- Piperlongumine derivative as well as preparation method and application thereof
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The invention discloses a Piperlongumine derivative as well as a preparation method and application thereof. The Piperlongumine derivative has the following structure: the Piperlongumine derivative provided by the invention contains a plurality of Michael addition receptor units, and the novel structure improves the electrophilicity, so that the Piperlongumine derivative has good protein targetingpotential, and the Piperlongumine derivative has a good inhibition effect on thioredoxin reductase; in an antitumor bioactive in-vitro screening experiment, the derivative also has a certain inhibition effect on the growth of tumor cells, and meanwhile, the derivative has an effect of promoting the generation of active oxygen in A549 human lung cancer cells.
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Paragraph 0033; 0038
(2021/01/28)
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- Design, synthesis, and biological evaluation of a novel indoleamine 2,3-dioxigenase 1 (IDO1) and thioredoxin reductase (TrxR) dual inhibitor
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Targeting the Trp-Kyn pathway is an attractive approach for cancer immunotherapy. Thioredoxin reductase (TrxR) enzymes are reactive oxygen species (ROS) modulators that are involved in the tumor cell growth and survival processes. The 4-phenylimidazole scaffold is well-established as useful for indoleamine 2,3-dioxygenase 1 (IDO1) inhibition, while piperlongumine (PL) and its derivatives have been reported to be inhibitors of TrxR. To take advantage of both immunotherapy and TrxR inhibition, we designed a first-generation dual IDO1 and TrxR inhibitor (ZC0101) using the structural combination of 4-phenylimidazole and PL scaffolds. ZC0101 exhibited better dual inhibition against IDO1 and TrxR in vitro and in cell enzyme assays than the uncombined forms of 4-phenylimidazole and PL. It also showed antiproliferative activity in various cancer cell lines, and a selective killing effect between normal and cancer cells. Furthermore, ZC0101 effectively induced apoptosis and ROS accumulation in cancer cells. Knockdown of TrxR1 and IDO1 expression induced cellular enzyme inhibition and ROS accumulation effects during ZC0101 treatment, but only reduced TrxR1 expression was able to improve ZC0101′s antiproliferation effect. This proof-of-concept study provides a novel strategy for cancer treatment. ZC0101 represents a promising lead compound for the development of novel antitumor agents that can also be used as a valuable probe to clarify the relationships and mechanisms of cancer immunotherapy and ROS modulators.
- Fan, Qing-Zhu,Zhou, Ji,Zhu, Yi-Bao,He, Lian-Jun,Miao, Dong-Dong,Zhang, Sheng-Peng,Liu, Xiao-Ping,Zhang, Chao
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- Design and synthesis of benzylidenecyclohexenones as TrxR inhibitors displaying high anticancer activity and inducing ROS, apoptosis, and autophagy
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Oxidative therapy, a strategy that specifically increases reactive oxygen species (ROS) levels in tumor cells by disrupting the redox homeostasis has gained increasing interest. The antitumor effects of the natural product piperlongumine (PL) appear to result from its ability to increase intracellular ROS levels via inhibition of antioxidative thioredoxin reductase (TrxR). Twenty-seven benzylidenecyclohexenone-based PL analogues (2a-v and 15a-e) were designed, synthesized and evaluated for their pharmacological properties. Most of the compounds exhibited potent antiproliferative activities against five human cancer cell lines, especially against breast tumor cells. One of the most promising analogueues 2c showed 12-fold higher inhibitory activity against the thioredoxin reductase (TrxR) than PL and surpressed the expression of TrxR1 protein in breast cancer cells and inhibited TrxR enzymatic activity. In addition, 2c increased ROS levels and resulted in marked apoptosis by regulating apoptosis-related proteins expressed in the breast cancer cells. Compound 2c also triggered the formation of autophagosomes and autolysosomes by promoting the expression of LC3-II and Beclin-1 and diminishing the expression of LC3-I and p62 proteins. Finally, 2c displayed low acute toxicity and good inhibitory potency to tumors in mice. Overall, 2c is a promising anti-breast cancer candidate warranting further investigation.
- Hsu, Pei-Ling,Lee, Kuo-Hsiung,Li, Yangyang,Ling, Yong,Liu, Ji,Meng, Chi,Morris-Natschke, Susan L.,Qian, Jianqiang,Xu, Zhongyuan,Yang, Yumin,Zhang, Yanan,Zhu, Weizhong
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- Activity-based protein profiling reveals GSTO1 as the covalent target of piperlongumine and a promising target for combination therapy for cancer
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Through systematic target identification for piperlongumine, a cancer-selective killing molecule, we identified GSTO1 as its major covalent target for cancer cell death induction. We also reveal that GSTO1 inhibition is a promising combination strategy with other anti-cancer agents by drug combination screening in which piperlongumine exhibits broad-spectrum synergistic effects with a large proportion of the tested anti-cancer agents, especially with PI3K/Akt/mTOR pathway inhibitors.
