Biomimetic Semisynthesis of Arglabin from Parthenolide

Zhai, Jiadai; Li, Dongmei; Long, Jing; Zhang, Haoliang; Lin, Jianping; Qiu, Chengjun; Zhang, Quan; Chen, Yue

doi:10.1021/jo300888s

Cited by 65 publications

(63 citation statements)

References 41 publications

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“…20 MCL is a guaianolide sesquiterpene lactone isolated from Michelia compressa and Michelia champaca and can also be in vitro synthesized from PTL. 24 The Michael adduct of MCL, dimethylaminomicheliolide (DMAMCL), exhibits remarkable therapeutic efficacy in murine models of acute myelogenous leukemia. 20 In plasma, DMAMCL and DMAPT are transformed into MCL and PTL, respectively, but DMAPT is rapidly converted to PTL, whereas DMAMCL releases MCL slowly but continuously.…”

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confidence: 99%

Micheliolide, a new sesquiterpene lactone that inhibits intestinal inflammation and colitis-associated cancer

Viennois

Xiao

Ayyadurai

et al. 2014

Laboratory Investigation

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Inflammatory bowel diseases (IBD) are chronic inflammatory conditions of the gastrointestinal (GI) tract associated with an increased risk of colorectal cancer (CRC). Current treatments for both IBD and colitis-associated CRC suffer from numerous side effects. Parthenolide (PTL) is a sesquiterpene lactone with anti-inflammatory activity, and previous studies have demonstrated that PTL is a potent inhibitor of the NF-kB pathway. Micheliolide (MCL), substantially more stable than PTL in vivo, was recently developed, and this study aimed to decipher its suitability as therapeutic tool for IBD and IBDassociated diseases. Similar to PTL, MCL inhibited NF-kB activation and subsequent pro-inflammatory pathways activation in vitro. Pro-drug forms of both compounds inhibited the DSS-induced colitis when administrated intraperitoneally or encapsulated in a polysaccharide gel designed to release drugs in the colon. Interestingly, MCL was found to attenuate carcinogenesis in AOM/DSS-induced CRC, thus providing new candidate for the treatment of inflammatory bowel disease and CRC.Laboratory Investigation (2014) 94, 950-965;

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confidence: 99%

Micheliolide, a new sesquiterpene lactone that inhibits intestinal inflammation and colitis-associated cancer

Viennois

Xiao

Ayyadurai

et al. 2014

Laboratory Investigation

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“…p-toluenesulfonic acid (pTSA) in dichloromethane. 2 With the synthesized fluorinated-PTL analogs (27,28,30, and 32) in hand, we checked their chemical stability compared with 2. The synthesized fluorinated-PTL analogs (27,28,30, and 32) stayed nearly intact over 48 h under the same condition.…”

Section: Chemical Stabilitymentioning

confidence: 99%

Syntheses and Biological Evaluation of Costunolide, Parthenolide, and Their Fluorinated Analogues

Yang

et al. 2015

J. Med. Chem.

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Inspired by the biosynthesis of sesquiterpene lactones (SLs), herein we report the asymmetric total synthesis of the germacrane ring (24). The synthetic strategy features a selective aldol reaction between β,γ-unsaturated chiral sulfonylamide 15a and aldehyde 13, as well as the intramolecular α-alkylation of sulfone 21 to construct a 10-membered carbocylic ring. The key intermediate 24 can be used to prepare the natural products costunolide and parthenolide (PTL), which are the key precursors for transformation into other SLs. Furthermore, the described synthetic sequences are amenable to the total synthesis of SL analogues, such as trifluoromethylated analogues 32 and 45. Analogues 32 and 45 maintained high activities against a series of cancer cell lines compared to their parent PTL and costunolide, respectively. In addition, 32 showed enhanced tolerance to acidic media compared with PTL. To our surprise, PTL and 32 showed comparable half-lives in rat plasma and in the presence of human liver microsomes.

