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Oleanane triterpenes from Camellia japonica inhibit growth of breast cancer cell lines via PTP1B inhibition

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Author(s)
우딘모함마드나시르
Issued Date
2013
Abstract
유방암의 심각한 사망률은 화학요법, 방사선요법, 수술을 포함한 현재의 치료방법에 의하여 어느정도 치료되고 있다. 그러므로 새로운 치료방법의 개발은 이러한 심각한 유방암의 치료법에 있어서 중요한 것이다. PTP1B와 유방암 질환의 발병에 관한 최근 연구는 선택적인 PTP1B 저해가 유방암 치료에 중요한 역할을 할수 있다고 제안되고 있다. 흥미롭게도, 강력한 PTP1B 저해제로서 인식되어온 식물기원의 triterpenes 역시 유방암에 대한 치료효과가 있음을 보여주었다. 그러므로 계속적인 triterpenes에 대한 연구로서 8개의 이미 알려진 oleanane-type triterpenes (7-14)과 함께 6개의 새로운 oleanane-type triterpenes (1-6)계 화합물을 동백나무의 열매껍질 (Camellia japonica L.,Theaceae)의 EtOAc분획물로 부터 분리하였다. 모든 얻어진 신규 화합물의 화학구조는 물리화학적 방법과 스펙트럼 분석법 (IR, 1D, 2D-NMR, and MS)를 통하여 3,16-dioxo-olean-12(13),17(18)-diene (1), 3β,16α,17–trihydroxy-olean-12-ene (2), 4,28,29-trihydroxy-16-oxo-3,4-seco-olean-12-ene-3-oic acid methyl ester (Camelliaolean A) (3), 4,7β,17-trihydroxy-16-oxo-3,4-seco-olean-12-ene-3-oic acid methyl ester (Camelliaolean B) (4), 7β,17,29-trihydroxy-16-oxo-3,4-seco-olean-4(23),12(13)-diene-3-oic acid methyl ester (Camelliaolean C) (5), and 17,29-dihydroxy-16-oxo-3,4-seco-olean-4(23),12(13)-diene-3-oic acid (Camelliaolean D) (6) 으로 확인하였다. 분리한 화합물 모두에 대하여 MCF7, MCF7/ADR, MDA-MB-231 유방암 세포주에 대한 활성과 in vitro PTP1B효소에 대한 효과가 평가되었다. C-3 hydroxy group이나 C-28 carboxy group을 가진 화합물인 화합물 2, 8, 10, 11, 그리고 13은 좋은 세포독성 (IC50 수치는 0.51 ± 0.05에서부터 9.32 ± 0.62 µM까지 이른다) 보여주었을 뿐만 아니라 강력한 PTP1B 저해활성 (IC50 수치는 3.77 ± 0.11 에서 6.40 ± 0.81 μM에 이른다)을 보여주었다. 그러나, C-3위치에 ketone기가 결합된 화합물인 화합물 1과 5는 MCF7, MCF7/ADR, MDA-MB-231 유방암 세포주에 대한 성장 억제효과와 in vitro PTP1B효소에 대한 저해 효과가 감소하였다. 이러한 결과들은 C. japonica로부터 분리된 oleanane triterpenes화합물들이 PTP1B 저해제로서 유방암 세포주에 대한 세포독성을 갖는 새로운 화합물로서 가능성을 갖음을 제시한다.|The significant morbidity of advanced breast cancer has been only somewhat impacted by current treatment modalities including chemotherapy, radiotherapy and surgery. Therefore, development of novel therapeutic approaches would be of interest in combating this disease. Recent studies on PTP1B and breast tumorigenesis suggest that selective PTP1B inhibition might play an important role in breast cancer treatment. Interestingly, plant triterpenes, which have already been appreciated as strong PTP1B inhibitors, also showed therapeutic potential in breast cancer. Therefore, as part of research on triterpenes, six new (1-6) along with eight known (7-14) oleanane-type triterpenes were isolated from the EtOAc extract of the fruit peels of Camellia japonica L. (Theaceae). The chemical structures of new compounds were elucidated by physicochemical and spectroscopic (IR, 1D, 2D-NMR, and MS) data analysis as 3,16-dioxo-olean-12(13),17(18)-diene (1), 3β,16α,17-trihydroxy-olean-12-ene (2), 4,28,29-trihydroxy-16-oxo-3,4-seco-olean-12-ene-3-oic acid methyl ester (Camelliaolean A) (3), 4,7β,17-trihydroxy-16-oxo-3,4-seco-olean-12-ene-3-oic acid methyl ester (Camelliaolean B) (4), 7β,17,29-trihydroxy-16-oxo-3,4-seco-olean-4(23),12(13)-diene-3-oic acid methyl ester (Camelliaolean C) (5), and 17,29-dihydroxy-16-oxo-3,4-seco-olean-4(23),12(13)-diene-3-oic acid (Camelliaolean D) (6). All the isolates were evaluated for their inhibitory effects on PTP1B enzyme, as well as their growth inhibition on MCF7, adriamycin-resistant MCF7 (MCF7/ADR) and MDA-MB-231 breast cancer cell lines. Compounds 2, 8, 10, 11, and 13 with C-3 hydroxy group or/and C-28 carboxy group showed strong PTP1B inhibitory activity (IC50 values ranging from 3.77 ± 0.11 to 6.40 ± 0.81 µM) as well as significant cytotoxicity (IC50 values ranging from 0.51 ± 0.05 to 9.32 ± 0.62 µM) while attachment of ketone group at C-3 position reduced both type effects in 1, and 5. These results suggested that, oleanane triterpenes from C. japonica as PTP1B inhibitors could be considered as new anticancer materials for breast cancer treatment.
