Part II Publications in peer-reviewed journals

2011-2019

  1. “Total Synthesis of Hoiamide A Using an Evans-Tishchenko Reaction As a Key Step” Yian Guo, Jingjing Zhou, Bowen Gao, Meng Zhao, Jia-Lei Yan, Zhengshuang Xu, Sun Choi, Tao Ye Lett. 2019, 21, 5471-4

Abstract: The first total synthesis of neurotoxic cyclodepsipeptide hoiamide A (1) has been accomplished. The synthesis features the use of an Evans-Tishchenko fragment coupling between a five-stereogenic-center-containing -hydroxyketone and a chiral aldehyde derived from threonine.

 

  1. “Total Synthesis of Psymberin (Irciniastatin A)” Jie Yu, Mingze Yang, Yian Guo, Tao Ye

Org. Lett. 2019, 21, 3670-3673

Abstract: A convergent, stereocontrolled total synthesis of psymberin, an architecturally complex marine antitumor agent, has been achieved in 27 steps from the known aldehyde 8. Highlights of this synthesis include a novel and efficient transannular Michael addition/lactone reduction sequence to construct the highly substituted 2,6-trans-tetrahydropyran, a diastereoselective IBr-induced iodocarbonate cyclization to introduce the C(17) stereogenic center, and a Diels-Alder/aromatization reaction to install the highly substituted aromatic ring.

 

  1. “Discovery of Amantamide, a Selective CXCR7 Agonist from Marine Cyanobacteria” X. Liang, D. Luo, J. Yan, M. A. Rezaei, L. A. Salvador-Reyes, S. P. Gunasekera, C. Li, Tao Ye, V. J. Paul, H. Luesch, Lett. 2019, 21, 1622–1626

Abstract: CXCR7 plays an emerging role in several physiological processes. A linear peptide, amantamide (1), was isolated from marine cyanobacteria and the structure determined by NMR and mass spectrometry. The total synthesis was achieved by solid-phase method. After screening two biological target libraries, 1 was identified as a selective CXCR7 agonist. The selective activation of CXCR7 by 1 could provide the basis for developing CXCR7 targeted therapeutics and deciphering the role of CXCR7 in different diseases.

 

  1. “Isolation, Structure Elucidation and Biological Evaluation of Lagunamide D: A New Cytotoxic Macrocyclic Depsipeptide from Marine Cyanobacteria” D. Luo, M. Y. Putra, Tao Ye, V. J. Paul, H. Luesch, Drugs 2019, 17, 83; doi:10.3390/md17020083

Abstract: LagunamideD, a new cytotoxic macrocyclic depsipeptide, was discovered from a collection of marine cyanobacteria from Loggerhead Key in the Dry Tortugas, Florida. An intramolecular ester exchange was observed, where the 26-membered macrocycle could contract to a 24-membered compound via acyl migration at the 1,3-diol unit, and the transformation product was named lagunamide D’. The planar structures of both compounds were elucidated using a combination of nuclear magnetic resonance (NMR) spectroscopy and high-resolution mass spectroscopy (HRMS). The absolute configurations were determined on the basis of enantioselective analysis, modified Mosher’s analysis, Kishi NMR database, and direct comparison with lagunamide A, a structure closely resembling lagunamide D. Lagunamides A and D displayed low-nanomolar antiproliferative activity against A549 human lung adenocarcinomacells, while the structural transformation from the 26-membered lagunamide D macrocycle to the 24-membered ring structure for lagunamide D’ led to a 9.6-fold decrease in activity. Lagunamide D also displayed potent activity in triggering apoptosis in a dose- and time-dependent manner. Further investigation on the mechanism of action of the lagunamide scaffold is needed to fully explore its therapeutic potential as an anticancer agent.

 

  1. “Chemical and Metagenomic Studies of the Lethal Black Band 2 Disease of Corals Reveal Two Broadly Distributed, Redox-Sensitive 3 Mixed Polyketide/Peptide Macrocycles” P. Gunasekera, J. L. Meyer, Y. Ding, K. A. Abboud, D. Luo, J. E. Campbell, A. Angerhofer, J. L. Goodsell, L. J. Raymundo, J. Liu, Tao Ye, H. Luesch, M. Teplitski, V. J. Paul, J. Nat. Prod. 2019, 82, 111-121

Abstract: Black band disease (BBD), a lethal, polymicro bial disease consortium dominated by the cyanobacterium Roseofilum reptotaenium, kills many species of corals worldwide. To uncover chemical signals or cytotoxins that could be important in proliferation of Roseofilum and the BBD layer, we examined the secondary metabolites present in geographically diverse collections of BBD from Caribbean and Pacific coral reefs. Looekeyolide A (1), a 20-membered macrocyclic compound formed by a 16-carbon polyketide chain, 2 deamino-2-hydroxymethionine, and D-leucine, and its autoxidation product looekeyolide B (2) were extracted as major compounds (∼1 mg g −1 dry wt) from more than a dozen field-collected BBD samples. Looekeyolides A and B were also produced by a nonaxenic R. reptotaenium culture under laboratory conditions at similar concentrations. R. reptotaenium genomes that were constructed from four different metagenomic data sets contained a unique nonribosomal peptide/polyketide biosynthetic cluster that is likely responsible for the biosynthesis of the looekeyolides. Looekeyolide A, which readily oxidizes to looekeyolide B, may play a biological role in reducing H2O2 and other reactive oxygen species that could occur in the BBD layer as it overgrows and destroys coral tissue.

 

  1. “Solution-Phase Total Synthesis of Teixobactin” B. Gao, S. Chen, Y. Hou, Y. Zhao, T. Ye, Z. Xu, Biomol. Chem. 2019, 16, 1141-1153

Abstract: The first solution-phase total synthesis of the cyclic depsipeptide teixobactin is described. Stereoselective construction of L-allo-enduracididine was established, the protective groups for peptide coupling reactions and conditions for fragments assembly were also optimised. The total synthesis featured by 20-step longest linear steps from the known Lcis-4-hydroxyproline derivative in 5.6% overall yield. This solution-phase total synthesis could serve as complement for current solid-phase synthesis of teixobactin.

 

  1. “Total Synthesis of Asperphenins A and B” Jia-Lei Yan, Yingying Cheng, Jing Chen, Ranjala Ratnayake, Long H. Dang, Hendrik Luesch, Yian Guo, Tao Ye Lett. 2018, 20, 6170-3

Abstract: The first total synthesis of asperphenins A and B has been accomplished in a concise, highly stereoselective fashion from commercially available materials (15 steps, 9.7% and 14.2% overall yields, respectively). The convergent route featured the judicious choice of protecting groups, fragment assembly strategy and a late-stage iron-catalyzed Wacker-type selective oxidation of an internal alkene to the corresponding ketone.

 

  1. “Total Synthesis of Anti-tuberculosis Natural Products Ilamycins E1 and F” Yingying Cheng, Shoubin Tang, Yian Guo, Tao Ye Lett. 2018, 20, 6166-9;

Abstract: The first total synthesis of the potent antituberculosis cyclopeptide natural products ilamycins E1 and F was achieved. This highly convergent strategy consists of the synthesis of the two units 10 and 11 and linking them together to form the macrocyclic lactam 31. The upper unit 10 was prepared from tryptophan in five steps, and the lower unit 11 was prepared from glutamic acid in thirteen steps. Conversion of ilamycin F, the most abundant of the cyclopeptides, into the more active congener, ilamycin E1, was also accomplished. This would provide sufficient material of ilamycin E1 for more extensive biological studies.

