6040-37-5Relevant academic research and scientific papers
Total synthesis of (+)-pleuromutilin
Fazakerley, Neal J.,Helm, Matthew D.,Procter, David J.
, p. 6718 - 6723 (2013)
The first enantiospecific total synthesis of the antibacterial natural product (+)-pleuromutilin has been achieved. The approach includes the synthesis of a non-racemic cyclisation substrate from (+)-trans-dihydrocarvone, a highly selective SmI2-mediated cyclisation cascade, an electron transfer reduction of a hindered ester, and the first efficient conversion of (+)-mutilin to the target. Copyright
Synthesis of bridged oxafenestranes from pleuromutilin
Hicklin, Robert W.,Lopez Silva, Tania L.,Hergenrother, Paul J.
, p. 9880 - 9883,4 (2014)
Fenestranes are an intriguing class of highly strained molecules possessing a quaternary carbon with bonds that deviate from the canonical tetrahedral geometry. Herein we report the discovery that the natural product pleuromutilin can be used as a structurally complex starting material for the synthesis of a series of bridged cis,cis,cis,cis-[4.5.5.5]- and cis,cis,cis,cis-[4.5.7.5] oxafenestranes through a carbocation rearrangement cascade. X-ray crystallographic analysis of several cis,cis,cis,cis-[4.5.5.5]oxafenestranes shows a significant planarization of the central tetracoordinate carbon atom and demonstrates the influence of bridgehead substituents and bridging rings on planarity.
Directed C-H Bond Oxidation of (+)-Pleuromutilin
Ma, Xiaoshen,Kucera, Roman,Goethe, Olivia F.,Murphy, Stephen K.,Herzon, Seth B.
, p. 6843 - 6892 (2018)
Antibiotics derived from the diterpene fungal metabolite (+)-pleuromutilin (1) are useful agents for the treatment Gram-positive infections in humans and farm animals. Pleuromutilins elicit slow rates of resistance development and minimal cross-resistance with existing antibiotics. Despite efforts aimed at producing new derivatives by semisynthesis, modification of the tricyclic core is underexplored, in part due to a limited number of functional group handles. Herein, we report methods to selectively functionalize the methyl groups of (+)-pleuromutilin (1) by hydroxyl-directed iridium-catalyzed C-H silylation, followed by Tamao-Fleming oxidation. These reactions provided access to C16, C17, and C18 monooxidized products, as well as C15/C16 and C17/C18 dioxidized products. Four new functionalized derivatives were prepared from the protected C17 oxidation product. C6 carboxylic acid, aldehyde, and normethyl derivatives were prepared from the C16 oxidation product. Many of these sequences were executed on gram scales. The efficiency and practicality of these routes provides an easy method to rapidly interrogate structure-activity relationships that were previously beyond reach. This study will inform the design of fully synthetic approaches to novel pleuromutilins and underscores the power of the hydroxyl-directed iridium-catalyzed C-H silylation reaction.
Diverse compounds from pleuromutilin lead to a thioredoxin inhibitor and inducer of ferroptosis
Llabani, Evijola,Hicklin, Robert W.,Lee, Hyang Yeon,Motika, Stephen E.,Crawford, Lisa A.,Weerapana, Eranthie,Hergenrother, Paul J.
, p. 521 - 532 (2019)
The chemical diversification of natural products provides a robust and general method for the creation of stereochemically rich and structurally diverse small molecules. The resulting compounds have physicochemical traits different from those in most screening collections, and as such are an excellent source for biological discovery. Herein, we subject the diterpene natural product pleuromutilin to reaction sequences focused on creating ring system diversity in few synthetic steps. This effort resulted in a collection of compounds with previously unreported ring systems, providing a novel set of structurally diverse and highly complex compounds suitable for screening in a variety of different settings. Biological evaluation identified the novel compound ferroptocide, a small molecule that rapidly and robustly induces ferroptotic death of cancer cells. Target identification efforts and CRISPR knockout studies reveal that ferroptocide is an inhibitor of thioredoxin, a key component of the antioxidant system in the cell. Ferroptocide positively modulates the immune system in a murine model of breast cancer and will be a useful tool to study the utility of pro-ferroptotic agents for treatment of cancer.
