Benke Hong, Chao Li, Zhen Wang, Jie Chen, Houhua Li and Xiaoguang Lei?
J. Am. Chem. Soc. 2015, 137, 11946-11949
Abstract: We report herein the first total synthesis of (-)-incarviatone A (1) in 14 steps starting from commercially available inexpensive phenylacetic acid (9). Our early-stage synthesis relies on the scalable and sequential C-H functionalization to rapidly assemble the indanyl dialdehyde framework. Further biomimetic cascade strategy allows us to obtain the natural product in a one-pot […]
Chao Li, Alexander Jones, and Xiaoguang Lei
Nat. Prod. Rep. , 2015, DOI: 10.1039/C5NP00089K
Abstract: In this highlight we describe two case studies from our laboratory, involving the biomimetic syntheses and the biological mechanism elucidation of the bioactive oligomeric sesquiterpenoids, (+)-ainsliadimer A (4) and (?)-ainsliatrimer A (5). Ainsliadimer A possesses potent anti-inflammatory activity by inhibition of the NF-κB signalling pathway?via?binding at a previously untargeted allosteric site. (?)-Ainsliatrimer A induces […]
Qin, X.; Chen, B.; Fu, J.; Shan, L.; Lei, X.; Zhang, W
Eur. J. Med. Chem. 2015, 102, 256-265.
The eight novel ivangustin enantiomer analogues possessing α-methylene-γ-butyrolactone moiety have been synthesized using (4S6R, 4S6S)-4-tert-butyldimethylsilyloxy-6-methylcyclohex-2-en-1-one (1) as starting material. These transformations were mainly carried out by aldol condensation reaction and one-pot annelation procedure. The stereochemistry of these synthesized analogues was determined by NOE analysis. Their cytoxicity was evaluated against the human cancer cell lines HCT-116 (colon), HL-60 (leukemia), QGY-7701 (liver), SMMC-7721 (liver), A549 (lung), MCF-7 (breast). The results showed that these analogues were more selective against the cell lines HL-60 and QGY-7701. Analogue 17 exhibited potent cytotoxicity and high selectivity toward HL-60 cell line with IC50 value of 1.02 μM, which suggested that it might be a promising anti-cancer lead compound. The inhibitory activities against NO production and the cytotoxicities in RAW 264.7 macrophages were determined at the same time. All of the analogues significantly inhibited the NO production with IC50 value in the range of 3.44-6.99 μM. Analogues 17, 22, 23 and 7 showed higher cytotoxicities, indicated their inhibitory activities against NO production may be influenced by the cytotoxicities.
Insulin-induced gene 1 (Insig-1) and Insig-2 are endoplasmic reticulum membrane–embedded sterol sensors that regulate the?cellular accumulation of sterols. Despite their physiological importance, the structural information on Insigs remains limited.?Here we report the high-resolution structures of MvINS, an Insig homolog from Mycobacterium vanbaalenii. MvINS exists as a homotrimer. Each protomer comprises six transmembrane segments (TMs), with […]
The steroid hormone dafachronic acid (DA) regulates dauer formation and lifespan in Caenorhabditis elegans by binding to the nuclear receptor DAF-12. However, little is known about how DA concentrations change under various physiologic conditions and about how DA/DAF-12 signaling interacts with other signaling pathways that also regulate dauer formation and lifespan. Using a sensitive bioanalytical method, we quantified the endogenous DA concentrations in a long-lived germline-less glp-1 mutant and in the Dauer formation-defective (Daf-d) mutants daf-12, daf-16, daf-5, and daf-3. We found that the DA concentration in the glp-1 mutant was similar to that in the wild type (WT). This result is contrary to the long-held belief that germline loss-induced longevity involves increased DA production and suggests instead that this type of longevity involves an enhanced response to DA. We also found evidence suggesting that increased DA sensitivity underlies lifespan extension triggered by exogenous DA. At the L2/L3 stage, the DA concentration in a daf-12 null mutant decreased to 22% of the WT level. This finding is consistent with the previously proposed positive feedback regulation between DAF-12 and DA production. Surprisingly, the DA concentrations in the daf-16, daf-5, and daf-3 mutants were only 19–34% of the WT level at the L2/L3 stage, slightly greater than those in the Dauer formation-constitutive (Daf-c) mutants at the pre-dauer stage (4–15% of the WT L2 control). Our experimental evidence suggested that the positive feedback between DA and DAF-12 was partially induced in the three Daf-d mutants.