- Li, Li,Zhao, Yue,Cao, Ran,Li, Lin,Cai, Gaihong,Li, Jiaojiao,Qi, Xiangbing,Chen, She,Zhang, Zhiyuan
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p. 4407 - 4410
(2019/04/26)
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- Novel Ligustrazine-Based Analogs of Piperlongumine Potently Suppress Proliferation and Metastasis of Colorectal Cancer Cells in Vitro and in Vivo
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Piperlongumine 1 increases reactive oxygen species (ROS) levels and preferably induces cancer cell apoptosis by triggering different pathways. However, the poor solubility of 1 limits its intensive investigation and clinical application. Ligustrazine possesses a water-soluble pyrazine skeleton and can inhibit proliferation and metastasis of cancer cells. We synthesized compound 3 by replacement of the trimethoxyphenyl of 1 with ligustrazine moiety and further introduced 2-Cl, -Br, and -I to 3 for synthesis of 4-6, respectively. Compound 4 possessed 14-fold greater aqueous solubility than 1 and increased ROS levels in colorectal cancer HCT-116 cells. Additionally, 4 preferably inhibited proliferation, migration, invasion, and heteroadhesion of HCT-116 cells. Treatment with 4 suppressed tumor growth and lung metastasis in vivo and prolonged the survival of tumor-bearing mice. Furthermore, 4 mitigated TGF-β1-induced epithelial-mesenchymal transition and Wnt/β-catenin activation by inhibiting the Akt and GSK-3β phosphorylation in HCT-116 cells. Collectively, 4 displayed significant antiproliferation and antimetastasis activities, superior to 1.
- Zou, Yu,Zhao, Di,Yan, Chang,Ji, Yanpeng,Liu, Jin,Xu, Jinyi,Lai, Yisheng,Tian, Jide,Zhang, Yihua,Huang, Zhangjian
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supporting information
p. 1821 - 1832
(2018/03/21)
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- Synthesis and evaluation of N-heteroaromatic ring-based analogs of piperlongumine as potent anticancer agents
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Piperlongumine (PL) selectively targets a wide spectrum of cancer cells and induces their death by triggering various pathways, including apoptosis, necrosis and autophagy. However, the poor solubility is a serious concern for intensive study and clinical application. We synthesized its analogs 1–9 by replacement of the trimethoxyphenyl of PL with an N-heteroaromatic ring and/or not introduction of 2-Cl. These compounds improved aqueous solubility and displayed potent anticancer activity. The most active compound 9 selectively enhanced ROS levels in colon cancer cells and inhibited the cell proliferation but sparing non-tumor colon cells. Importantly, 9 significantly repressed tumor growth in an HCT-116 xenograft mouse model, suggesting that these N-heteroaromatic ring-based analogs of PL warrant further investigation.
- Zou, Yu,Yan, Chang,Zhang, Huibin,Xu, Jinyi,Zhang, Dayong,Huang, Zhangjian,Zhang, Yihua
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supporting information
p. 313 - 319
(2017/07/07)
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- Direct Catalytic Desaturation of Lactams Enabled by Soft Enolization
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A direct catalytic method is described for the α,β-desaturation of N-protected lactams to their conjugated unsaturated counterparts under mildly acidic conditions. The reaction is consistently operated at room temperature and tolerates a wide range of functional groups, showing reactivity complementary to that of prior desaturation methods. Lactams with various ring sizes and substituents at different positions all reacted smoothly. The synthetic utility of this method is demonstrated in a concise synthesis of Rolipram. In addition, linear amides also prove to be competent substrates, and the phthaloyl-protected product serves as a convenient precursor to access various conjugated carboxylic acid derivatives. Strong bases are avoided in this desaturation approach, and the key is to merge soft enolization with a Pd-catalyzed oxidation process.
- Chen, Ming,Dong, Guangbin
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p. 7757 - 7760
(2017/06/21)
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- Cinnamamide derivatives as well as preparation method and medical application thereof
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The invention belongs to the technical field of medicinal chemistry and medicines and discloses cinnamamide derivatives (I) and (II) as well as a preparation method and a medical application thereof. The novel compound has remarkable anti-platelet aggregation activity, and a new candidate medicine is provided for patients suffering from thromboembolic diseases.