 

  1. “Sameuramide A, a new cyclic depsipeptide isolated from an ascidian of the family Didemnidae” Koshi Machida, Daisuke Arai, Ryosuke Katsumata, Satoshi Otsuka, Jun K. Yamashita, Tao Ye, Shoubing Tang, Nobuhiro Fusetani and Yoichi Nakao Med. Chem. 2018, 26, 3852-3857

Abstract: Sameuramide A (1), a new cyclic depsipeptide encompassing one each of alanine, N-methyl alanine, N-methyl dehydroalanine, N,O-dimethyl threonine, phenyllactic acid, three β-hydroxy leucines, and two propionates, was isolated from a didemnid ascidian collected at the northern part of Japan. The planar structure was established based on the interpretation of MS and NMR data. The absolute configuration of the subunits was determined by the advanced Marfey’s method and the chiral LC-MS analysis. Compound 1 exhibited the activity of maintaining colony formation of murine embryonic stem (mES) cells without leukemia inhibitory factor (LIF). Down regulation of the gene expression of Krüppel-like transcription factor 4 (Klf4) indicated that 1 itself was not able to maintain the undifferentiated state of the mES cells. However, the expression levels of the marker genes (Nestin, T, Sox17) for three germ layers were upregulated in embryoid bodies (EBs) after treatment of 1 together with LIF, suggesting that 1 plays a supportive role for LIF in maintaining the multipotency of mES cells .

 

  1. “Discovery and Characterization of Brintonamides A‒E, Novel Dual Protease and GPCR Modulators from a Marine Cyanobacterium Targeting Breast Cancer Metastasis” Fatma H. Al-Awadhi, Bowen Gao, Mohammad A. Rezaei, Jason C. Kwan, Chenglong Li, Tao Ye, Valerie J. Paul, Hendrik Luesch, J. Med. Chem. 2018, 61, 6364−6378

Abstract: Five novel modified peptides named brintonamides A‒E (1‒5) were discovered from a marine cyanobacterium collected from Brinton Channel, Florida. The total synthesis of 1‒5 in addition to two other structurally related analogues (6 and 7) was pursued, which provided more material to allow rigorous biological evaluation and SAR studies. Initial protease profiling identified KLK7 as a hit; however, due to the weak enzymatic activity and lack of SAR among brintonamides, we applied for the first time GPCR profiling as an orthogonal platform which enabled the identification of five additional targets. The best hit identified was CCR10 which was inhibited by submicromolar IC50 of 4. We also carried out in silico modeling to understand the structural basis underlying the differences in the antagonistic activity among brintonamides towards CCR10. Due to the significance of KLK7 and CCR10 in cancer progression and metastasis we demonstrated the ability of brintonamide D (4) at 10 µM to significantly target downstream cellular substrates of KLK7: Dsg-2 and E-cad, CCL27 induced proliferation, and the migration of highly invasive breast cancer cells.

 

  1. “Kakeromamide A, a new cyclic pentapeptide inducing astrocyte differentiation isolated from the marine cyanobacterium Moorea bouillonii” Fumiaki Nakamura, Hiroshi Maejima, Midori Kawamura, Daisuke Arai, Tatsufumi Okino, Meng Zhao, Tao Ye, Jungyeol Lee, Young-Tae Chang, Nobuhiro Fusetani, Yoichi Nakao Med. Chem. Lett. 2018, 28, 2206-2209

Abstract: Kakeromamide A (1), a new cyclic pentapeptide encompassing a thiazole ring moiety and a β-amino acid, was isolated from the marine cyanobacterium Moorea bouillonii. Its structure was elucidated by the spectral analysis and the modified Marfey’s method. Compound 1 induced differentiation of neural stem cells into astrocytes at the concentration of 10 µM.

 

  1. “Studies toward the Synthesis of Iriomoteolide-2a: Construction of the C(6)−C(28) Fragment” Lushun Wang, Fusong Wu, Xuelei Jia, Zhengshuang Xu, Yian Guo, Tao Ye Lett. 2018, 20, 2213-15

Abstract: The synthesis of an appropriately functionalized advanced C(6−28) fragment (3) of the marine macrolide iriomoteolide-2a (1) has been achieved in a highly efficient manner. The C(6)−C(18) fragment of 1 is prepared via a radical cyclization of a vinyl ether intermediate and palladium-promoted hydrostannylation/iodination. Paterson aldol reaction and Peterson olefination are used to construct the C(19)−C(28) fragment. The union of the C(6)−C(18) and C(19)−C(28) fragments is accomplished via a Suzuki−Miyaura coupling reaction.

 

  1. “Formal Synthesis of Kanamienamide” Yang Li, Yian Guo, Zhengshuang Xu, Tao Ye, Synlett, 2018, 29, 964-8

Abstract: A formal total synthesis of the anticancer natural product kanamienamide has been accomplished. This communication describes two approaches to the macrocyclic core of the natural product. The key features of the route include an efficient macrolactamization, a Corey–Bakshi–Shibata asymmetric reduction, and a Stork–Zhao–Wittig olefination.

 

  1. “Total Synthesis of Luteoalbusin A and Formal Synthesis of T988 C” Lushun Wang, Xuelei Jia, Honghui Lei, Zhengshuang Xu, Tao Ye, Synlett, 2018, 29, 613-6

Abstract: An efficient total synthesis of luteoalbusin A was achieved in nine linear steps and in 17% overall yield from the known and easily accessible 3a-(3-indolyl)-hexahydropyrrolo[2,3-b]indole. A formal synthesis of (+)-T988 C through manipulation of the key intermediate is also reported.

 

  1. “Genome Mining and Assembly-Line Biosynthesis of the UCS1025A Pyrrolizidinone Family of Fungal Alkaloids” Li Li, Man-Cheng Tang, Shoubin Tang, Shu-Shan Gao, sameh.S.Msoliman, Leibniz Hang, Wei Xu, Tao Ye, Kenji Watanabe, Yi Tang, Am. Chem, Soc. 2018, 140, 2067-2071.

Abstract: UCS1025A is a fungal polyketide/alkaloid that displays strong inhibition of telomerase. The structures of UCS1025A and related natural products are featured by a tricyclic furopyrrolizidine connected to a trans-decalin fragment. We mined the genome of a thermophilic fungus and activated the ucs gene cluster to produce UCS1025A at a high titer. Genetic and biochemical analysis revealed a PKS-NRPS assembly line that activates 2S,3S-methylproline derived from l-isoleucine, followed by Knoevenagel condensation to construct the pyrrolizidine moiety. Oxidation of the 3S-methyl group to a carboxylate leads to an oxa-Michael cyclization and furnishes the furopyrrolizidine. Our work reveals a new strategy used by nature to construct heterocyclic alkaloid-like ring systems using assembly line logic.

 

  1. “Total synthesis of amphidinins E, F and epi-amphidinin F” Kai Chen, Zhengshuang Xu, Tao Ye Chem. Front. 2018, 5, 629-632

Abstract: A unified approach leading to the total synthesis of amphidinins E, F and epi-amphidinin F of a new structural class of linear marine polyketides is described.

