16-nor Limonoids from Harrisonia perforata as promising selective 11β-HSD1 inhibitors

Yan, Xiaohui; Yi, Ping; Cao, Ping; Yang, Shumei; Fang, Xin; Wu, Bin; Liu, Ying; Di, Ying‐Tong; Lv, Yang; Hao, Xiao‐Jiang

doi:10.1038/srep36927

Cited by 17 publications

(8 citation statements)

References 26 publications

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“…Finally, taking advantage of the presence of the hydroxyl group at C-6, treatment of 29 with SOCl 2 /py produced an intermediary cyclic sulfate, which was then treated with 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) to give (+)-haperforin G ( 6 ) in a 50% overall yield. The structure of 6 was unequivocally confirmed by single-crystal X-ray analysis; the spectroscopic and optical rotation data for the synthetic 6 matched well with those reported for the natural product …”

supporting

confidence: 66%

“…A trace compound, (+)-haperforin G ( 6 ) (37 mg/25 kg), isolated from Harrisonia perforata, is a newly discovered member of a biologically important class of limonoid tetranortriterpenoid natural products (Figure ). Haperforin G has captured the attention of the biomedical community, because it is a potent inhibitor of human 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) (IC 50 0.58 μM).…”

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confidence: 99%

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Total Synthesis of (+)-Haperforin G

Zhang

Tang

et al. 2020

J. Am. Chem. Soc.

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A concise chemical synthesis of (+)-haperforin G in 20 steps from commercially available starting materials is achieved with the integration of the Co-catalyzed intramolecular Pauson−Khand reaction for the stereoselective construction of cyclopentanone bearing an all-carbon quaternary stereogenic center at the bridge-head position and the light-initiated photocatalysis for convergent and asymmetric cross-coupling of the unstabilized C(sp 3 )-radical with an enone. The developed chemistry paves the way to synthesizing structurally diverse analogs of haperforin G (6).

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supporting

confidence: 66%

mentioning

confidence: 99%

Total Synthesis of (+)-Haperforin G

Zhang

Tang

et al. 2020

J. Am. Chem. Soc.

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“…Alcohol 62 ■ TOTAL SYNTHESIS OF (+)-HAPERFORIN G (+)-Haperforin G (9, Figure 8), a flagship member of this biologically important class of limonoid tetranortriterpenoid natural product family, was isolated as a trace compound (37 mg/25 kg) from Harrisonia perforate. 44 Since its initial isolation in 2001, 9 has been demonstrated to inhibit human 11βhydroxysteroid dehydrogenase type 1 (11β-HSD1) (IC 50 0.58 μM), 45 suggesting its potential as an agent for treatment of Alzheimer's disease, vascular inflammation, cardiovascular disease, and glaucoma. 46 Structurally, 9 is characterized by a novel limonoid 6/5/6 tricyclic carbon framework featuring six stereogenic centers, two of which are all-carbon quaternary stereogenic centers, and two lactones and a 3-substituted furan ring.…”

Section: ■ Total Synthesis Of Crinipellin Amentioning

confidence: 99%

Navigating the Pauson–Khand Reaction in Total Syntheses of Complex Natural Products

Yang

2021

Acc. Chem. Res.

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Conspectus “Total synthesis endeavors provide wonderful opportunities to discover and invent new synthetic reactions as a means to advance organic synthesis in general. Such discoveries and inventions can occur when the practitioner faces intransigent problems that cannot be solved by known methods and/or when method improvements are desired in terms of elegance, efficiency, cost-effectiveness, practicality, or environmental friendliness” (K. C. Nicolaou et al. from their review in CCS Chem.20191337). To date tens of thousands of bioactive compounds have been isolated from plants, microbes, marine invertebrates, and other sources. These chemical structures have been studied by chemists who scanned the breadth of natural diversity toward drug discovery efforts. Drug-likeness of natural products often possesses common features including molecular complexity, protein-binding ability, structural rigidity, and three-dimensionality. Considering certain biologically important natural products are scarce from natural supply, total synthesis may provide an alternative solution to generating these compounds and their derivatives for the purpose of probing their biological functions. Natural products bearing quaternary carbon stereocenters represent a group of biologically important natural entities that are lead compounds in the development of pharmacological agents and biological probes. However, the stereocontrolled introduction of quaternary carbons, with vicinal patterns that substantially expand the complexity of molecular architectures and chemical space in particular, presents distinct challenges because of the high steric repulsion between substituents. Though remarkable advance has been seen for quaternary carbon stereocenter generation, the process remains a daunting challenge given that the formation of highly congested stereocenters increases the difficulty in achieving orbital overlap. In the past two decades, our group has initiated a program to develop synthetic strategies and methods with the aim of advancing the frontiers of the total syntheses of biologically important complex natural products bearing all-carbon quaternary stereogenic centers. Typical endeavors have involved the use of a Pauson–Khand (PK) reaction as a key step in constructing core structures with all-carbon quaternary stereogenic center(s), with the aid of well-orchestrated thiourea–Co- and thiourea–Pd-catalyzed PK reactions. These methodological advances have enabled us to achieve total syntheses of a series of topologically complex natural products with diverse structural features. These methods will enable the assembly of molecules with improved biological functions and provide tool compounds for elucidation of mechanism of action or identification of potential cellular targets.

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“…(+)-Haperforin G ( 6 ), which is a trace compound (37 mg/25 kg) isolated from Harrisonia perforata, is a newly discovered member of a biologically important class of limonoid tetranortriterpenoid natural products (Figure ). Haperforin G has captured the attention of the biomedical community because it is a potent inhibitor of human 11β-hydroxysteroid dehydrogenase type 1 (half-maximal inhibitory concentration: 0.58 μM).…”

Section: Introductionmentioning

confidence: 99%

Total Synthesis of (+)–Haperforin G

Zhang

Tang

et al. 2023

J. Org. Chem.

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Haperforin G was synthesized in 20 steps from commercially available starting materials. A Co-catalyzed intramolecular Pauson−Khand reaction was used for stereoselective construction of cyclopentanone bearing an all-carbon quaternary stereogenic center at the bridge-head position. Lightinitiated photocatalysis was used for convergent and asymmetric cross-coupling of the unstabilized C(sp 3 ) radical with an enone. The developed chemistry paves the way to the synthesis of structurally diverse analogs of haperforin G (6).

show abstract

16-nor Limonoids from Harrisonia perforata as promising selective 11β-HSD1 inhibitors

Cited by 17 publications

References 26 publications

Total Synthesis of (+)-Haperforin G

Total Synthesis of (+)-Haperforin G

Navigating the Pauson–Khand Reaction in Total Syntheses of Complex Natural Products

Total Synthesis of (+)–Haperforin G

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