Formal Synthesis of (+)-Madindoline A a Potent IL-6 Inhibitor Utilizing Enzymatic Discrimination of Quaternary Carbon

Shimizu, K.; Tomita, Mina; Fuhshuku, Ken‐ichi; Sugai, Takeshi; Shoji, Mitsuru

doi:10.1177/1934578x1300800710

Cited by 5 publications

(7 citation statements)

References 23 publications

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“…Shimizu et al 37 successfully executed a formal synthesis of madindolines, commencing with acetoxycyclopentenone 85, achieved through inversion of the secondary alcohol, introduction of a carbon-carbon double bond, and a regioselective oxidative cleavage of the terminal vinyl group (Scheme 11). 37 In the outlined process, previously reported acetoxycyclopentenone 85 underwent acid-catalyzed hydrolysis to furnish alcohol 86. A Mitsunobu S C H E M E 9 Total synthesis of (+)-madindolines A (1) and B (2) by Wan et al 35 reaction, followed by methanolysis under basic conditions, provided the volatile secondary alcohol possessing the requisite stereochemistry at the C-3 carbon.…”

Section: Formal Synthesis By Shimizu Et Al (2013)mentioning

confidence: 99%

“…Shimizu et al 37 successfully executed a formal synthesis of madindolines, commencing with acetoxycyclopentenone 85 , achieved through inversion of the secondary alcohol, introduction of a carbon‐carbon double bond, and a regioselective oxidative cleavage of the terminal vinyl group (Scheme 11). 37 In the outlined process, previously reported acetoxycyclopentenone 85 underwent acid‐catalyzed hydrolysis to furnish alcohol 86 . A Mitsunobu reaction, followed by methanolysis under basic conditions, provided the volatile secondary alcohol possessing the requisite stereochemistry at the C‐3 carbon.…”

Section: Madindolinesmentioning

confidence: 99%

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Natural products as IL‐6 inhibitors for inflammatory diseases: Synthetic and SAR perspective

Harmalkar,

Sivaraman,

Nada

et al. 2024

Medicinal Research Reviews

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Interleukin‐6 (IL‐6), a pleiotropic cytokine, plays a pivotal role in the pathophysiology of various diseases including diabetes, atherosclerosis, Alzheimer's disease, multiple myeloma, rheumatoid arthritis, and prostate cancer. The signaling pathways associated with IL‐6 offer promising targets for therapeutic interventions in inflammatory diseases and IL‐6‐dependent tumors. Although certain anti‐IL‐6 monoclonal antibodies are currently employed clinically, their usage is hampered by drawbacks such as high cost and potential immunogenicity, limiting their application. Thus, the imperative arises to develop novel small non‐peptide molecules acting as IL‐6 inhibitors. Various natural products derived from diverse sources have been investigated for their potential to inhibit IL‐6 activity. Nevertheless, these natural products remain inadequately explored in terms of their structure‐activity relationships. In response, our review aims to provide syntheses and structure activity perspective of natural IL‐6 inhibitors. The comprehensive amalgamation of information presented in this review holds the potential to serve as a foundation for forthcoming research endeavors by medicinal chemists, facilitating the design of innovative IL‐6 inhibitors to address the complexities of inflammatory diseases.

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Section: Formal Synthesis By Shimizu Et Al (2013)mentioning

confidence: 99%

“…Shimizu et al 37 successfully executed a formal synthesis of madindolines, commencing with acetoxycyclopentenone 85 , achieved through inversion of the secondary alcohol, introduction of a carbon‐carbon double bond, and a regioselective oxidative cleavage of the terminal vinyl group (Scheme 11). 37 In the outlined process, previously reported acetoxycyclopentenone 85 underwent acid‐catalyzed hydrolysis to furnish alcohol 86 . A Mitsunobu reaction, followed by methanolysis under basic conditions, provided the volatile secondary alcohol possessing the requisite stereochemistry at the C‐3 carbon.…”

Section: Madindolinesmentioning

confidence: 99%

Natural products as IL‐6 inhibitors for inflammatory diseases: Synthetic and SAR perspective