 

  1. “Regio- and Stereospecific Construction of 3a-(1H‑Indol-3-yl)pyrrolidinoindolines and Application to the Formal Syntheses of Gliocladins B and C” Honghui Lei, Lushun Wang, Zhengshuang Xu, Tao Ye, Lett. 2017, 19, 5134−5137;

Abstract: A one-pot regio- and stereospecific strategy for the construction of 3a-(3-indolyl)-hexahydropyrrolo[2,3-b]indoles based on the condensation of an indole and an in situ generated cyclopropylazetoindoline has been developed. This unified strategy works with a variety of substituted indoles to produce 3a-(3-indolyl)-hexahydropyrrolo[2,3-b]indole products in high yields. The utility of this transformation was highlighted in the formal total syntheses of gliocladins B and C.

 

  1. “Total syntheses of smenothiazoles A and B” Xiao Ma, Yajie Chen, Sigui Chen, Zhengshuang Xu, Tao Ye, Biomol. Chem. 2017, 15, 7196-7203;

Abstract: Concise total syntheses of smenothiazoles A (1) and B (2), two distinguished vinyl chloride containing natural products isolated from the marine sponge S. aurea, have been developed. Silastannation, Stille reaction and a carefully controlled desilylchlorination were employed as key steps to construct unique polyketide acid fragments, and the optimized reaction conditions avoided migration of 2,5-diene to a 2,4- conjugated system. This report unambiguously confirmed the structures of both natural products.

 

  1. “Are there limits to rational chemical synthesis?” ZhengShuang Xu, Tao Ye, Chinese Science Bulletin 2017, 62, 2313-2322;

Abstract: Chemical synthesis is the purposeful execution of one or more reactions to obtain a product, or several products, which could modify the existing molecular frameworks, or make a complex (often natural) molecule from simple reagents. There are several possible reasons to make complex molecules by total chemical synthesis. A century ago the aim was often to identify a molecular structure. With the advent of routine X-ray crystallography and high-field FT NMR in the late 1960s, total chemical synthesis served as a necessary structural confirmation became much less compelling. Another reason that chemists synthesized natural products was because of their useful properties. In some cases, molecules could be cheaper to make from scratch than to obtain from nature source. The history of chemistry is essentially the history of finding out the structure of molecules and of developing new and efficient methods of making them. Putting these molecules to new uses is what underpins our modern world, but it was really a secondary goal for most of chemistry’s history. Great synthetic chemists of the mid-to-late twentieth century are revered not so much for what they made but for how they made it. Synthesis cultivates an understanding of the basic principles of chemistry: how and why reactions occur, the relationships between molecular shape and function, and so on. Today, synthetic chemists still need to pursue “ideality” in the way molecules are synthesized, and total synthesis should be able to provide large quantities of complex natural products with a minimum amount of labor and material expense. In future years, the emphasis of synthetic chemistry, also natural product synthesis, will shift from delivering structures to delivering functions. Natural products will continue to serve a central role in the discovery and development of pharmaceutical agents as well as the elucidation of new biological targets of therapeutic relevance. Synthetic chemists are in a unique position to define those very important molecules that we want, which allow us to access to non-natural derivatives that may offer superior biological and physical properties in comparison to the natural material. The research in natural products synthesis has indeed been the impetus for many fundamental discoveries and could also motivate future research in chemistry and biology.

 

  1. “Total Synthesis and Stereochemical Assignment of Actinoranone” Yi-an Guo, Meng Zhao, Zhengshuang Xu, Tao Ye, Eur. J. 2017, 23, 3572–3576

Abstract: The total synthesis of four actinoranone stereoisomers led to unambiguous assignment of relative and absolute stereochemistry of the natural product. Key features of the convergent, fully stereocontrolled route include the use of a Negishi carbozirconation/iodination, a Friedel–Crafts cyclization, a Felkin-controlled addition reaction, a Mitsunobu reaction, and a late-stage C H oxidation.

 

  1. “Total Synthesis and Stereochemical Assignment of Nostosin B” Xiaoji Wang, Junmin

Feng, Zhengshuang Xu, Tao Ye, Yi Meng, Zhiyu Zhang, Marine Drugs, 2017, 15, 59; doi:10.3390/md15030058

Abstract: Nostosins A and B were isolated from a hydrophilic extract of Nostoc sp. strain from Iran, which exhibits excellent trypsin inhibitory activity. Nostosin A was the most potent natural tripeptide aldehyde as trypsin inhibitor up to now. Both R‐ and S‐2‐hydroxy‐4‐(4‐hydroxy phenyl) butanoic acid (Hhpba) were prepared and incorporated into the total synthesis of nostosin B, respectively. Careful comparison of the NMR spectra and optical rotation data of synthetic nostosin B (1a and 1b) with the natural product led to the unambiguous identification of the R‐configuration of the Hhpba fragment, which was further confirmed by co‐injection with the authentic sample on HPLC using both reversed phase column and the chiral AD‐RH column.

 

  1. “Concise Total Synthesis of Nannocystin A”, Linping Liao, Jingjing Zhou, Zhengshuang Xu, Tao Ye Chem. Int. Ed. 2016, 55, 13263-13266. This paper has been featured by SYNFACTS Highlights in Current Synthetic Organic Chemistry 2016, 12, 1228

 

Abstract: Nannocystin A, a structurally unique 21-membered macrocyclic depsipeptide with low nanomolar inhibitory activity against elongation factor-1A, was synthesized according to a strategy employing vinylogous Mukaiyama aldol reaction, Sharpless epoxidation, Brown crotylation, olefin metathesis reaction, Mitsunobu reaction, and a palladium-catalyzed intramolecular Suzuki coupling of a highly complex cyclization substrate. The overall synthesis is efficient (17.3% overall yield for 10 linear steps) and paves the way for efficient preparation of analogues for drug development efforts.

 

  1. “Total Synthesis and Stereochemical Assignment of Callyspongiolide” Jingjing Zhou, Bowen Gao, Zhengshuang Xu, Tao Ye, Am. Chem. Soc. 2016, 138, 6948-6951

Abstract: Total synthesis of four callyspongiolide stereoisomers led to unambiguous assignment of relative and absolute stereochemistry of the natural product. Key features of the convergent, fully stereocontrolled route include the use of Krische allylation, Kiyooka Aldol reaction, Kociénski−Julia olefination, Still-Gennari olefination, Yamaguchi macrocy-clization and Sonogashira coupling reaction. Biological eval-uation of the synthesized compounds against an array of cancer cells revealed that the stereochemistry of the macro-lactone core played an important role.

