Pornphimol Meesakul, Wuttichai Jaidee, Christopher Richardson, Raymond J. Andersen, Brian O.Patrick, Anthony C.Willis, Chatchai Muanprasat, Jin Wang, Xiaoguang Lei, Sarinya Hadsadee, Siriporn Jungsuttiwong, Stephen G.Pyne, Surat Laphookhieo
Phytochemistry, 2020, 171, 112248 https://doi.org/10.1016/j.phytochem.2019.112248
The phytochemical investigation of the twig and leaf extracts of Goniothalamus tamirensis led to the isolation and identification of 15 compounds including three rare previously undescribed styryllactones, goniotamirenones A-C, together with 12 known compounds. (Z)-6-Styryl-5,6-dihydro-2-pyranone and 5-(1-hydroxy-3-phenyl-allyl)-dihydro-furan-2-one are reported here for the first time as previously undescribed natural products. Their structures were elucidated by spectroscopic methods. Goniotamirenone A was synthesized via a [2 + 2] cycloaddition reaction of 6-styrrylpyran-2-one in quantitative yield. The absolute configurations of goniotamirenones B and C were identified from experimental and calculated ECD data, while the absolute configurations of (−)–5-acetoxygoniothalamin, (−)-isoaltholactone, parvistone E, and 5-(1-hydroxy-3-phenyl-allyl)-dihydro-furan-2-one were identified by single-crystal X-ray diffraction analysis using Cu Kα radiation. The absolute configurations of the other related compounds were determined from comparisons of their ECD spectra with relevant compounds reported in the literature. (−)–5-Acetoxygoniothalamin exhibited potent cytotoxicity against the colon cancer cell line (HCT116) with an IC50 value of 8.6 μM which was better than the standard control (doxorubicin, IC50 = 9.7 μM), while (Z)-6-styryl-5,6-dihydro-2-pyranone was less active with an IC50 value of 22.1 μM.
Jin Wang, Benke Hong, Dachao Hu, Yuichiro Kadonaga, Ruyao Tang, Xiaoguang Lei*
J. Am. Chem. Soc. 2020, 142, 5, 2238-2243
The Yu's Rh-catalyzed [3+2+1] cycloaddition followed by a Pd-mediated 5-endo cycloalkenylation is shown to be a general and powerful approach for efficient construction of the tetracyclic core structure of ent-kaurane diterpenoids. The utility of this strategy was further demonstrated by concise and protecting-group-free total syntheses of ent-1α-hydroxykauran-12-one, 12-oxo-9,11-dehydrokaurene, and 12α-hydroxy-9,11-dehydrokaurene.
Rhytidenones family are spirobisnaphthalene natural products isolated from mangrove endophytic fungus Rhytidhysteron rufulum AS21B. The biomimetic synthesis of complex rhytidenone A was achieved via a sequence of Michael reaction, aldol and lactonization cascade in a single step, from the proposed biosynthetic precursor rhytidenone F. Moreover, the mode of action of the highly cytotoxic rhytidenone F has been investigated. The pulldown assay coupled with mass spectrometry analysis revealed the target protein PA28γ is covalently attached to rhytidenone F at the Cys92 residue. The interactions of rhytidenone F with PA28γ would lead to the accumulation of p53 which is an essential tumor suppressor in humans. Consequently, the Fas‐dependent signalling pathway will be activated to initiate cellular apoptosis. Our studies have identified the first small molecule inhibitor targeting PA28γ, suggesting rhytidenone F may serve as a promising natural product lead for future anticancer drug development.
