- A synthetic approach to kingianin A based on biosynthetic speculation
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A synthetic approach towards the structurally complex dimer, kingianin A is reported. The strategy involved a cascade of complexity generating reactions, inspired through biosynthetic speculation. A concise protecting group free synthesis of the proposed monomeric precursor pre-kingianin A has been achieved using a tandem Stille cross-coupling reaction and electrocyclisation process. However, preliminary studies of the key dimerisation reaction have been conducted, which indicate that the process is not spontaneous, raising questions as to the origin of this complex natural product.
- Sharma, Pallavi,Ritson, Dougal J.,Burnley, James,Moses, John E.
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- The total synthesis of berberine and selected analogues, and their evaluation as amyloid beta aggregation inhibitors
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The total synthesis of berberine and selected analogues. And their evaluation as amyloid β (Aβ) aggregation inhibitors is described. The key step in the synthesis, the assembly of the berberine framework, was accomplished using an intermolecular Heck reaction. Berberine analog 17 incorporating a tertiary amine moiety showed good anti Aβ aggregation activity, water solubility, and almost no toxicity to nerve cells.
- Tajiri, Misato,Yamada, Ryo,Hotsumi, Mayumi,Makabe, Koki,Konno, Hiroyuki
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- Structural elucidation, bio-inspired synthesis, and biological activities of cyclic diarylpropanes from Horsfieldia kingii
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Bioactivity-guided phytochemical investigation on 70% aqueous acetone extracts of the twigs and leaves of Horsfieldia kingii led to the isolation of two novel cyclic diarylpropanes (1 and 2) bearing a 2,3-dihydro-1H-indene core, one new diarylpropane (3), six known diarylpropanes (4–9), one flavanol (10), and seven lignans (11–17). Their structures were determined by extensive spectroscopic analysis, electronic circular dichroism calculations, and X-ray diffraction crystallography. Moreover, a biomimetic synthesis of 1 and 2 were accomplished in four steps. The in vitro nitric oxide production inhibition tests of these compounds revealed that compounds (±)-2, (+)-2, (?)-2, and 10 were potential with IC50 values lower than 10 μM. Compound 2 could inhibit iNOS expression in LPS-induced RAW264.7 cells at a series of non-cytotoxic concentrations (20 μM). Furthermore, the bioassay results also suggested the primary SARs of 1-phenyl-2,3-dihydro-1H-indene based scaffold.
- Chen, Lei,Chen, Ye-Gao,Li, Dashan,Liu, Yuan-Lie,Shao, Li-Dong,Wang, Wen-Jing,Xie, Xiao-Yan,Zhan, Rui
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- Synthesis of Arylacetaldehydes by Iridium-Catalyzed Arylation of Vinylene Carbonate with Arylboronic Acids
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The one-step synthesis of arylacetaldehydes by carbon–carbon bond formation between formylmethyl and aryl groups has been realized by the reaction of vinylene carbonate with arylboronic acids in the presence of an iridium/bisphosphine catalyst and a catalytic amount of tetrahydroxydiboron.
- Wang, Zhe,Xue, Fei,Hayashi, Tamio
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supporting information
p. 11054 - 11057
(2019/07/17)
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- Novel Hypoxia-Inducible Factor 1α (HIF-1α) Inhibitors for Angiogenesis-Related Ocular Diseases: Discovery of a Novel Scaffold via Ring-Truncation Strategy
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Ocular diseases featuring pathologic neovascularization are the leading cause of blindness, and anti-VEGF agents have been conventionally used to treat these diseases. Recently, regulating factors upstream of VEGF, such as HIF-1α, have emerged as a desirable therapeutic approach because the use of anti-VEGF agents is currently being reconsidered due to the VEGF action as a trophic factor. Here, we report a novel scaffold discovered through the complete structure-activity relationship of ring-truncated deguelin analogs in HIF-1α inhibition. Interestingly, analog 6i possessing a 2-fluorobenzene moiety instead of a dimethoxybenzene moiety exhibited excellent HIF-1α inhibitory activity, with an IC50 value of 100 nM. In particular, the further ring-truncated analog 34f, which showed enhanced HIF-1α inhibitory activity compared to analog 2 previously reported by us, inhibited in vitro angiogenesis and effectively suppressed hypoxia-mediated retinal neovascularization. Importantly, the heteroatom-substituted benzene ring as a key structural feature of analog 34f was identified as a novel scaffold for HIF-1α inhibitors that can be used in lieu of a chromene ring.