 

  1. “Discovery, Total Synthesis and Key Structural Elements for the Immunosuppressive Activity of Cocosolide, a Symmetrical Glycosylated Macrolide Dimer from Marine Cyanobacteria” S. P. Gunasekera, Yang Li, Ranjala Ratnayake, Danmeng Luo, Jeannette Lo, Joseph H. Reibenspies, Zhengshuang Xu, Michael J. Clare-Salzler, T. Ye, V. J. Paul, H. Luesch, Eur. J. 2016, 22, 8158-8166

 

Abstract: A new dimeric macrolide xylopyranoside, cocosolide (1), was isolated from the marine cyanobacterium preliminarily identified as Symploca sp. from Guam. The structure was determined by a combination of NMR spectroscopy, HRMS, X-ray diffraction studies and Mosher’s analysis of the base hydrolysis product. Its carbon skeleton closely resembles that of clavosolides A–D isolated from the sponge Myriastra clavosa, for which no bioactivity is known. We performed the first total synthesis of cocosolide (1) along with its [a,a]-anomer (26) and macrocyclic core (28), thus leading to the confirmation of the structure of natural 1. The convergent synthesis featured Wadsworth–Emmons cyclopropanation, Sakurai annulation, Yamaguchi macrocyclization/dimerization reaction, a-selective glycosidation and b-selective glycosidation. Compounds 1 and 26 potently inhibited IL-2 production in both T-cell receptor dependent and independent manners. Full activity requires the presence of the sugar moiety as well as the intact dimeric structure. Cocosolide also suppressed the proliferation of anti-CD3-stimulated Tcells in a dose-dependent manner.

 

  1. “Towards theory driven structure elucidation of complex natural products: mandelalides and coibamide A” K. M. Snyder, J. Sikorska, Tao Ye, L. Fang, W. Su, R. G. Carter, K. L. McPhail, P. H.-Y. Cheong, Biomol. Chem., 2016,14, 5826–5831.

 

Abstract: The effectiveness of computational tools in determining relative configurations of complex molecules is investigated, using natural products mandelalides A–D and coibamide A, towards a generalized recipe for the scientific community at large. Ultimately, continuing efforts in this vein will accelerate and strengthen relative structure elucidation of complex molecules, such as natural products. Molecular mechanics conformational search, quantum mechanical NMR chemical shift predictions, and DP4 analyses led to confirmation of the revised structures of mandelalides A–D and coibamide A. All chiral centers in the northern hemisphere of mandelalides A–D are inverted with respect to the originally proposed structures, in agreement with recent total syntheses of mandelalide A by Ye, Fürstner & Carter. In the case of coibamide A, it was found that Fang & Su’s revision, in which both the macrocycle [MeAla11] and the side chain [HIV2] residues are inverted from L to D, was consistent with the authentic natural product and computations.

 

  1. “Discovery of Mandelalide E and Determinants of Cytotoxicity for the Mandelalide Series” M. Nazari, J. D. Serrill, J. Sikorska, T. Ye, J. E. Ishmael, K. L. McPhail, Lett. 2016, 18, 1374-1377.

 

Abstract: Recollection of the tunicate source of the mandelalides has provided new and known analogues that have facilitated expanded analyses of the disputed cancer cytotoxicity of mandelalide A following a number of recent reported total syntheses. Using newly characterized mandelalide E, reisolated natural mandelalides B and C, and synthetic mandelalide A, the cytotoxicity of the mandelalides is demonstrated to be strongly influenced by compound glycosylation and assay cell density. Glycosylated mandelalides reduced the viability of human cancer cells cultured at a high starting density with a rank order of potency A > B >> E, yet display dramatically reduced cytotoxic efficacy against low density cultures.

 

  1. “The total synthesis and stereochemical assignment of scytonemin A”, Junyang Liu, Lei Wang, Juefei Zhang, Zhengshuang Xu, Tao Ye Commun., 2016, 52, 1002-1005

Abstract: The total synthesis of scytonemin A and its C-9 epimer, as well as elucidation of   the absolute stereochemistry of natural scytonemin A is described.

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  1. “Synthesis of Lysine Methyltransferase Inhibitors” Chunngai Hui, Tao Ye Chem., 23 July 2015, http://dx.doi.org/10.3389/fchem.2015.00044

Abstract: Lysine methyltransferase which catalyze methylation of histone and nonhistone proteins, play a crucial role in diverse biological processes and has emerged as a promising target for the development of various human diseases, including cancer, inflammation, and psychiatric disorders. However, inhibiting lysine methyltransferases selectively has presented many challenges to medicinal chemists. During the past decade, lysine methyltransferase inhibitors covering many different structural classes have been designed and developed. In this review, we describe the development of selective, small-molecule inhibitors of lysine methyltransferases with an emphasis on their discovery and chemical synthesis. We highlight the current state of lysine methyltransferase inhibitors and discuss future directions and opportunities for lysine methyltransferase inhibitor discovery.

 

  1. “Total synthesis of the putative structure of the proposed Banyasin A” Xuguang Gao, Qi Ren, Sun Choi, Zhengshuang Xu, Tao Ye, Front. Chem., 17 March 2015; DOI:10.3389/fchem.2015.00019

Abstract: The first total synthesis of four possible isomers of a molecule possessing the configuration proposed for banyasin A is described. The structure synthesized appears to be different from that of the natural product.

 

  1. “Studies toward the Total Synthesis of Itralamide B and Biological Evaluation of Its Structural Analogs” Xiaoji Wang, Chanshan Lv, Junmin Feng, Linjun Tang, Zhuo Wang, Yuqing Liu, Yi Meng, Tao Ye, Zhengshuang Xu, Marine Drugs, 2015, 13, 2085-2104.

ABSTRACT: Itralamides A and B were isolated from the lipophilic extract of Lyngbya majuscula collected from the eastern Caribbean. Itralamide B (1) showed cytotoxic activity towards human embryonic kidney cells (HEK293, IC50 = 6 μM). Preliminary studies disapproved the proposed stereochemistry of itralamide. In this paper, we will provide a full account of the total synthesis of four stereoisomers of itralamide B and the results derived from biological tests of these structural congeners.

  1. “Total Synthesis of Largamide B” Shiwei Qu, Ying Chen, Xiaoji Wang, Shipeng Chen, Zhengshuang Xu, Tao Ye, Commun. 2015, 51, 2510-2513. This paper has been featured on the intra-front cover of issue 13, volume 51 (2015) of Chemical Communications.

Abstract: Total synthesis of the cyanobacterial metabolite largamide B and the disapproval of its originally assigned stereochemistry as well as confirmation of the revised stereochemistry are reported

 

 

  1. “Total Synthesis and Stereochemical Reassignment of Mandelalide A”, Honghui Lei, Jialei Yan, Jie Yu, Yuqing Liu, Zhuo Wang, Zhengshuang                         Xu, Tao Ye Chem. Int.        Ed.. 2014, 53, 6533-6537. This paper has been selected as a “HOT PAPER” by             Angewandte Chemie International Edition.

Abstract: Total synthesis of the tunicate metabolite mandelalide A and the correction     of its originally assigned stereochemistry are reported. Key features of our convergent,    fully stereocontrolled route include the use of Prins cyclization for the      diastereoselective construction of the tetrahydropyran subunit, Rychnovsky-Bartlett       cyclization for the preparation of the tetrahydrofuran moiety, Suzuki coupling reaction,            Horner-Wadsworth-Emmons macrocyclization and glycosylation to append the L-  rhamnose-derived pyranoside.

 

  1. “Grassypeptolides as Natural Inhibitors of Dipeptidyl Peptidase 8 and T-Cell Activation”, Jason C. Kwan, Yanxia, Liu,; Ranjala Ratnayake, Ryo Hatano, Akiko     Kuribara, Chiko Morimoto, Kei Ohnuma, Valerie J. Paul, Tao Ye, Luesch, Hendrik,   ChemBioChem, 2014, 15, 799-804.

