflammatory diseases. In this study, a series of novel non-peptide biaryl diamide compounds was synthesized and evaluated as antibradykinin agents by utilizing guinea-pig ileum smooth muscle. Among the twenty seven synthesized compounds, (Z)-4-(4-(bis(4-fluorophenyl)methyl)piperazin-1-yl)-4-oxo-N-(4-phenylbutan-2-yl)but-2-enamide (35) showed the most favorable bradykinin inhibitory activity (87% inhibition at 1 μM) and demonstrated analgesic efficacies in the rat models of inflammatory and neuropathic pain. In addition, given that T-type calcium channels play important roles in pain perception, ten novel diphenylpiperazine derivatives were synthesized and evaluated for their inhibitory activity against T-type calcium channel by patch-clamp assay. Among the test compounds, 1-(4-((4-chlorophenyl)(phenyl)methyl)piperazin-1-yl)-4-(ethylami-no)butan-1-one (40, IC_(50) = 0.42 μM for Ca_(V)3.1) and 1-(4-((4-chlorophenyl)(phenyl)methyl)piperazin-1-yl)-4-(cyclohexyl-methylamino)butan-1-one (43, IC_(50) = 0.19 μM for Ca_(V)3.1) showed the analgesic effects on both nociceptive and inflammatory pain in the rat formalin test. Moreover, compound 43 showed analgesic effect in in vivo animal model of neuropathic pain. Lastly, a series of twenty novel biaryl propanamide and monoamide compounds with diverse substituents targeting sodium channel was designed and synthesized to evaluate their analgesic activity. Among the final compounds, 4-amino-1-(4-((4-chlorophenyl)(phenyl)methyl)piperazin-1-yl)butan-1-one (39) demonstrated its sodium channel blocking activity (90% inhibition at 10 μM, rat sodium channel site 2). In addtion, simultaneous peripheral local administration of 39 with formalin significantly reduced pain behaviors during both the early and late phases. Compound 39 was also effective in rat tail nerve injury model of neuropathic pain. In the second part, isolancifolide was synthesized by employing the stereoselective reaction of optically active sulfoxide and to the synthesized isolancifolide gave the name of isolancifolide-s ((S,E)-3-decylidene-dihydro-4-hydroxy-5-methylenefuran-2(3H)-one). Moreover, HEP-1 ((S,E)-dihydro-4-hydroxy-5-methylene-3-(pent-4-enylidene)furan-2(3H)-one), a derivative of isolancifolide-s, was synthesized modifying the α-alkylidene unit of isolancifolide-s to a shorter alkyl chain with a double bond at the end. Isolancifolide is an extract from stems of Actinodaphne lancifolia which is an evergreen tree in the family Lauraceae. Recent studies demonstrated that among the extract of Actinodaphne lancifolia, isolancifolide and lancifolide were effective on tumor cell growth inhibition by in vitro assay using cancer cell lines and in vivo mouse model. However, studies about synthesis of these natural products have not been reported yet. In this study, total synthesis of isolancifolide-s and its derivative HEP-1 were developed in five steps with 15-52% yield in each step. These results can be useful as potential tools to identify biological activities of isolancifolide-s and its derivative HEP-1.
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