Structure Determination and Total Synthesis of New Bioactive Compounds from Marine Sponges
해양 해면동물 유래의 신규 생리활성 물질에 대한 구조결정과 전합성

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서울대학교 대학원
marine natural productsspongesstructure determinationtotal synthesisstructure-activity relationship해양 천연물해면동물구조결정전합성구조-활성 상관관계
학위논문 (박사) -- 서울대학교 대학원 : 약학대학 약학과, 2021. 2. 신종헌.
Marine natural products have been proven to be a promising source of inspiration for the development of new classes of therapeutic agents. To date, there are seven FDA approved drugs and thirteen agents in clinical trial that originated from marine or marine-drived compounds. Due to novel structures and biologically diverse activities including anticancer, anti-microbial, anti-virus, and immunomodulation, secondary metabolites were studied in many researchers from various disciplines. Approximately 18,000 research articles and 17,000 new compounds have been reported from marine organisms. Among marine natural products, more than 30% of the compounds were isolated from sponges. Marine sponges belong to the phylum Porifera inhabit a wide variety of marine ecosystems which lead to production wide range of secondary metabolites, the main chemical classes are alkaloids, terpenes/terpenoids, peptides.
The purpose of this study is to investigate new marine natural products from sponges and determine their physical, chemical, and biological properties.
During the course of searching for bioactive novel compounds from marine sponges, one Korean sponge Psammocinia sp. as well as three tropical marine sponges Stylissa flabelliformis, Hyrtios erectus and Agelas kosrae were selected for chemical investigation based on chemical analysis and bioassay screening. Secondary metabolites from the selected organisms were isolated through chromatographic methods. As a result, 20 new compounds and 26 known compounds were structurally determined using combined spectroscopic analysis and chemical, computational approaches. Also 3 new compounds and related 5 analogs were total synthesized by various laboratory techniques. These 51 compounds belonged to various structural classes with diverse biogenetic origins: cyclopeptides, bromopyrrole-alkaloids, terpenoids, and indole-alkaloids. All isolated compounds have been examined under various bioactivities: cytotoxicity, anti-angiogenic activity, antimicrobial activities, adiponectin secretion-stimulating activity, and inhibition against the enzymes isocitrate lyase (ICL) and sortase A (SrtA). Several compounds displayed significant cytotoxicity and adiponectin secretion-stimulating activity. Structure-activity relationships were also deduced.

1. Total Synthesis of New Indole-lactams which have a Novel Pharmacophore of Pan-PPAR Modulators from the Psammocinia sp. Sponge
Three indole-bearing alkaloids, Psammocinins A-C (1-3), were isolated from a Korean specimen of Psammocinia sp. sponge. The structures of these compounds were the indole--lactams of a new structural class derived from three amino acid residues by combined spectroscopic and chemical analyses. To identify absolute configuration and molecular targets responsible for their adiponectin secretion-stimulating effects, compounds 1-3, a synthetic enantiomer psammocinin D (4), and their isopsammocinin N-lactam isomers (5-8) were synthesized. Compounds 1, 2, and 4 exhibited significant adiponectin secretion-stimulating activities during adipogenesis in human bone marrow mesenchymal stem cells.
2. Cytotoxic Cyclopeptides from the Sponge Stylissa flabelliformis
Thirteen cyclopeptides, including three new cyclopeptides (25-27) of the phakellistatin class, were isolated from the tropical sponge Stylissa flabelliformis. The new compounds were structurally elucidated to be an epimeric mixture of cycloheptapeptides (25) and two epimeric cyclodecapeptides (26 and 27) by a combination of chemical and spectroscopic methods. The cyclopeptides were evaluated for in vitro cytotoxicity against a variety of cancer cell lines, and several compounds exhibited significant inhibition. Structure-activiy relationship between phakellistatin class and cytotoxicity was revealed.

3. Cytotoxic Scalarane Sesterterpenes from the Sponge Hyrtios erectus
Twelve new sesterterpenes along with eight known sesterterpenes were isolated from the tropical sponge Hyrtios erectus. Based upon a combination of spectroscopic and computational analyses, these compounds were determined to be eight glycine-bearing scalaranes (38–45), a 3-keto scalarane (46), two oxidized furan-containing scalaranes (47 and 48), and a salmahyrtisane derivative (49). Several of these compounds exhibited weak antiproliferation against diverse cancer cell lines as well as moderate anti-angiogenesis activities. The antiproliferative activities were found to be associated with G0/G1 arrest in the cell cycle. This work demonstrates both the structural diversity of sponge-derived sesterterpenes and the prosperity of Hyrtios erectus as their source.

4. Anti-angiogenic Bromopyrrole Alkaloids from the Sponge Agelas kosrae
Two new sceptrin derivatives (58, 59) and eight structurally-related known bromopyrrolebearing alkaloids were isolated from the tropical sponge Agelas kosrae. By a combination of spectroscopic methods, the new compounds, designated dioxysceptrin (58) and ageleste C (59), were determined to be structural analogs of each other that differ at the imidazole moiety. Dioxysceptrin was also found to exist as a mixture of -amido epimers. The sceptrin alkaloids exhibited weak cytotoxicity against cancer cells. Compounds 58 and 59 also moderately exhibited anti-angiogenic and isocitrate lyase-inhibitory activities, respectively.
화학적 분석 방법과 생리활성 측정을 통하여 선별한 4 종의 해면동물(Psammocinia sp., Stylissa flabelliformis, Hyrtios erectus 그리고 Agelas kosrae)에서 추출한 유기물질들을 다양한 크로마토그래피 방법으로 분리 및 정제하여 46 개의 순수한 물질들을 얻었다.
각각의 분광학 자료에 의하여 20 종의 신규 물질들을 구조 결정하였으며 26 종의 기지 물질들을 동정하였다. 또한 3 종의 신규 물질과 5 종의 관련된 신규 유도체를 전합성하였다. 입체구조 결정을 위하여 분광학 자료분석, 유기 반응과 컴퓨터 모델링 등 다양한 방법을 시도하였다. 분리 또는 합성된 51개의 물질들은 다양한 계열의 화합물(8 종의 indole-lactam 계열의 indole alkaloids, 13 종의 phakellistatin 계열의 cyclopeptides, 20 종의 scalarane 계열의 sesterterpenoids, 그리고 10 종의 sceptrin 계열의 bromopyrrole alkaloids)인 것으로 밝혀졌다. 분리된 물질들은 아디포넥틴 분비 촉진 검사, 세포독성 검사, 항미생물 검사(그람양성박테리아, 그람음성 박테리아, 병원성 진균), 효소 저해 검사(isocitrate lyase, sortase A)등이 실시되었고, 몇몇의 물질들은 주목할만한 아디포넥틴 분비 촉진 활성과 세포독성이 있는 것으로 나타났다.
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College of Pharmacy (약학대학)Dept. of Pharmacy (약학과)Theses (Ph.D. / Sc.D._약학과)
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