Sourav Banerjee, Tiantian Wei, Jue Wang, Jenna J. Lee, Haydee L. Gutierrez, Owen Chapman, Sandra E. Wiley, Joshua E. Mayfield, Vasudha Tandon, Edwin F. Juarez, Lukas Chavez, Ruqi Liang, Robert L. Sah, Caitlin Costello, Jill P. Mesirov, Laureano de la Vega, Kimberly L. Cooper, Jack E. Dixon*, Junyu Xiao*, Xiaoguang Lei*
PNAS 2019, 116(49), 24881-24891
Dependence on the 26S proteasome is an Achilles' heel for triple-negative breast cancer (TNBC) and multiple myeloma (MM). The therapeutic proteasome inhibitor, bortezomib, successfully targets MM but often leads to drug-resistant disease relapse and fails in breast cancer. Here we show that a 26S proteasome-regulating kinase, DYRK2, is a therapeutic target for both MM and TNBC. Genome editing or small-molecule mediated inhibition of DYRK2 significantly reduces 26S proteasome activity, bypasses bortezomib resistance, and dramatically delays in vivo tumor growth in MM and TNBC thereby promoting survival. We further characterized the ability of LDN192960, a potent and selective DYRK2-inhibitor, to alleviate tumor burden in vivo. The drug docks into the active site of DYRK2 and partially inhibits all 3 core peptidase activities of the proteasome. Our results suggest that targeting 26S proteasome regulators will pave the way for therapeutic strategies in MM and TNBC.
Alexander X. Jones, Yong Cao , Yu-Liang Tang, Jian-Hua Wang, Yue-He Ding, Hui Tan,Zhen-Lin Chen, Run-Qian Fang, Jili Yin, Rong-Chang Chen, Xing Zhu, Yang She, Niu Huang , Feng Shao , Keqiong Ye , Rui-Xiang Sun, Si-Min He , Xiaoguang Lei* & Meng-Qiu Dong*.
Nature Communications 2019, 10, 3911
Chemical cross-linking of proteins coupled with mass spectrometry analysis (CXMS) is widely used to study protein-protein interactions (PPI), protein structures, and even protein dynamics. However, structural information provided by CXMS is still limited, partly because most CXMS experiments use lysine-lysine (K-K) cross-linkers. Although superb in selectivity and reactivity, they are ineffective for lysine deficient regions. Herein, we develop aromatic glyoxal cross-linkers (ArGOs) for arginine-arginine (R-R) cross-linking and the lysine-arginine (K-R) cross-linker KArGO. The R-R or K-R cross-links generated by ArGO or KArGO fit well with protein crystal structures and provide information not attainable by K-K cross-links. KArGO, in particular, is highly valuable for CXMS, with robust performance on a variety of samples including a kinase and two multi-protein complexes. In the case of the CNGP complex, KArGO cross-links covered as much of the PPI interface as R-R and K-K cross-links combined and improved the accuracy of Rosetta docking substantially
Pseudopaline is an opine carboxylate metallophore produced by Pseudomonas aeruginosa for harvesting divalent metals. However, the structure of pseudopaline is not fully elucidated. Herein, we report the first de novo total synthesis and isolation of pseudopaline, which allows unambiguous determination and confirmation of both the absolute and the relative configuration of the natural product. The synthesis highlights an efficient and stereocontrolled route using the asymmetric Tsuji–Trost reaction as the key step. The preliminary structure–activity relationship study indicated that one pseudopaline derivative shows comparable activity to pseudopaline. Moreover, a pseudopaline-fluorescein conjugate was prepared and evaluated, which confirmed that pseudopaline could be transported in the bacteria. Since the metal acquisition by P. aeruginosa is crucial for its ability to cause diseases, our extensive structural and functional studies of pseudopaline may pave the way for developing new therapeutic strategies such as the “Trojan horse” antibiotic conjugate against P. aeruginosa.
The first total syntheses of chaetoglines C–F via a bioinspired and divergent synthetic strategy are reported. Chaetolines C and D were obtained from the condensation of hemiacetal and tryptophan methyl ester building blocks followed by functional group transformations. The synthesis of chaetogline E employed the diastereoselective Pictet–Spengler reaction, and the tetrahydro-carboline skeleton was further utilized as a precursor for an oxidative aromatization reaction to introduce the β-carboline moiety of chaetogline F.
Protecting-group-free synthesis of (+)-ent-kauradienone and (-)-jungermannenone C has been accomplished through sequential applications of three radical-based reactions, including late-stage photoinduced skeletal rearrangements of bicyclo[3.2.1]octene ring systems. Further investigations on various terpenoids showed good functional-group tolerance and suggest that some terpenoids could also be produced via such photoinduced rearrangements pathways in nature. Our work demonstrates how paying more attention to unconventional radical mechanisms can reveal new chemistries that facilitate the synthesis of complex natural products.