- An, Hongchan,Lee, Seungbeom,Lee, Jung Min,Jo, Dong Hyun,Kim, Joohwan,Jeong, Yoo-Seong,Heo, Mi Jeong,Cho, Chang Sik,Choi, Hoon,Seo, Ji Hae,Hwang, Seyeon,Lim, Jihye,Kim, Taewoo,Jun, Hyoung Oh,Sim, Jaehoon,Lim, Changjin,Hur, Joonseong,Ahn, Jungmin,Kim, Hyun Su,Seo, Seung-Yong,Na, Younghwa,Kim, Seok-Ho,Lee, Jeewoo,Lee, Jeeyeon,Chung, Suk-Jae,Kim, Young-Myeong,Kim, Kyu-Won,Kim, Sang Geon,Kim, Jeong Hun,Suh, Young-Ger
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p. 9266 - 9286
(2018/10/24)
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- Modular synthesis and biological investigation of 5-hydroxymethyl dibenzyl butyrolactones and related lignans
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Dibenzyl butyrolactone lignans are well known for their excellent biological properties, particularly for their notable anti-proliferative activities. Herein we report a novel, efficient, convergent synthesis of dibenzyl butyrolactone lignans utilizing the acyl-Claisen rearrangement to stereoselectively prepare a key intermediate. The reported synthetic route enables the modification of these lignans to give rise to 5-hydroxymethyl derivatives of these lignans. The biological activities of these analogues were assessed, with derivatives showing an excellent cytotoxic profile which resulted in programmed cell death of Jurkat T-leukemia cells with less than 2% of the incubated cells entering a necrotic cell death pathway.
- Davidson, Samuel J.,Pilkington, Lisa I.,Dempsey-Hibbert, Nina C.,El-Mohtadi, Mohamed,Tang, Shiying,Wainwright, Thomas,Whitehead, Kathryn A.,Barker, David
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- Hypervalent Iodine(III)-Mediated Cascade Cyclization of Propargylguanidines and Total Syntheses of Kealiinine B and C
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An oxidative cascade cyclization of propargylguanidines promoted by phenyliodonium diacetate (PIDA) was developed. The protocol provides an efficient route for the synthesis of the alkaloids kealiinines B and C as well as homologues. The difference in the electronic nature of the acetylene substituent resulted in two ways of the cyclization. A plausible mechanism is proposed based on the experimental results.
- Tian, Guilong,Fedoseev, Pavel,Van der Eycken, Erik V.
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p. 5224 - 5227
(2017/04/24)
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- Strategies for the construction of morphinan alkaloid AB-rings: Regioselective Friedel-Crafts-type cyclisations of γ-aryl-β-benzoylamido acids with asymmetrically substituted γ-aryl rings
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The regioselectivity of the Friedel-Crafts-type cyclisation of a range of γ-aryl-β-benzoylamido acids, bearing oxy substituents at the C(3)- and C(4)-positions of the γ-aryl ring, has been investigated. In all of the cases examined (with 3,4-dimethoxy, 3,4-methylenedioxy and 3-hydroxy-4-methoxy substituents) the Lewis acid promoted cyclisation proceeds with exclusive regioselectivity for attack at the C(6)-position rather than at the C(2)-position, and furnishes the corresponding N- and O-protected 3-amino-6,7-dihydroxy-1-tetralone derivatives. This inherent regioselectivity can be overturned by the regioselective introduction of chlorine as a blocking group for the C(6)-position; subsequent Lewis acid promoted cyclisation then proceeds with exclusive regioselectivity for attack at the C(2)-position to deliver the corresponding N- and O-protected 3-amino-5-chloro-7,8-dihydroxy-1-tetralone derivative. These complementary cyclisation protocols represent useful methods for the preparation of these benzo-fused carbocyclic ring systems, which are the functionalised AB-rings of a range of morphinan alkaloids.
- Davies, Stephen G.,Goddard, Euan C.,Roberts, Paul M.,Russell, Angela J.,Smith, Andrew D.,Thomson, James E.,Withey, Jonathan M.