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Paragraph 0011; 0020
(2017/08/28)
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- Piperlongumine (piplartine) and analogues: Antiproliferative microtubule-destabilising agents
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Piperlongumine (piplartine, 1) is a small molecule alkaloid that is receiving intense interest due to its antiproliferative and anticancer activities. We investigated the effects of 1 on tubulin and microtubules. Using both an isolated tubulin assay, and a combination of sedimentation and western blotting, we demonstrated that 1 is a tubulin-destabilising agent. This result was confirmed by immunofluorescence and confocal microscopy, which showed that microtubules in MCF-7 breast cancer cells were depolymerized when treated with 1. We synthesised a number of analogues of 1 to explore structure-activity relationships. Compound 13 had the best cytotoxic profile of this series, showing potent effects in human breast carcinoma MCF-7?cells whilst being relatively non-toxic to non-tumorigenic MCF-10a cells. These?compounds will be further developed as potential clinical candidates for the treatment of breast cancer.
- Meegan, Mary J.,Nathwani, Seema,Twamley, Brendan,Zisterer, Daniela M.,O'Boyle, Niamh M.
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p. 453 - 463
(2016/10/04)
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- Horner-Wadsworth-Emmons approach to piperlongumine analogues with potent anti-cancer activity
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Natural products with anti-cancer activity play a vital role in lead and target discovery. We report here the synthesis and biological evaluation of the plant-derived alkaloid, piperlongumine and analogues. Using a Horner-Wadsworth-Emmons coupling approach, a selection of piperlongumine-like compounds were prepared in good overall yield from a novel phosphonoacetamide reagent. A number of the compounds displayed potent anti-cancer activity against colorectal (HCT 116) and ovarian (IGROV-1) carcinoma cell lines, via a mechanism of action which may involve ROS generation. Contrary to previous reports, no selective action in cancer cell (MRC-5) was observed for piperlongumine analogues.
- Han, Li-Chen,Stanley, Paul A.,Wood, Paul J.,Sharma, Pallavi,Kuruppu, Anchala I.,Bradshaw, Tracey D.,Moses, John E.
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p. 7585 - 7593
(2016/08/16)
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- Design and synthesis of a C7-aryl piperlongumine derivative with potent antimicrotubule and mutant p53-reactivating properties
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Small molecules that can restore biological function to the p53 mutants found in human cancers have been highly sought to increase the anticancer efficacy. In efforts to generate hybrid anticancer drugs that can impact two or more targets simultaneously, we designed and developed piperlongumine (PL) derivatives with an aryl group inserted at the C-7 position. This insertion bestowed a combretastatin A4 (CA4, an established microtubule disruptor) like structure while retaining the piperlongumine configuration. The new compounds exhibited potent antiproliferative activities against eight cancer cell lines, in particular, were more cytotoxic against the SKBR-3 breast cancer cells which harbor a R175H mutation in p53 suppressor. KSS-9, a representative aryl PL chosen for further studies induced abundant ROS generation and protein glutathionylation. KSS-9 strongly disrupted the tubulin polymerization in vitro, destabilized the microtubules in cells and induced a potent G2/M cell cycle block. More interestingly, KSS-9 showed the ability to reactivate the p53 mutation and restore biological activity to the R175H mutant protein present in SKBR3 cells. Several procedures, including immunocytochemistry using conformation-specific antibodies for p53, immunoprecipitation combined with western blotting, electrophoretic shift mobility shift assays showed a reciprocal loss of mutant protein and generation of wildtype like protein. p53 reactivationwas accompanied by the induction of the target genes, MDM2, p21cip1 and PUMA. Mechanistically, the redox-perturbation in cancer cells by the hybrid drug appears to underlie the p53 reactivation process. This anticancer drug approach merits further development.
- Punganuru, Surendra R.,Madala, Hanumantha Rao,Venugopal, Sanjay N.,Samala, Ramakrishna,Mikelis, Constantinos,Srivenugopal, Kalkunte S.
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p. 233 - 244
(2015/11/27)
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- A facile approach to α,β-unsaturated lactams by ring-closing metathesis
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[MediaObject not available: see fulltext.]A facile and efficient strategy for the synthesis of α,β-unsaturated lactams through ring-closing metathesis of easily prepared diene amides is being reported here. Reaction conditions were optimized for metathetic cyclization of diene amides to obtain five- to sevenmembered unsubstituted and β-substituted α,β-unsaturated lactams in good to excellent yield.