A Novel Anticancer Stem Cell Compound Derived from Pleuromutilin Induced Necroptosis of Melanoma Cells
Gao, Ruolin,Li, Ning,Li, Xuechun,Ma, Lan,Mu, Linrong,Song, Wei,Sun, Yue,Tang, Zhiwen,Wang, Ning,Wang, Ruonan,Wei, Mingming,Yang, Cheng,Yang, Guang,Yu, Xuan,Zhang, Kun,Zhang, Yan,Zheng, Nan
, p. 15825 - 15845 (2021/11/16)
Necroptosis has been recently confirmed as a non-apoptotic form of programmed cell death. Discovery of novel chemical entities, capable of inducing necroptosis of cancer cells, is likely to act as an alternative strategy for dealing with drug resistance clinically. In this study, the identification of a novel Pleuromutilin derivative (compound 38) is presented, capable of significantly increasing the cellular level of ROS and inducing melanoma cancer cell death via necroptosis. Furthermore, compound 38 noticeably ablated various cancer stem cells and inhibited the growth of melanoma cancer cells both in vitro and in vivo. Moreover, 38 exhibited low toxicity in animal models and excellent PK properties, which is currently being verified as a potential anticancer drug candidate.
Diterpene derivative as well as preparation method, pharmaceutical composition and application thereof
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Paragraph 0039-0043, (2021/09/21)
The invention discloses a diterpene derivative as well as a preparation method, a pharmaceutical composition and application thereof, and the structure of the diterpene derivative is as shown in formula I, wherein R1 is oxygen, hydroxyl or ester group; R2 is oxygen, hydroxyl or ester group; and R3 is ethyl or vinyl. The novel diterpene derivative is obtained by means of semi-synthesis modification, the preparation process is simple and easy to implement, and pharmacological experiments find that the diterpene derivative provided by the invention shows strong activity of inhibiting proliferation of various tumor cells, has obvious in-vitro and in-vivo anticancer activity, generally does not have antibiotic activity, and is suitable for development of anti-tumor drugs.
COMPOUNDS THAT INDUCE FERROPTIC CELL DEATH
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Page/Page column 50; 56; 67, (2020/10/21)
The diterpene natural product pleuromutilin was subjected to reaction sequences focused on creating ring system diversity in few synthetic steps. This effort resulted in a collection of compounds with previously unreported ring systems, providing a novel
NOVEL FULLY SYNTHETIC AND SEMISYNTHETIC PLEUROMUTILIN DERIVATIVES AS NEW ANTIBIOTICS AND THEIR PREPARATION
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Page/Page column 44; 115-116, (2019/10/19)
The present invention is directed to novel pleuromutllin antibiotic compounds, intermediates which are useful for making these novel antibiotic compounds, methods of synthesizing these compounds and related methods and pharmaceutical compositions for treating pathogens? especially bacterial infections, including gram negative bacteria.
BORON-CONTAINING SMALL MOLECULES
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Paragraph 0376, (2017/09/19)
Compounds, pharmaceutical formulations, and methods of treating bacterial infections are disclosed.
A scalable synthesis of 2S-hydroxymutilin via a modified rubottom oxidation
Wang, Huan,Andemichael, Yemane W.,Vogt, Frederick G.
experimental part, p. 478 - 481 (2009/04/10)
(Chemical Equation Presented) A scalable synthesis of 2S-hydroxymutilin from pleuromutilin was developed. The synthesis is highlighted by the Rubottom oxidation of a silyl enol ether, conducted in the presence of acetic acid and pyridine, which allows for