Keywords: dafachronic acid, steroid hormone, glp-1, daf-12, C. elegans dauer
Xiaoyun Zhang, Ting Dong, Qiang Li, Xiaohui Liu, Lin Li, She Chen, and Xiaoguang Lei*
ACS Chem. Biol. 2015, 10, 1676-1683
ABSTRACT: Bioorthogonal ligations play a crucial role in labeling diverse types of biomolecules in living systems. Herein, we describe a novel class of ortho-quinolinone quinone methide (oQQM) precursors that show faster kinetic rate in the “click cycloaddition” with thio-vinyl ether (TV) than the first generation TQ-ligation in both chemical and biological settings. We further demonstrate […]
Liu, W.; Li, X.; Chen, J.; Li, T.; Dong, M.; Lei, X.*
Chem. Eur. J. 2015, 21, 5345-5349
Abstract: Steroid hormones play significant roles in both worms and mammalians. (25S)-Δ7-Dafachronic acid (Δ7-DA, 1) is a member of dafachronic acid hormonal series which regulates both development and lifespan of C. elegans. Despite its importance, effective tools for the illumination of its mode of action are lacking. Herein, we report an efficient synthesis of trideuterated […]
Aberrant activation of NF-kB is associated with the development of cancer and autoimmune and inflammatory diseases. IKKs are well recognized as key regulators in the NF-kB pathway and therefore represent attractive targets for intervention with small molecule inhibitors. Herein, we report that a complex natural product ainsliadimer A is a potent inhibitor of the NF-kB […]
Jing Zhang, Jie Chen, Xiaoyun Zhang, and Xiaoguang Lei*
J. Org. Chem. 2014, 79, 10682-10688
Abstract Isoquinoline alkaloids are attractive natural products due to their diverse chemical structures as well as remarkable bioactivities. Herein, we report the concise total syntheses of two isoquinoline alkaloids menisporphine and daurioxoisoporphine C through a mild and efficient photoredox-catalyzed direct C–H arylation of isoquinoline core with aryldiazonium salt. This new strategy is complementary to the […]
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Enantioselective Total Synthesis of (-)-Incarviatone A
Benke Hong, Chao Li, Zhen Wang, Jie Chen, Houhua Li and Xiaoguang Lei?
J. Am. Chem. Soc. 2015, 137, 11946-11949
Abstract: We report herein the first total synthesis of (-)-incarviatone A (1) in 14 steps starting from commercially available inexpensive phenylacetic acid (9). Our early-stage synthesis relies on the scalable and sequential C-H functionalization to rapidly assemble the indanyl dialdehyde framework. Further biomimetic cascade strategy allows us to obtain the natural product in a one-pot […]
Synthesis and mode of action of oligomeric sesquiterpene lactones
Chao Li, Alexander Jones, and Xiaoguang Lei
Nat. Prod. Rep. , 2015, DOI: 10.1039/C5NP00089K
Abstract: In this highlight we describe two case studies from our laboratory, involving the biomimetic syntheses and the biological mechanism elucidation of the bioactive oligomeric sesquiterpenoids, (+)-ainsliadimer A (4) and (?)-ainsliatrimer A (5). Ainsliadimer A possesses potent anti-inflammatory activity by inhibition of the NF-κB signalling pathway?via?binding at a previously untargeted allosteric site. (?)-Ainsliatrimer A induces […]
Synthesis, cytotoxicity and inhibition of NO production of ivangustin enantiomer analogues
Qin, X.; Chen, B.; Fu, J.; Shan, L.; Lei, X.; Zhang, W
Eur. J. Med. Chem. 2015, 102, 256-265.
The eight novel ivangustin enantiomer analogues possessing α-methylene-γ-butyrolactone moiety have been synthesized using (4S6R, 4S6S)-4-tert-butyldimethylsilyloxy-6-methylcyclohex-2-en-1-one (1) as starting material. These transformations were mainly carried out by aldol condensation reaction and one-pot annelation procedure. The stereochemistry of these synthesized analogues was determined by NOE analysis. Their cytoxicity was evaluated against the human cancer cell lines HCT-116 (colon), HL-60 (leukemia), QGY-7701 (liver), SMMC-7721 (liver), A549 (lung), MCF-7 (breast). The results showed that these analogues were more selective against the cell lines HL-60 and QGY-7701. Analogue 17 exhibited potent cytotoxicity and high selectivity toward HL-60 cell line with IC50 value of 1.02 μM, which suggested that it might be a promising anti-cancer lead compound. The inhibitory activities against NO production and the cytotoxicities in RAW 264.7 macrophages were determined at the same time. All of the analogues significantly inhibited the NO production with IC50 value in the range of 3.44-6.99 μM. Analogues 17, 22, 23 and 7 showed higher cytotoxicities, indicated their inhibitory activities against NO production may be influenced by the cytotoxicities.
Recent Advances in the Total Synthesis of Prenylflavonoid and Related Diels—Alder Natural Products
Han, J.; Jones, A.; Lei, X
Synthesis 2015, 47, 1519-1533.