A concise and enantioselective total synthesis of (+)‐jungermatrobrunin A (1), possessing a unique bicyclo[3.2.1]octene ring skeleton with an unprecedented peroxide bridge, was accomplished in 13 steps via a visible light mediated late‐stage Schenck ene reaction of (‐)‐1α,6α‐diacetoxyjungermannenone C (2). Along the way, a striking UV light induced bicyclo[3.2.1]octene ring rearrangement was applied to afford (+)‐12‐hydroxy‐1α,6α‐diacetoxy‐ent‐kaura‐9(11),16‐dien‐15‐one (4). The photoinduced divergent skeletal rearrangements strongly suggest a possible biogenetic relationship between 1, 2 and 4
We report the total synthesis of (±)-antroquinonol based on a concise and efficient route. Key features include two different strategies to install the required three contiguous stereogenic centers, which not only furnish the desired natural product but also provide natural product congeners for further biological studies.
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Styryllactones from Goniothalamus tamirensis
Pornphimol Meesakul, Wuttichai Jaidee, Christopher Richardson, Raymond J. Andersen, Brian O.Patrick, Anthony C.Willis, Chatchai Muanprasat, Jin Wang, Xiaoguang Lei, Sarinya Hadsadee, Siriporn Jungsuttiwong, Stephen G.Pyne, Surat Laphookhieo
Phytochemistry, 2020, 171, 112248 https://doi.org/10.1016/j.phytochem.2019.112248
The phytochemical investigation of the twig and leaf extracts of Goniothalamus tamirensis led to the isolation and identification of 15 compounds including three rare previously undescribed styryllactones, goniotamirenones A-C, together with 12 known compounds. (Z)-6-Styryl-5,6-dihydro-2-pyranone and 5-(1-hydroxy-3-phenyl-allyl)-dihydro-furan-2-one are reported here for the first time as previously undescribed natural products. Their structures were elucidated by spectroscopic methods. Goniotamirenone A was synthesized via a [2 + 2] cycloaddition reaction of 6-styrrylpyran-2-one in quantitative yield. The absolute configurations of goniotamirenones B and C were identified from experimental and calculated ECD data, while the absolute configurations of (−)–5-acetoxygoniothalamin, (−)-isoaltholactone, parvistone E, and 5-(1-hydroxy-3-phenyl-allyl)-dihydro-furan-2-one were identified by single-crystal X-ray diffraction analysis using Cu Kα radiation. The absolute configurations of the other related compounds were determined from comparisons of their ECD spectra with relevant compounds reported in the literature. (−)–5-Acetoxygoniothalamin exhibited potent cytotoxicity against the colon cancer cell line (HCT116) with an IC50 value of 8.6 μM which was better than the standard control (doxorubicin, IC50 = 9.7 μM), while (Z)-6-styryl-5,6-dihydro-2-pyranone was less active with an IC50 value of 22.1 μM.
Protecting-Group-Free Syntheses of ent-Kaurane Diterpenoids: [3+2+1] Cycloaddition/Cycloalkenylation Approach
Jin Wang, Benke Hong, Dachao Hu, Yuichiro Kadonaga, Ruyao Tang, Xiaoguang Lei*
J. Am. Chem. Soc. 2020, 142, 5, 2238-2243
The Yu's Rh-catalyzed [3+2+1] cycloaddition followed by a Pd-mediated 5-endo cycloalkenylation is shown to be a general and powerful approach for efficient construction of the tetracyclic core structure of ent-kaurane diterpenoids. The utility of this strategy was further demonstrated by concise and protecting-group-free total syntheses of ent-1α-hydroxykauran-12-one, 12-oxo-9,11-dehydrokaurene, and 12α-hydroxy-9,11-dehydrokaurene.