Abstract: Natural products made by marine cyanobacteria are often highly modified       peptides and depsipeptides that have the potential to act as inhibitors for proteases. In      the interests of finding new protease inhibition activity and selectivity, grassypeptolide       A (1) was screened against a panel of proteases and found to inhibit DPP8 selectively over    DPP4. Grassypeptolides were also found to inhibit IL-2 production and proliferation in      activated T-cells, consistent with a putative role of DPP8 in the immune system. These       effects were also observed in Jurkat cells, and DPP activity in Jurkat cell cytosol was   shown to be inhibited by grassypeptolides. In silico docking suggests two possible binding        modes of grassypeptolides—at the active site of DPP8 and at one of the entrances to the     internal cavity. Collectively these results suggest that grassypeptolides might be useful      tool compounds in the study of DPP8 function.

 

  1. “Total Synthesis of the Proposed Structure for Itralamide B”, Xiaoji Wang, Chanshan Lv,Junyang Liu, Linjun Tang, Junmin Feng, Shoubin Tang, Zhuo Wang, Yuqing Liu,     Yi Meng, Tao Ye, Zhengshuang XuSynlett, 2014, 25, 1014-1018.

Abstract: A stereocontrolled total synthesis of the cyclodepsipeptide, itralamide B has been achieved. Both R– and S-stereomers of the side chain were attached to the macrocyclic ring. The structure synthesized appears to be different from that of the marine natural product.

 

  1. “LSD1 Regulates Pluripotency of Embryonic Stem/Carcinoma Cells through HDAC1-mediated Deacetylation of Histone H4 at Lysine 16”, Feng Yin, Rongfeng        Lan, Xiaoming Zhang, Linyu Zhu, Fangfang Chen, Zhengshuang Xu, Yuqing Liu,       Tao Ye, Hong Sun, Fei Lu and Hui Zhang, Mol. Biology 2014, 34,  158-179

Abstract: LSD1 is essential for the maintenance of pluripotency of embryonic stem (ES) or embryonic carcinoma/teratocarcinoma (EC) cells. We have previously       developed novel LSD1 inhibitors that selectively inhibit ES/EC cells. However, the     critical targets of LSD1 remain unclear. Here, we found that LSD1 interacts with HDAC1      to regulate the proliferation of ES/EC cells through H4K16 acetylation, which we showed is a critical substrate of HDAC1. The LSD1 demethylase and HDAC1 deacetylase       activities were both inactivated if one of them in the complex was chemically inhibited in       ES/EC cells or in reconstituted protein complexes. Loss of HDAC1 phenocopied the    selective growth inhibitory effects and increased levels of H3K4 methylation and H4K16    acetylation of LSD1 inactivation on ES/EC cells. Reduction of acetylated H4K16 by       ablation of acetyltransferase MOF is sufficient to rescue the growth inhibition induced by LSD1 inactivation. While LSD1 or HDAC1 inactivation caused the down-regulation of      Sox2 and Oct4 and induction of differentiation genes such as FOXA2 or BMP2, depletion     of MOF restored the levels of Sox2, Oct4 and FOXA2 in LSD1 deficient cells. Our studies       reveal a novel mechanism by which LSD1 acts through the HDAC1- and MOF-mediated      regulation of H4K16 acetylation to maintain the pluripotency of ES/EC cells.

 

  1. “Cross-Metathesis Approach for Stereocontrolled Synthesis of the C1–C15 Fragment of Rhizopodin”, Honggang Gui, Junyang Liu, Liankai Song, Chunngai Hui, Junmin Feng, Zhengshuang Xu, Tao Ye Synlett, 2014, 25, 138-142

Abstract: The C1–C15 fragment of rhizopodin was synthesized through either Suzuki coupling reaction of vinyl iodide and vinyl boronate or cross-metathesis of a terminal olefin and a diene adduct in the presence of Hoveyda–Grubbs II catalyst.

 

  1. “Pluripotent Stem Cell Protein Sox2 Confers Sensitivity towards LSD1 Inhibition in Cancer Cell”, Xiaoming   Zhang, Fei Lu, Jing Wang, Feng Yin, Zhengshuang Xu,     Dandan Qi, Xianhui Wu, Yuwen Cao, Weihua Liang,    Yuqing Liu, Hong Sun, Tao Ye and Hui Zhang Cell    Reports, 2013, 5, 445-457.

Abstract: The gene amplification of Sox2 at 3q26.33 is a common event in squamous cell carcinomas (SCCs) of lung, esophagus, and several other cancers. Here, we show that the expression of LSD1/KDM1 histone demethylase is significantly elevated in Sox2-expressing lung SCCs. LSD1-specific inhibitors selectively impair the growth of Sox2-expressing lung SCC cells but not that of Sox2-negative cells. Sox2 expression is associated with the sensitivity towards LSD1 inhibition in lung, breast, ovarian, and other carcinoma cells. Inactivation of LSD1 reduces Sox2 expression, promotes G1 cell cycle arrest, and induces genes for differentiation by selectively modulating methylations of histone H3 at lysines 4 (H3K4) and 9 (H3K9). Reduction of Sox2 further suppresses Sox2-dependent lineage-survival oncogenic potential, elevates trimethylation of histone H3 at lysine 27 (H3K27), and enhances growth arrest and cellular differentiation. Our studies suggest that LSD1 serves as a selective and specific epigenetic target for the therapy of Sox2-expressing cancers.

 

  1. “Synthesis of the Macrocyclic Core of Rhizopodin” Liankai Song, Junyang Liu, Honggang Gui, Chunngai Hui, Jingjing Zhou, Yian Guo, Pengpeng Zhang,                   Zhengshuang Xu, Tao Ye Asian J. 2013, 8, 2955-2959.

Abstract: Rhizing star: A stereoselective synthesis of the fully functionalized    macrocyclic core of rhizopodin, a cytotoxic 38-membered macrolide, has been               disclosed. The key steps involve Sharpless epoxidation, Robinson–Gabriel oxazole       synthesis, olefin cross-metathesis, Suzuki coupling, Yamaguchi esterificationn, and       Shiina macrolactonization.

 

  1. “Total Synthesis and Biological Evaluation of Grassypeptolide A” Hui Liu, Yuqing Liu, Zhuo Wang, Xiangyou Xing, Anita R. Maguire, Hendrik Luesch, Hui Zhang, Zhengshuang Xu, Tao Ye Eur. J.  2013, 19, 6774-6784.

Abstract: Herein, we describe in full our investigations into the synthesis of grassypeptolide A (1) in 17 linear steps with an overall yield of 11.3 %. In particular, this work features the late-stage introduction of sensitive bis(thiazoline) heterocycles and 31-membered macrocyclization conducted at the sterically congested secondary amide site in superb conversion (72 % yield). Biological evaluation indicated that grassypeptolide A significantly inhibited cancer cell proliferation in a dose-dependent manner. It induced cancer cell apoptosis, which was associated with increased cleavage of poly(ADP-ribose) polymerase (PARP) and decreased expression of bcl-2 and bcl-xL. Furthermore, grassypeptolide A also caused cell cycle redistribution by increasing cells in the G1 phase and decreasing cells in the S and G2 phases. In addition, cell cycle arrest was correlated with downregulation of cyclin D and upregulation of p27 and p21.