- Gondal, Humaira Yasmeen,Buisson, Didier
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p. 183 - 191
(2016/07/28)
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- Design and synthesis of N-acylated aza-goniothalamin derivatives and evaluation of their in vitro and in vivo antitumor activity
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Herein we describe the synthesis of a focused library of compounds based on the structure of goniothalamin (1) and the evaluation of the potential antitumor activity of the compounds. N-Acylation of aza-goniothalamin (2) restored the in vitro antiproliferative activity of this family of compounds. 1- (E)-But-2-enoyl-6-styryl-5,6-dihydropyridin-2(1H)-one (18) displayed enhanced antiproliferative activity. Both goniothalamin (1) and derivative 18 led to reactive oxygen species generation in PC-3 cells, which was probably a signal for caspase-dependent apoptosis. Treatment with derivative 18 promoted Annexin V/7-aminoactinomycin D double staining, which indicated apoptosis, and also led to G2/M cell-cycle arrest. In vivo studies in Ehrlich ascitic and solid tumor models confirmed the antitumor activity of goniothalamin (1), without signs of toxicity. However, derivative 18 exhibited an unexpectedly lower in vivo antitumor activity, despite the treatments being administered at the same site of inoculation. Contrary to its in vitro profile, aza-goniothalamin (2) inhibited Ehrlich tumor growth, both on the ascitic and solid forms. Our findings highlight the importance of in vivo studies in the search for new candidates for cancer treatment.
- Barcelos, Rosimeire Coura,Pastre, Julio Cezar,Vendramini-Costa, Dbora Barbosa,Caixeta, Vanessa,Longato, Giovanna Barbarini,Monteiro, Paula Araffljo,De Carvalho, Joo Ernesto,Pilli, Ronaldo Aloise
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p. 2725 - 2743
(2015/02/02)
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- Synthesis of piperlogs and analysis of their effects on cells
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Piperlongumine (PL) is a naturally occurring small molecule previously shown to induce cell death preferentially in cancer cells relative to non-cancer cells. An initial effort to synthesize analogs highlighted the reactivities of both of piperlongumine's α,β-unsaturated imide functionalities as key features determining PL's cellular effects. In this study, a second-generation of analogs was synthesized and evaluated in cells to gain further insight into how the reactivity, number, and orientation of PL's reactive olefins contribute to its ability to alter the physiology of cells.
- Boskovic, Zarko V.,Hussain, Mahmud M.,Adams, Drew J.,Dai, Mingji,Schreiber, Stuart L.
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p. 7559 - 7567
(2013/08/23)
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- Synthesis and biological evaluation of new piplartine analogues as potent aldose reductase inhibitors (ARIs)
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As a continuation of our efforts directed towards the development of anti-diabetic agents from natural sources, piplartine was isolated from Piper chaba, and was found to inhibit recombinant human ALR2 with an IC50 of 160 μM. To improve the efficacy, a series of analogues have been synthesized by modification of the styryl/aromatic and heterocyclic ring functionalities of this natural product lead. All the derivatives were tested for their ALR2 inhibitory activity, and results indicated that adducts 3c, 3e and 2j prepared by the Michael addition of piplartine with indole derivatives displayed potent ARI activity, while the other compounds displayed varying degrees of inhibition. The active compounds were also capable of preventing sorbitol accumulation in human red blood cells.
- Rao, Vidadala Ramasubba,Muthenna, Puppala,Shankaraiah, Gundeti,Akileshwari, Chandrasekhar,Babu, Kothapalli Hari,Suresh, Ganji,Babu, Katragadda Suresh,Chandra Kumar, Rotte Sateesh,Prasad, Kothakonda Rajendra,Yadav, Potharaju Ashok,Petrash, J. Mark,Reddy, Geereddy Bhanuprakash,Rao, Janaswamy Madhusudana
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p. 344 - 361
(2013/01/15)
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- Photochemical rearrangement of N -chlorolactams: A route to N -heterocycles through concerted ring contraction
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We report a novel ring contraction allowing the direct conversion of N-chlorolactams to their corresponding ring-contraction N-heterocycles upon photolysis. Results show that the rearrangement occurs with a variety of N-chlorolactams and that the greater the substitution at the migrating carbon, the greater the yield of product. Importantly, stereochemistry at the migrating carbon is conserved in the product. Rearranged products were isolated as their methyl carbamates in yields varying from 17% to 58%, with the major side product being the recyclable parent lactam.