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“…An effective approach to treat such hormone-dependent cancer involves interfering with hormone production. Aromatase, or estrogen synthase, has always been considered the most promising target for the endocrine treatment of breast cancer [3]. Among all inhibitors, nonsteroidal inhibitors have proved to be the best therapeutic agents, as they reversibly inhibit the enzyme [2,4].…”

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confidence: 99%

“…Taking a cue from this literature, we previously synthesized the 1, 2, 3 triazole-based analogs [7] of this molecule to develop more potent and less toxic compounds, and screened them against breast cancer cells. Among all of the synthesized compounds, only one compound, namely, (11R)-13-[1-(3,4-dimethylphenyl) [1][2][3] triazol-4-ylmethylamine]-11R,13-dihydroludartin, displayed a potent effect with an IC 50 of 8.5 µM and the parent ludartin molecule displayed an IC 50 of 0.5 µM. Based on the close resemblance of ludartin (3) to arglabin (5) (position isomers), we also synthesized the amino analogs of ludartin [8], wherein compound 9 displayed a selective and potent biological effect, and, finally, we also developed a route for the hemisynthesis of arglabin from ludartin [9].…”

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confidence: 99%

Diastereoselective Synthesis of 1,10β-Epoxy-11R,13-dihydroamino Analogs of Ludartin as Anti-breast Cancer Agents

Lone

Bhat

Malik

et al. 2016

PMIO

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Abstract! Diverse 11R,13-dihydroamino and 1,10β-epoxy-11R,13-dihydroamino analogs of ludartin were synthesized using a highly diastereoselective Michael addition and epoxidation reaction. The semisynthetic analogs were characterized using rigorous spectral data analysis. All the compounds were subjected to sulphorhodamine B cytotoxicity screening against a panel of three breast cancer cells, viz., T47D, MCF-7, and MDA-MB 231. Among the synthesized analogs, compounds 11, 19, and 20 proved to be active against the breast cancer cell lines. Compound 11 represents an epoxy analog of arglabin (5), which is a noteworthy and clinically significant antitumor agent and exhibited an IC 50 s of 0.75 µM and 1.20 µM against MCF-7 and MDA MB-231 cell lines, respectively. Compounds 19 and 20 displayed selectivity among the three breast cancer cell lines and were active against MCF-7 cell lines only displaying IC 50 s of 1.00 and 1.21 µM, respectively. This study provides initial structure-activity relationship data on ludartin and its analogs against breast cancer cell lines based on the previous literature reports of ludartin as an aromatase inhibitor.Key words ludartin · amino analogs · epoxy amino analogs · breast cancer · cytotoxicity Supporting information available online at http://www.thieme-connect.de/products Leaving apart the cancers of skin, breast cancer is the most frequently occurring cancer in women [1]. It ranks second as a cause of tumor-related death only after lung cancer. Presently, it is envisaged that one in eight American women will develop breast cancer sometime during her life. Two-thirds of breast cancer tumors are hormone dependent, requiring estrogen to flourish [2]. An effective approach to treat such hormone-dependent cancer involves interfering with hormone production. Aromatase, or estrogen synthase, has always been considered the most promising target for the endocrine treatment of breast cancer [3]. Among all inhibitors, nonsteroidal inhibitors have proved to be the best therapeutic agents, as they reversibly inhibit the enzyme [2,4]. Aromatase inhibitors (AIs) are further divided into categories based on the order in which they were discovered or synthesized: first-, second-, and third-generation AIs. Currently, the third generation aromatase inhibitors are triazole-derived AIs and are approved as front-line therapy for early and advanced cases of breast cancer in postmenopausal women [1,5,6]. Brueggemeier and Cruz [1] framed a list of 65 molecules with potent aromatase inhibitory activity, among which the four sesquiterpene lactones, designated 1, 2, 3, and 4 (l " Fig. 1), display strong aromatase inhibition. The research group opined that the triazole-based compounds display a potent inhibitory effect. Taking a cue from this literature, we previously synthesized the 1, 2, 3 triazole-based analogs [7] of this molecule to develop more potent and less toxic compounds, and screened them against breast cancer cells. Among all of the synthesized compounds, only one compound, namely, (11R)-13-[1-(...

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Biomimetic Semisynthesis of Arglabin from Parthenolide

Cited by 65 publications

References 41 publications

Micheliolide, a new sesquiterpene lactone that inhibits intestinal inflammation and colitis-associated cancer

Micheliolide, a new sesquiterpene lactone that inhibits intestinal inflammation and colitis-associated cancer

Syntheses and Biological Evaluation of Costunolide, Parthenolide, and Their Fluorinated Analogues

Diastereoselective Synthesis of 1,10β-Epoxy-11R,13-dihydroamino Analogs of Ludartin as Anti-breast Cancer Agents

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