Biomimetic synthesis of rhytidenone A and elucidation of mode of action of the cytotoxic rhytidenone F
Zongwei Yue, Hiu C. Lam, Kaiqi Chen, Ittipon Siridechakorn, Yaxi Liu, Khanitha Pudhom,
Xiaoguang Lei*
Angew. Chem. Int. Ed. doi: 10.1002/anie.201914257
Rhytidenones family are spirobisnaphthalene natural products isolated from mangrove endophytic fungus Rhytidhysteron rufulum AS21B. The biomimetic synthesis of complex rhytidenone A was achieved via a sequence of Michael reaction, aldol and lactonization cascade in a single step, from the proposed biosynthetic precursor rhytidenone F. Moreover, the mode of action of the highly cytotoxic rhytidenone F has been investigated. The pulldown assay coupled with mass spectrometry analysis revealed the target protein PA28γ is covalently attached to rhytidenone F at the Cys92 residue. The interactions of rhytidenone F with PA28γ would lead to the accumulation of p53 which is an essential tumor suppressor in humans. Consequently, the Fas‐dependent signalling pathway will be activated to initiate cellular apoptosis. Our studies have identified the first small molecule inhibitor targeting PA28γ, suggesting rhytidenone F may serve as a promising natural product lead for future anticancer drug development.
Inhibition of Dual-Specificity Tyrosine-phosphorylation Regulated Kinase 2 Perturbs 26S Proteasome-addicted Neoplastic Progression
Sourav Banerjee, Tiantian Wei, Jue Wang, Jenna J. Lee, Haydee L. Gutierrez, Owen Chapman, Sandra E. Wiley, Joshua E. Mayfield, Vasudha Tandon, Edwin F. Juarez, Lukas Chavez, Ruqi Liang, Robert L. Sah, Caitlin Costello, Jill P. Mesirov, Laureano de la Vega, Kimberly L. Cooper, Jack E. Dixon*, Junyu Xiao*, Xiaoguang Lei*
PNAS 2019, 116(49), 24881-24891
Dependence on the 26S proteasome is an Achilles' heel for triple-negative breast cancer (TNBC) and multiple myeloma (MM). The therapeutic proteasome inhibitor, bortezomib, successfully targets MM but often leads to drug-resistant disease relapse and fails in breast cancer. Here we show that a 26S proteasome-regulating kinase, DYRK2, is a therapeutic target for both MM and TNBC. Genome editing or small-molecule mediated inhibition of DYRK2 significantly reduces 26S proteasome activity, bypasses bortezomib resistance, and dramatically delays in vivo tumor growth in MM and TNBC thereby promoting survival. We further characterized the ability of LDN192960, a potent and selective DYRK2-inhibitor, to alleviate tumor burden in vivo. The drug docks into the active site of DYRK2 and partially inhibits all 3 core peptidase activities of the proteasome. Our results suggest that targeting 26S proteasome regulators will pave the way for therapeutic strategies in MM and TNBC.
Improving mass spectrometry analysis of protein structures with arginine-selective chemical cross-linkers
Alexander X. Jones, Yong Cao , Yu-Liang Tang, Jian-Hua Wang, Yue-He Ding, Hui Tan,Zhen-Lin Chen, Run-Qian Fang, Jili Yin, Rong-Chang Chen, Xing Zhu, Yang She, Niu Huang ,
Feng Shao , Keqiong Ye , Rui-Xiang Sun, Si-Min He , Xiaoguang Lei* & Meng-Qiu Dong*.
Nature Communications 2019, 10, 3911
Chemical cross-linking of proteins coupled with mass spectrometry analysis (CXMS) is widely used to study protein-protein interactions (PPI), protein structures, and even protein dynamics. However, structural information provided by CXMS is still limited, partly because most CXMS experiments use lysine-lysine (K-K) cross-linkers. Although superb in selectivity and reactivity, they are ineffective for lysine deficient regions. Herein, we develop aromatic glyoxal cross-linkers (ArGOs) for arginine-arginine (R-R) cross-linking and the lysine-arginine (K-R) cross-linker KArGO. The R-R or K-R cross-links generated by ArGO or KArGO fit well with protein crystal structures and provide information not attainable by K-K cross-links. KArGO, in particular, is highly valuable for CXMS, with robust performance on a variety of samples including a kinase and two multi-protein complexes. In the case of the CNGP complex, KArGO cross-links covered as much of the PPI interface as R-R and K-K cross-links combined and improved the accuracy of Rosetta docking substantially
De novo synthesis, structural assignment and biological evaluation of pseudopaline, a metallophore produced by Pseudomonas aeruginosa
Jian Zhang, Tianhu Zhao, Rongwen Yang, Ittipon Siridechakorn, Sanshan Wang, Qianqian Guo,Yingjie Bai, Hong C. Shen, Xiaoguang Lei*
Chem. Sci.,2019,10, 6635
Pseudopaline is an opine carboxylate metallophore produced by Pseudomonas aeruginosa for harvesting divalent metals. However, the structure of pseudopaline is not fully elucidated. Herein, we report the first de novo total synthesis and isolation of pseudopaline, which allows unambiguous determination and confirmation of both the absolute and the relative configuration of the natural product. The synthesis highlights an efficient and stereocontrolled route using the asymmetric Tsuji–Trost reaction as the key step. The preliminary structure–activity relationship study indicated that one pseudopaline derivative shows comparable activity to pseudopaline. Moreover, a pseudopaline-fluorescein conjugate was prepared and evaluated, which confirmed that pseudopaline could be transported in the bacteria. Since the metal acquisition by P. aeruginosa is crucial for its ability to cause diseases, our extensive structural and functional studies of pseudopaline may pave the way for developing new therapeutic strategies such as the “Trojan horse” antibiotic conjugate against P. aeruginosa.