 

  1. “Total Synthesis of Padanamides A and B”, Bohua Long, Shoubin Tang, Ligong Chen, Shiwei Qu, Bo Chen, Junyang Liu, Anita R. Maguire, Zhuo Wang,     Yuqing Liu, Hui Zhang, Zhengshuang Xu and Tao Ye, Commun. 2013, 49, 2977-2979.

            This paper has been featured on the intra-front    cover of issue 29, volume 49 (2013) of Chemical Communications. This cover image contains PolyU’s Logo.

Abstract: The first total syntheses of padanamides     A and B have been achieved, unambiguously confirming their structures.

 

  1. “A Novel CyclinE/CyclinA-CDK2 Inhibitor Targets p27(Kip1) Degradation, Cell Cycle    Progression and Cell Survival: Implications in Cancer Therapy” Lu Dai, Yuqing Liu,        Junyang Liu, Xiaoming Wen, Zhengshuang Xu, Zhuo Wang, Hong Sun, Shoubin Tang,     Anita R Maguire, Junmin Quan, Hui Zhang, Tao Ye Cancer Letters, 2013, 333, 103-112.

Abstract: p27(Kip1) (p27) binds and inhibits the cyclin E- or cyclin A-associated cyclin-dependent kinases (CDKs)2 and other CDKs, and negatively regulates G1-G2 cell cycle progression. To develop specific CDK inhibitors, we have modeled the interaction between p27 and cyclin A-CDK2, and designed a novel compound that mimics p27 binding to cyclin A-CDK2. The chemically synthesized inhibitor exhibited high potency and selective inhibition towards cyclin E/cyclin A-CDK2 kinase in vitro but not other kinases. To facilitate permeability of the inhibitor, a cell penetrating peptide (CPP) was conjugated to the inhibitor to examine its effect in several cancer cell lines. The CPP-conjugated inhibitor significantly inhibited the proliferation of cancer cells. The treatment of the inhibitor resulted in the increased accumulation of p27 and p21(Cip1/Waf1) (p21) and hypo-phosphorylation of retinoblastoma protein (Rb). The degradation of p27, mediated through the phosphorylation of threonine-187 in p27, was also inhibited. Consequently, exposure of cells to the inhibitor caused cell cycle arrest and apoptosis. We conclude that specific cyclinE/cyclin A-CDK2 inhibitors can be developed based on the interaction between p27 and cyclin/CDK to block cell cycle progression to prevent tumor growth and survival.

 

  1. “A Histone Deacetylase Inhibitor, Largazole, Decreases Liver Fibrosis and Angiogenesis by Inhibiting Transforming Growth Factor-beta and Vascular Endothelial Growth Factor   Signalling ” Yuqing Liu, Zhuo Wang, Jianing Wang, Wingchi Lam, Shuqin Kwong,    Furong Li, Scott L. Friedman, Shuyan Zhou, Qi Ren, Zhengshuang Xu, XinGen Wang,   Ling Ji, Shoubin Tang, Hui Zhang, Eric L. Lui and Tao Ye Liver International, 2013, 33,   504-515.

Abstract: Largazole is a novel histone deacetylase (HDAC) inhibitor. This study investigated the effects of largazole against liver fibrosis. METHODS: The in vitro effects of largazole were examined using hepatic stellate cells (HSCs). In vivo effects of largazole were studied using a mouse liver fibrotic model induced by CCl(4). RESULTS: Largazole augmented acetylation of histone H3 (H3) and histone H4 (H4) in HSCs. It directly inhibited the activation of HSCs owing to HDAC inhibitory activity as the antifibrotic effect of largazole was significantly decreased in cells with HDAC1, HDAC2 and HDAC3 knockdown. Largazole also induced apoptosis of HSCs. Largazole not only inhibited the expression of TGFbetaR2, but also reduced phosphorylation of Smad2 and Akt induced by TGF-beta1. Largazole also inhibited the expression of vascular endothelial growth factor (VEGF) and its receptor. VEGF-induced proliferation of HSCs and activation of Akt and p38MAPK were also suppressed by largazole. In vivo, largazole reduced the expression of collagen I, alpha-smooth muscle actin and tissue inhibitor of metalloproteinase-1 in CCl(4) -induced fibrosis, and these antifibrotic effects were associated with increased acetylation of H3 and H4. Largazole also induced HSCs to undergo apoptosis in vivo, which was correlated with downregulation of bcl-2 and bcl-xL. Furthermore, largazole inhibited angiogenesis in vivo as evidenced by reduced expression of CD34, VEGF and VEGFR. In addition to its antifibrotic activity, the drug reduced inflammatory activity in CCl(4) -induced liver fibrosis. CONCLUSIONS: Our findings revealed a novel role of largazole in the treatment of liver fibrosis. Through multiple mechanisms, largazole could be a potentially effective antifibrotic agent.

 

  1. “Superoxide constitutes a major signal of mitochondrial superoxide flash” Xing Zhang,      Zhanglong Huang,Tingting Hou, Jiejia Xu,Yanru Wang, Wei Shang, Tao Ye, Heping Cheng, Feng Gao, Xianhua Wang, Life sciences, 2013, 93, 178-186.

Abstract: AIMS: Mitochondrial flashes detected with an N- and C-terminal circularly-    permuted yellow fluorescent protein (cpYFP) have been thought to represent transient and       quantal bursts of superoxide production under physiological, stressful and       pathophysiological conditions. However, the superoxide nature of the cpYFP-flash has   been challenged, considering the pH-sensitivity of cpYFP and the distinctive regulation of      the flash versus the basal production of mitochondrial reactive oxygen species (ROS). Thus, the aim of the study is to further determine the origin of mitochondrial flashes.

MAIN METHODS: We investigated the origin of the flashes using the widely-used pH-insensitive ROS indicators, mitoSOX, an indicator for superoxide, and 2, 7-dichlorodihydrofluorescein diacetate (DCF), an indicator for H2O2 and other oxidants.

KEY FINDINGS: Robust, quantal, and stochastic mitochondrial flashes were detected with either mitoSOX or DCF in several cell-types and in mitochondria isolated from the heart. Both mitoSOX-flashes and DCF-flashes showed similar incidence and kinetics to those of cpYFP-flashes, and were equally sensitive to mitochondria-targeted antioxidants. Furthermore, they were markedly decreased by inhibitors or an uncoupler of the mitochondrial electron transport chain, as is the case with cpYFP-flashes. The involvement of the mitochondrial permeability transition pore in DCF-flashes was evidenced by the coincidental loss of mitochondrial membrane potential and matrix-enriched rhod-2, as well as by their sensitivity to cyclosporine A.SIGNIFICANCE: These data indicate that all the three types of mitochondrial flashes stem from the common physiological process of bursting superoxide and ensuing H2O2 production in the matrix of single mitochondrion.

 

  1. “First Total Synthesis and Stereochemical Revision of Laxaphycin B and Its Extension to Lyngbyacyclamide A.” France Boyaud, Zahia Mahiout, Christine Lenoir,     Shoubin Tang, Joanna Wdzieczak-Bakala, Anne Witczak, Isabelle Bonnard, Bernard   Banaigs, Tao Ye, Nicolas Inguimbert, Lett. 2013, 15, 3898-3901.