Alternative Title
동백나무로부터 분리한 올레안계 화합물의 PTP1B 효소 저해를 경유한 유방암 세포주 저해활성 연구
Alternative Author(s)
Uddin Mohammad Nasir
Affiliation
조선대학교 대학원
Department
일반대학원 약학과
Advisor
Prof. Choi Hong Seok, Ph.D.
Awarded Date
2013-08
Table Of Contents
Contents ………………………………………………………………………………..i
List of Schemes ………………………………………………………………………..iii
List of Tables …………………………………………………………………………..iv
List of Figures …………………………………………………………………………v
List of Abbreviations ………………………………………………………………….viii
Abstract ………………………………………………………………………………..x
Korean ………………………………………………………………………………….x
English ………………………………………………………………………………….xii
1. Introduction ………………………………………………………………………1
1.1. Breast cancer ………………………………………………………………..1
1.2. PTP1B ………………………………………………………………………3
1.3. PTP1B role in breast cancer ………………………………6
1.4. Plant triterpenoids ………………………………………………………7
1.5. Triterpenoids and breast cancer ………………………8
1.6. Camellia japonica L. (Theaceae) …………………………11
2. Materials and Methods …………………………………………………………13
2.1. Materials ………………………………………………………………….13
2.1.1. Plant material ………………………………………………………13
2.1.2. Chemicals, reagents and chromatography ……………13
2.1.3. General experimental procedures …………………………………14
2.2. Methods …………………………………………………………………….14
2.2.1. Extraction and isolation ………………………………14
2.2.2. PTP1B inhibition assay …………………………………………20
2.2.3. Kinetic parameters for PTP1B inhibition type ……20
2.2.4. Cell culture ……………………………………………………….20
2.2.5. MTT cytotoxicity assay ……………………………………21
2.2.6. Statistical analysis ………………………………………………21
3. Results and Discussions ……………………………………………22
3.1. Structural determination of new compounds 1-6 …22
3.1.1. Structural determination of compound 1 …………22
3.1.2. Structural determination of compound 2 ……………28
3.1.3. Structural determination of compound 3 ……………34
3.1.4. Structural determination of compound 4 ………………40
3.1.5. Structural determination of compound 5 ………………46
3.1.6. Structural determination of compound 6 ………………52
3.2. PTP1B inhibitory effects of isolated compounds 1-14 ………57
3.3. PTP1B inhibition mode for isolated compounds-Lineweaver-Burk and Dixon plots ……………………………………………………60
3.4. Growth inhibitory effects of isolated compounds (1-14) against breast cancer cell lines ……………………………………62
3.5. Structure activity relationships …………………………………65
4. Conclusions ……………………………………………………………………….66
5. References …………………………………………………………………………67
6. Acknowledgements ………………………………………………………………79
Degree
Master
Publisher
조선대학교 대학원
Citation
우딘모함마드나시르. (2013). Oleanane triterpenes from Camellia japonica inhibit growth of breast cancer cell lines via PTP1B inhibition.
Type
Dissertation
URI
https://oak.chosun.ac.kr/handle/2020.oak/9871
http://chosun.dcollection.net/common/orgView/200000263921
Appears in Collections:
General Graduate School > 3. Theses(Master)
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