Harmalkar,

Sivaraman,

Nada

et al. 2024

Medicinal Research Reviews

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“…Owing to the importance of (2S, 3S)−2,2-disubstituted-3-hydroxyketones, which could be used for the preparation of many natural products, such as cortistatin A, clavulactone, madindoline A, digitoxigenin and hygrophorone (Supplementary Fig. 8) [36][37][38][39][40][41] , enzyme kinetic parameters of CbAR towards 1e were then analyzed. It showed that its K m and k cat values were 5.13 ± 0.33 mM and 0.58 ± 0.01 min −1 (Supplementary Table 4), respectively, suggesting that the catalytic activity of CbAR towards 1e is much lower than that towards to 1a (Supplementary Fig.…”

Section: Molecular Insights Of Emodin Recognition and Binding Of Cbarmentioning

confidence: 99%

Structural analysis of an anthrol reductase inspires enantioselective synthesis of enantiopure hydroxycycloketones and β-halohydrins

Hou

Yuan

et al. 2023

Nat Commun

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Asymmetric reduction of prochiral ketones, particularly, reductive desymmetrization of 2,2-disubstituted prochiral 1,3-cyclodiketones to produce enantiopure chiral alcohols is challenging. Herein, an anthrol reductase CbAR with the ability to accommodate diverse bulky substrates, like emodin, for asymmetric reduction is identified. We firstly solve crystal structures of CbAR and CbAR-Emodin complex. It reveals that Tyr210 is critical for emodin recognition and binding, as it forms a hydrogen-bond interaction with His162 and π-π stacking interactions with emodin. This ensures the correct orientation for the stereoselectivity. Then, through structure-guided engineering, variant CbAR-H162F can convert various 2,2-disubstituted 1,3-cyclodiketones and α-haloacetophenones to optically pure (2S, 3S)-ketols and (R)-β-halohydrins, respectively. More importantly, their stereoselectivity mechanisms are also well explained by the respective crystal structures of CbAR-H162F-substrate complex. Therefore, this study demonstrates that an in-depth understanding of catalytic mechanism is valuable for exploiting the promiscuity of anthrol reductases to prepare diverse enantiopure chiral alcohols.

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“…2,2-Disubstituted-3-hydroxycyclopentanones with two chiral centers are important chiral intermediates for the synthesis of natural products and drugs, − such as bicyclo[9.3.0]tetradecenone, (+)-digitoxigenin, (+)-madindoline A, (+)-estrone, and cortistatins (Figure A). (2 R ,3 R )-Ketol is the key chiral intermediate for the synthesis of (+)-estrone and cortistatins.…”

Section: Introductionmentioning

confidence: 99%

Semirational Engineering of a Thermostable Carbonyl Reductase for the Precision Synthesis of (2R,3R)-2-Methyl-2-benzyl-3-hydroxycyclopentanone and Its Analogues

Zhu,

Chen,

Feng

et al. 2023

J. Org. Chem.

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2,2-Disubstituted-3-hydroxycyclopentanones are important chiral intermediates for natural products and pharmaceuticals. Through semirational engineering of a thermostable carbonyl reductase CBCR from Cupriavidus sp. BIS7, a mutant L91C/F93I was obtained. Mutant L91C/F93I showed 4- to 36-fold enhanced activities toward 2-methyl-2-benzyl-1,3-cyclopentanedione and its analogues, affording the (2R,3R)-stereoisomers with >99% ee and >99% de. Enzyme–substrate docking studies were performed to reveal the molecular basis for the activity and stereoselectivity improvements.

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Formal Synthesis of (+)-Madindoline A a Potent IL-6 Inhibitor Utilizing Enzymatic Discrimination of Quaternary Carbon

Cited by 5 publications

References 23 publications

Natural products as IL‐6 inhibitors for inflammatory diseases: Synthetic and SAR perspective

Natural products as IL‐6 inhibitors for inflammatory diseases: Synthetic and SAR perspective

Structural analysis of an anthrol reductase inspires enantioselective synthesis of enantiopure hydroxycycloketones and β-halohydrins

Semirational Engineering of a Thermostable Carbonyl Reductase for the Precision Synthesis of (2R,3R)-2-Methyl-2-benzyl-3-hydroxycyclopentanone and Its Analogues

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