Abstract: The first total synthesis of laxaphycin B was accomplished through stepwise   automated Solid Phase Peptide Synthesis (SPPS), leading to the structural revision of      its stereochemistry especially with regard to the configuration of one of the two 3- hydroxyleucines of this cyclic dodecapeptide of marine origin. The analogous    Lyngbyacyclamide A was obtained by an extension of this synthesis.

 

  1. “NuRD Blocks Reprogramming of Mouse Somatic Cells into Pluripotent Stem Cells” Min Luo, Te Ling, Wenbing Xie, He Sun, Yonggang Zhou, Qiaoyun Zhu, Meili Shen,      Le Zong, Guoliang Lyu, Yun Zhao, Tao Ye, Jun Gu, Wei Tao, Zhigang Lu, Ingrid       Grummt, Stem Cells, 2013, 31, 1278-86.

Abstract: Reprogramming of somatic cells into induced pluripotent stem cells (iPSCs) by overexpression of a defined set of transcription factors requires epigenetic changes in pluripotency genes. Nuclear reprogramming is an inefficient process and the molecular mechanisms that reset the epigenetic state during iPSC generation are largely unknown. Here, we show that downregulation of the nucleosome remodeling and deacetylation (NuRD) complex is required for efficient reprogramming. Overexpression of Mbd3, a subunit of NuRD, inhibits induction of iPSCs by establishing heterochromatic features and silencing embryonic stem cell-specific marker genes, including Oct4 and Nanog. Depletion of Mbd3, on the other hand, improves reprogramming efficiency and facilitates the formation of pluripotent stem cells that are capable of generating viable chimeric mice, even in the absence of c-Myc or Sox2. The results establish Mbd3/NuRD as an important epigenetic regulator that restricts the expression of key pluripotency genes, suggesting that drug-induced downregulation of Mbd3/NuRD may be a powerful means to improve the efficiency and fidelity of reprogramming.

 

  1. “Role of histone deacetylase inhibitors in the aging of human umbilical cord mesenchymal stem cells.” Yunshuai Wang, Tao Chen, Hongjie Yan, Hui Qi, Chunyan     Deng, Tao Ye, Shuyan Zhou, FuRong Li, Cell. Biochem. 2013, 114, 2231-2239.

Abstract: Mesenchymal stem cells (MSCs) are self-renewing cells that exhibit differentiation capacity and immune regulation ability. These versatile cells have a wide range of potential applications. However, the spontaneous differentiation and aging of MSCs during long-term culturing restrict the amount of cells available for therapies and tissue engineering. Thus, maintaining the biological characteristics of MSCs during long-term culturing is crucial. Chromatic modification via epigenetic regulatory mechanisms (e.g., histone acetylation, deacetylation, and methylation) is crucial in stem cell pluripotency. We investigated the effects of largazole or trichostatin A (TSA), a novel histone deacetylase inhibitor (HDACi), against human umbilical cord (hUC)-MSCs aging. Results show that low concentrations of largazole or TSA can significantly improve hUC-MSCs proliferation and delay hUC-MSCs aging. Largazole can better improve MSCs proliferation than TSA. HDAC is modulate histone H3 acetylation and methylation in the telomerase reverse-transcriptase, octamer-binding transcription factor 4, Nanog, C-X-C chemokine receptor 4, alkaline phosphatase, and osteopontin genes. HDACis can promote hUC-MSCs proliferation and suppress hUC-MSCs spontaneous osteogenic differentiation. HDACis can affect histone H3 lysine 9 or 14 acetylation and histone H3 lysine 4 dimethylation, thus increasing the mRNA expression of pluripotent and proliferative genes and suppressing the spontaneous differentiation of hUC-MSCs.

 

  1. “Synergistic Triggering of Superoxide Flashes by Mitochondrial Ca2+ Uniport and Basal Reactive Oxygen Species Elevation”, Tingting Hou, Xing Zhang, Jiejia Xu, Chongshu Jian, Zhanglong Huang, Tao Ye, Keping Hu, Ming Zheng, Feng Gao,   Xianhua Wang and Heping Cheng, Biol. Chem. 2013, 288, 4602–4612.

Abstract: Mitochondrial superoxide flashes reflect a quantal, bursting mode of reactive oxygen species (ROS) production that arises from stochastic, transient opening of the mitochondrial permeability transition pore (mPTP) in many types of cells and in living animals. However, the regulatory mechanisms and the exact nature of the flash-coupled mPTP remain poorly understood. Here we demonstrate a profound synergistic effect between mitochondrial Ca2+ uniport and elevated basal ROS production in triggering superoxide flashes in intact cells. Hyperosmotic stress potently augmented the flash activity while simultaneously elevating mitochondrial Ca2+ and ROS. Blocking mitochondrial Ca2+ transport by knockdown of MICU1 or MCU, newly identified components of the mitochondrial Ca2+ uniporter, or scavenging mitochondrial basal ROS markedly diminished the flash response. More importantly, whereas elevating Ca2+ or ROS production alone was inefficacious in triggering the flashes, concurrent physiological Ca2+ and ROS elevation served as the most powerful flash activator, increasing the flash incidence by an order of magnitude. Functionally, superoxide flashes in response to hyperosmotic stress participated in the activation of JNK and p38.Thus, physiological levels of mitochondrial Ca2+ and ROS synergistically regulate stochastic mPTP opening and quantal ROS production in intact cells, marking the flash as a coincidence detector of mitochondrial Ca2+ and ROS signals.

 

  1. “Total Synthesis and Stereochemical Revision of Lagunamide A” Lu Dai, Bo Chen, Honghui Lei, Zhuo Wang, Yuqing Liu, Zhengshuang Xu, Tao Ye Commun. 2012,    48, 8697-8699.

Abstract: A revised configurational assignment for the marine metabolite lagunamide A       is proposed and validated by total synthesis.

 

  1. “Total Synthesis and Absolute Configuration of Nocardioazine B” Mingzhong Wang, Xiangyang Feng, Liangzhen Cai, Zhengshuang Xu and Tao Ye, Commun.        2012,    48, 4344 – 4346.

Abstract: The first total synthesis of the indole alkaloid nocardioazine B was    accomplished     in 10 steps with an overall yield of 11.8%, establishing the absolute stereochemistry of the natural product.

 

  1. “Total Synthesis and Stereochemical Revision of Burkholdac A” Junyang Liu, Xiao Ma, Yuqing Liu, Zhuo Wang, Shuqin Kwong, Qi Ren, Shoubin Tang, Yi Meng,       Zhengshuang     Xu, Tao Ye, Synlett, 2012, 23, 783-787.

Abstract: A stereocontrolled total synthesis of burkholdac A was completed, leading      to a revision of the reported stereochemistry.