Divergent Total Synthesis of Chaetoglines C to F
Yaocheng Shi, Zhi Xu, Renxiang Tan, Xiaoguang Lei*
J. Org. Chem. 2019, 84 (13), 8766
The first total syntheses of chaetoglines C–F via a bioinspired and divergent synthetic strategy are reported. Chaetolines C and D were obtained from the condensation of hemiacetal and tryptophan methyl ester building blocks followed by functional group transformations. The synthesis of chaetogline E employed the diastereoselective Pictet–Spengler reaction, and the tetrahydro-carboline skeleton was further utilized as a precursor for an oxidative aromatization reaction to introduce the β-carboline moiety of chaetogline F.
Photoinduced Skeletal Rearrangements Reveal Radical-Mediated Synthesis of Terpenoids
Benke Hong, Weilong Liu, Jin Wang, Jinbao Wu, Yuichiro Kadonaga, Pei-Jun Cai,Hong-Xiang Lou, Zhi-Xiang Yu, Houhua Li,,* and Xiaoguang Lei*
Chem 2019, 5(6), 1671-1681
Protecting-group-free synthesis of (+)-ent-kauradienone and
(-)-jungermannenone C has been accomplished through sequential applications
of three radical-based reactions, including late-stage photoinduced skeletal
rearrangements of bicyclo[3.2.1]octene ring systems. Further investigations on
various terpenoids showed good functional-group tolerance and suggest that
some terpenoids could also be produced via such photoinduced rearrangements
pathways in nature. Our work demonstrates how paying more attention to
unconventional radical mechanisms can reveal new chemistries that facilitate the
synthesis of complex natural products.
13‐step Enantioselective Total Synthesis of (+)‐Jungermatrobrunin A
Jinbao Wu, Yuichiro Kadonaga, Benke Hong, Jin Wang, Xiaoguang Lei*
Angew. Chem. Int. Ed. 2019, 58, 10879-10883
A concise and enantioselective total synthesis of (+)‐jungermatrobrunin A (1), possessing a unique bicyclo[3.2.1]octene ring skeleton with an unprecedented peroxide bridge, was accomplished in 13 steps via a visible light mediated late‐stage Schenck ene reaction of (‐)‐1α,6α‐diacetoxyjungermannenone C (2). Along the way, a striking UV light induced bicyclo[3.2.1]octene ring rearrangement was applied to afford (+)‐12‐hydroxy‐1α,6α‐diacetoxy‐ent‐kaura‐9(11),16‐dien‐15‐one (4). The photoinduced divergent skeletal rearrangements strongly suggest a possible biogenetic relationship between 1, 2 and 4
Total Synthesis of (±)-Antroquinonol
Xiaoming Wang, Chao Du, Benke Hong, Xiaoguang Lei*
Organic & Biomolecular Chemistry, 2019, 17(7), 1754-1757
We report the total synthesis of (±)-antroquinonol based on a concise and efficient route. Key features include two different strategies to install the required three contiguous stereogenic centers, which not only furnish the desired natural product but also provide natural product congeners for further biological studies.