- Winter, Dana K.,Drouin, Alexandre,Lessard, Jean,Spino, Claude
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supporting information; experimental part
p. 2610 - 2618
(2010/06/17)
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- Inter- and intraspecific comparisons of antiherbivore defenses in three species of rainforest understory shrubs
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Plants defend themselves against herbivores and pathogens with a suite of morphological, phenological, biochemical, and biotic defenses, each of which is presumably costly. The best studied are allocation costs that involve trade-offs in investment of resources to defense versus other plant functions. Decreases in growth or reproductive effort are the costs most often associated with antiherbivore defenses, but trade-offs among different defenses may also occur within a single plant species. We examined trade-offs among defenses in closely related tropical rain forest shrubs (Piper cenocladum, P. imperiale, and P. melanocladum) that possess different combinations of three types of defense: ant mutualists, secondary compounds, and leaf toughness. We also examined the effectiveness of different defenses and suites of defenses against the most abundant generalist and specialist Piper herbivores. For all species examined, leaf toughness was the most effective defense, with the toughest species, P. melanocladum, receiving the lowest incidence of total herbivory, and the least tough species, P. imperiale, receiving the highest incidence. Although variation in toughness within each species was substantial, there were no intraspecific relationships between toughness and herbivory. In other Piper studies, chemical and biotic defenses had strong intraspecific negative correlations with herbivory. A wide variety of defensive mechanisms was quantified in the three Piper species studied, ranging from low concentrations of chemical defenses in P. imperiale to a complex suite of defenses in P. cenocladum that includes ant mutualists, secondary metabolites, and moderate toughness. Ecological costs were evident for the array of defensive mechanisms within these Piper species, and the differences in defensive strategies among species may represent evolutionary trade-offs between costly defenses.
- Fincher,Dyer,Dodson,Richards,Tobler,Searcy,Mather,Reid,Rolig,Pidcock
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p. 558 - 574
(2008/09/20)
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- Efficient synthesis and astonishing supramolecular architectures of several symmetric macrolactams
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The synthesis of four Cn symmetric macrocyclic lactams cyclo-[NH-CH2-CH=CH-CH2-CO], (1, n = 2; 2, n = 3; 3, n = 4) and cyclo-[NH-CH2-CH2-CH=CH-CO]3 (4) has been achieved by two approaches. A linear route leads to precursors that are subsequently macrocyclized in a separate step. The second, convergent approach relies on the symmetry of the targets: it includes suitably activated subunits, which are subjected to macrocyclization conditions. The subunits first oligomerize, then cyclize to form either pure macrolactams or mixtures. The macrolactam units 1, 2 and 4 stack on top each other through weak interactions (hydrogen bond and van der Waals), to form endless square, rectangular and triangular prisms, respectively. These stacks are further packed side by side in crystals grown from isotropic media. The overall dipoles in the crystals from lactams 1 and 4, which result mostly from the alignment of amide groups, are zero and large, respectively. Macrolactam 2 displays an astonishing isomorphism when allowed to cool down in anisotropic liquid crystal solutions. Large hollow hexagonal tubes are then obtained through a fractal process. Contrary to the three previous rings, 3 yields crystals where prisms of any shape are absent.
- Baillargeon, Pierre,Bernard, Sylvain,Gauthier, David,Skouta, Rachid,Dory, Yves L.
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p. 9223 - 9235
(2008/12/20)
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- Xanthone receptors as oxyanion-hole mimics in artificial enzymes
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Different xanthone-based receptors (2-10) for lactones and lactams have been prepared, and the feasibility of these compounds to mimic the known enzymatic 'oxyanion-hole' structure is discussed. The self-association of the receptors was found to pose a serious drawback for complex formation. X-Ray crystal structures of receptor dimers allowed us to understand the reasons for their self-association and to improve the design of the catalysts. The catalytic activity of the receptors has been tested towards the nucleophilic addition of pyrrolidine to unsaturated lactones. Since the resulting complexes were very weak in organic solvents, new receptors were developed for lactams, which showed better stabilities, and their catalytic activities were studied.
- Simon, Luis,Muniz, Francisco M.,Saez, Silvia,Raposo, Cesar,Sanz, Francisca,Moran, Joaquin R.
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p. 1682 - 1701
(2007/10/03)
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- SYNTHESIS AND MOLECULAR STRUCTURE OF PIPLARTINE (=PIPERLONGUMINE)
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The structure of piplartine (=piperlongumine) was established as (E)-N-3',4',5'-trimethoxycinnamoyl-5,6-dihydro-2(1H)-pyridone (13) by synthesis and by an X-ray crystallographic analysis.Model condensation of (E)-3,4,5-trimethoxycinnamoyl chloride and crotonamide gave not the expected ciannamoylcrotonamide, but (E)-N-3',4',5'-trimethoxycinnamoyl-3-chlorobutyramide (12).
- Boll, Per M.,Hansen, Jesper,Simonsen, Ole,Thorup, Niels
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p. 171 - 176
(2007/10/02)
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