 

  1. “Novel Histone Demethylase LSD1 InhibitorsSelectively Target Cancer Cells with Pluripotent Stem Cell Properties” Jing Wang, Fei Lu, Qi Ren, Hong Sun, Zhengshuang Xu, Rongfeng Lan, Yuqing Liu, David Ward, Junmin Quan, Tao Ye, Hui Zhang, Cancer Research, 2011, 71, 7238-7249.  This paper was highlighted by NATURE (China). For     details, please see (http://www.nature.com/nchina/2012/120104/full/nchina.2012.1.html)

Abstract: Histone modification determines epigenetic patterns of gene expression with methylation of histone H3 at lysine 4 (H3K4) often associated with active promoters. LSD1/KDM1 is a histone demethylase that suppresses gene expression by converting dimethylated H3K4 to mono- and unmethylated H3K4. LSD1 is essential for metazoan development, but its pathophysiologic functions in cancer remain mainly uncharacterized. In this study, we developed specific bioactive small inhibitors of LSD1 that enhance H3K4 methylation and derepress epigenetically suppressed genes in vivo. Strikingly, these compounds inhibited the proliferation of pluripotent cancer cells including teratocarcinoma, embryonic carcinoma, and seminoma or embryonic stem cells that express the stem cell markers Oct4 and Sox2 while displaying minimum growth-inhibitory effects on nonpluripotent cancer or normal somatic cells. RNA interference–mediated knockdown of LSD1 expression phenocopied these effects, confirming the specificity of small molecules and further establishing the high degree of sensitivity and selectivity of pluripotent cancer cells to LSD1 ablation. In support of these results, we found that LSD1 protein level is highly elevated in pluripotent cancer cells and in human testicular seminoma tissues that express Oct4. Using these novel chemical inhibitors as probes, our findings establish LSD1 and histone H3K4 methylation as essential cancer-selective epigenetic targets in cancer cells that have pluripotent stem cell properties..

 

  1. “Total Synthesis of Hoiamide C” Lei Wang, Zhengshuang Xu, and Tao Ye Lett. 2011, 13, 2506-2509.

Abstract: Hoiamide C was synthesized in 16 steps with an overall yield of 1.8% starting       from homoallylic alcohol 18, unambiguously confirming its structure.

 

  1. “Inhibition of PDGF, TGF-β and Abl Signaling and Reduction of Liver Fibrosis by the Small Molecule Bcr-Abl Tyrosine Kinase Antagonist Nilotinib”, Yuqing Liu, Zhuo   Wang, Shu Qin Kwong, Eric Lik Hang Lui, Scott L. Friedman, Fu Rong Li, Reni Wing      Chi Lam, Guo Chao Zhang, Hui Zhang, and Tao Ye, Hepatology, 2011, 55, 612-625.

Abstract: BACKGROUND & AIMS: Nilotinib is a novel tyrosine kinase inhibitor of Bcr-Abl and other kinases. In this study, we have examined its activity as an anti-fibrotic agent. METHODS: The in vitro effect of Nilotinib on rat and human HSCs was assessed using proliferation assays and Western blotting. The in vivo antifibrotic efficacy of Nilotinib was assessed in mice with liver fibrosis induced by CCl(4) and bile duct ligation (BDL). RESULTS: Nilotinib inhibited proliferation, migration, and actin filament formation, as well as the expression of α-SMA and collagen in activated HSCs. Nilotinib induced apoptosis of HSCs, which was correlated with reduced bcl-2 expression, increased p53 expression, cleavage of PARP, as well as increased expression of PPARγ and TRAIL-R. Nilotinib also induced cell cycle arrest, accompanied by increased expression of p27 and downregulation of cyclin D1. Interestingly, Nilotinib not only inhibited activation of PDGFR, but also TGFRII through Src. Nilotinib significantly inhibited PDGF and TGFβ-simulated phosphorylation of ERK and Akt. Furthermore, PDGF- and TGFβ-activated phosphorylated form(s) of Abl in human HSCs were inhibited by Nilotinib. In vivo, Nilotinib reduced collagen deposition and α-SMA expression in CCl(4) and BDL-induced fibrosis. These beneficial effects were associated with suppressed expression of procollagen-(I), TIMP-1, CD31, CD34, VEGF, and VEGFR. Nilotinib could induce HSC undergoing apoptosis in vivo, which was correlated with downregulation of bcl-2. We also observed reduced expression of phosphorylated ERK, Akt, and Abl in the Nilotinib-treated CCl(4) and BDL livers. In addition to its antifibrotic activity, the drug was hepatoprotective and reduced the elevations of ALT and AST after CCl(4) and BDL. CONCLUSIONS: These studies uncover a novel role of Bcr-Abl activity in treatment of liver fibrosis through multiple mechanisms and indicate that Nilotinib represents a potentially effective antifibrotic agent.

 

  1. “Development of an Oral Form of Azacytidine: 2’3’5’triacetylazacytidine” Amy Ziemba, Eugene Hayes, Burgess B. Freeman III, Tao Ye and Giuseppe Pizzorno1, Chemotherapy     Prac., 2011 965826, 9 pp. DOI: 10.1155/2011/965826

Abstract: Myelodysplastic syndromes (MDSs) represent a group of incurable stem-cell malignancies which are predominantly treated by supportive care. Epigenetic silencing through promoter methylation of a number of genes is present in poor-risk subtypes of MDS and often predicts transformation to acute myelogenous leukemia (AML). Azacitidine and decitabine, two FDA-approved DNA methyltransferase (DNMT) inhibitors, are able to improve overall response although their oral bioavailability complicates their clinical use. This study evaluated 2′, 3′, 5′-triacetyl-5-azacitidine (TAC) as a potential prodrug for azacitidine. The prodrug demonstrated significant pharmacokinetic improvements in bioavailability, solubility, and stability over the parent compound. In vivo analyses indicated a lack of general toxicity coupled with significantly improved survival. Pharmacodynamic analyses confirmed its ability to suppress global methylation in vivo. These data indicate that esterified nucleoside derivatives may be effective prodrugs for azacitidine and encourages further investigation of TAC into its metabolism, activity, and possible clinical evaluation.

 

  1. “Superoxide Flashes Early Mitochondrial Signals for Oxidative Stress-induced Apoptosis”, Qi Ma, Huaqiang Fang, Wei Shang, Lei Liu, Zhengshuang Xu, Tao Ye,       Xianhua Wang, Ming Zheng, Quan Chen and Heping Cheng, Biol. Chem. 2011,       286, 27573-27581.

Abstract: Irreversible mitochondrial permeability transition and the resultant cytochrome c release signify the commitment of a cell to apoptotic death. However, the role of transient MPT (tMPT) because of flickering opening of the mitochondrial permeability transition pore remains elusive. Here we show that tMPT and the associated superoxide flashes (i.e. tMPT/superoxide flashes) constitute early mitochondrial signals during oxidative stress-induced apoptosis. Selenite (a ROS-dependent insult) but not staurosporine (a ROS-independent insult) stimulated an early and persistent increase in tMPT/superoxide flash activity prior to mitochondrial fragmentation and a global ROS rise, independently of Bax translocation and cytochrome c release. Selectively targeting tMPT/superoxide flash activity by manipulating cyclophilin D expression or scavenging mitochondrial ROS markedly impacted the progression of selenite-induced apoptosis while exerting little effect on the global ROS response. Furthermore, the tMPT/superoxide flash served as a convergence point for pro- and anti-apoptotic regulation mediated by cyclophilin D and Bcl-2 proteins. These results indicate that tMPT/superoxide flashes act as early mitochondrial signals mediating the apoptotic response during oxidative stress, and provide the first demonstration of highly efficacious local mitochondrial ROS signaling in deciding cell fate.