Crystal structure of a mycobacterial Insig homolog provides insight into how these sensors monitor sterol levels
Ren, R.; Zhou, X.; He, Y.; Ke, M.; Wu, J.; Liu, X.; Yan, C.; Wu, Y.; Gong, X.; Lei, X.; Yan, S. F.; Radhakrishnan, A.; Yan, N.*
Science 2015, 349, 187-191
Insulin-induced gene 1 (Insig-1) and Insig-2 are endoplasmic reticulum membrane–embedded sterol sensors that regulate the?cellular accumulation of sterols. Despite their physiological importance, the structural information on Insigs remains limited.?Here we report the high-resolution structures of MvINS, an Insig homolog from Mycobacterium vanbaalenii. MvINS exists as a homotrimer. Each protomer comprises six transmembrane segments (TMs), with […]
No Significant Increase in the Δ4- and Δ7-Dafachronic Acid Concentration in the Long-Lived glp-1 Mutant and in Dauer Formation-Defective Mutants
Li, T.; Liu, W.; Lu, S.; Zhang, Y-P.; Jia, L-M.; Chen, J.; Li, X.; Lei, X.; Dong, M.*
G3 (Bethesda). 2015 Jul; 5(7): 1473–1479. Published online 2015 May 12. doi: 10.1534/g3.115.018812
The steroid hormone dafachronic acid (DA) regulates dauer formation and lifespan in Caenorhabditis elegans by binding to the nuclear receptor DAF-12. However, little is known about how DA concentrations change under various physiologic conditions and about how DA/DAF-12 signaling interacts with other signaling pathways that also regulate dauer formation and lifespan. Using a sensitive bioanalytical method, we quantified the endogenous DA concentrations in a long-lived germline-less glp-1 mutant and in the Dauer formation-defective (Daf-d) mutants daf-12, daf-16, daf-5, and daf-3. We found that the DA concentration in the glp-1 mutant was similar to that in the wild type (WT). This result is contrary to the long-held belief that germline loss-induced longevity involves increased DA production and suggests instead that this type of longevity involves an enhanced response to DA. We also found evidence suggesting that increased DA sensitivity underlies lifespan extension triggered by exogenous DA. At the L2/L3 stage, the DA concentration in a daf-12 null mutant decreased to 22% of the WT level. This finding is consistent with the previously proposed positive feedback regulation between DAF-12 and DA production. Surprisingly, the DA concentrations in the daf-16, daf-5, and daf-3 mutants were only 19–34% of the WT level at the L2/L3 stage, slightly greater than those in the Dauer formation-constitutive (Daf-c) mutants at the pre-dauer stage (4–15% of the WT L2 control). Our experimental evidence suggested that the positive feedback between DA and DAF-12 was partially induced in the three Daf-d mutants.
Keywords: dafachronic acid, steroid hormone, glp-1, daf-12, C. elegans dauer
Second Generation TQ-Ligation for Cell Organelle Imaging
Xiaoyun Zhang, Ting Dong, Qiang Li, Xiaohui Liu, Lin Li, She Chen, and Xiaoguang Lei*
ACS Chem. Biol. 2015, 10, 1676-1683
ABSTRACT: Bioorthogonal ligations play a crucial role in labeling diverse types of biomolecules in living systems. Herein, we describe a novel class of ortho-quinolinone quinone methide (oQQM) precursors that show faster kinetic rate in the “click cycloaddition” with thio-vinyl ether (TV) than the first generation TQ-ligation in both chemical and biological settings. We further demonstrate […]
Site-selective and Metal-free Aliphatic C-H Oxidation Enabled Synthesis of [5,24,25-D3]-(25S)-Δ7-Dafachronic acid
Liu, W.; Li, X.; Chen, J.; Li, T.; Dong, M.; Lei, X.*
Chem. Eur. J. 2015, 21, 5345-5349
Abstract: Steroid hormones play significant roles in both worms and mammalians. (25S)-Δ7-Dafachronic acid (Δ7-DA, 1) is a member of dafachronic acid hormonal series which regulates both development and lifespan of C. elegans. Despite its importance, effective tools for the illumination of its mode of action are lacking. Herein, we report an efficient synthesis of trideuterated […]
Ainsliadimer A selectively inhibits IKKα/β by covalently binding a conserved cysteine
Dong, T.; Li, C.; Wang, X.; Dian, L.; Zhang, X.; Chen, X.; Li, L.; Cao, R.; Huang, N.; He, S. *; Lei, X.*
Nature Commun. 2015, 6, 6522
Aberrant activation of NF-kB is associated with the development of cancer and autoimmune and inflammatory diseases. IKKs are well recognized as key regulators in the NF-kB pathway and therefore represent attractive targets for intervention with small molecule inhibitors. Herein, we report that a complex natural product ainsliadimer A is a potent inhibitor of the NF-kB […]
Total Syntheses of Menisporphine and Daurioxoisoporphine C Enabled by Photoredox-Catalyzed Direct C–H Arylation of Isoquinoline with Aryldiazonium Salt
Jing Zhang, Jie Chen, Xiaoyun Zhang, and Xiaoguang Lei*
J. Org. Chem. 2014, 79, 10682-10688
Abstract Isoquinoline alkaloids are attractive natural products due to their diverse chemical structures as well as remarkable bioactivities. Herein, we report the concise total syntheses of two isoquinoline alkaloids menisporphine and daurioxoisoporphine C through a mild and efficient photoredox-catalyzed direct C–H arylation of isoquinoline core with aryldiazonium salt. This new strategy is complementary to the […]