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p. 274 - 284
(2017/03/01)
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- An unexpected pentacarbonyl chromium complexation of a cyano group of the ABC core of cephalotaxine
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A new penta-carbonyl chromium(0) complex of the type [Cr(CO)5(L)] (L = tetracyclic pyrrolobenzazepine unit 3) was surprisingly obtained by reacting [Cr(CO)3(naphthalene)] or [Cr(CO)3(tmtach)] with the tetracyclic pyrrolobenzazepine unit 3 in octane-ether/THF-solvent mixtures or acetone under ambient temperature or reflux. The new complex 13 has been characterized by spectral analysis including IR, 1H and 13C NMR data. For comparison purposes, the safrole-tricarbonyl chromium(0) complex 12 was prepared and characterized. X-ray diffraction analyses of both complexes were determined. Based on the above data, an octahedral structure has been assigned to the new complex 13.
- Quteishat, Laith,Panossian, Armen,Le Bideau, Franck,Alsalim, Rana,Retailleau, Pascal,Troufflard, Claire,Rose, Eric,Dumas, Fran?oise
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- The catalytic potential of Coptis japonica NCS2 revealed - Development and utilisation of a fluorescamine-based assay ETI
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The versatility and potential of a norcoclaurine synthase (NCS) from Coptis japonica NCS2 has been investigated, together with the development and application of a novel fluorescence-based high-throughput assay using nearly forty amines/aldehydes. The stereocontrol exerted by CjNCS2 on selected non-natural substrates has been determined, where the tetrahydroisoquinolines (THIAs) were formed as the (1S)-isomer in >95% ee, as observed with the natural product norcoclaurine. Docking calculations involving THIA mechanism intermediates, utilising the reported Thalictrum flavum NCS X-ray crystallographic structure, were carried out and combined with the CjNCS2 screening results to further understand the mode of action of NCS. These findings suggested that in addition to the key active-site residues K122 and E110, D141 is also mechanistically essential for the enzymatic transformation. The exceptional tolerance of NCS towards aldehyde substrates is furthermore supported by our proposed mechanism in which the aldehydes protrude out of the enzymatic pocket. Copyright
- Pesnot, Thomas,Gershater, Markus C.,Ward, John M.,Hailes, Helen C.
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supporting information
p. 2997 - 3008
(2013/01/15)
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- Concise and diversity-oriented route toward polysubstituted 2-aminoimidazole alkaloids and their analogues
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Alkaloids of the naamine family were synthesized from diverse propargylamines in just two steps (see scheme: R1=Me, R 2=substituted benzyl, R3=Ar). Thus, the addition to a propargylamine of a carbodiimide generated in situ
- Ermolat'Ev, Denis S.,Bariwal, Jitender B.,Steenackers, Hans P. L.,De Keersmaecker, Sigrid C. J.,Van Der Eycken, Erik V.
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supporting information; experimental part
p. 9465 - 9468
(2011/02/28)
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- 4-(CONDENSED CYCLICMETHYL)-IMIDAZOLE-2-THIONES ACTING AS ALPHA2 ADRENERGIC AGONISTS
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Compounds of Formula 1 where the variables have the meaning defined in the specification are agonists of alpha2 adrenergic receptors. Several compounds of the disclosure are specific or selective to alpha 2B and/or alpha2C adrenergic receptors in preferen
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Page/Page column 22-23
(2008/06/13)
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- Synthesis and preliminary pharmacological evaluation of 4′-arylalkyl analogues of clozapine. II. Effect of the nature and length of the linker
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We report the synthesis of a second generation of tricyclic analogues of clozapine, investigating the length and nature of the chain between an ionizable nitrogen atom at physiological pH and the introduced aryl moiety. The chemistry, structural characterization, and pharmacological evaluation of this series of 4′-arylalkyl analogues of clozapine are described. Preliminary findings on the effects on activity of the nature and length of the linker, degree of unsaturation, and type of aryl moiety on blockade of dopamine D4 and serotonin 5-HT2A receptors are discussed and animal behavioural data for key compounds presented.
- Capuano, Ben,Crosby, Ian T.,Lloyd, Edward J.,Podloucka, Anna,Taylor, David A.
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p. 875 - 886
(2007/10/03)
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- The Oxidation of 3-Aryl-1-propenes by Oxidative System of RuCl 3-NaIO4-Phase Transfer Catalyst
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Methyleugenol 1a was oxidized to give 3,4-dimethoxyphenylacetaldehyde by the oxidative system containing the RuCl3-NaIO4-phase transfer catalyst. The yield and spectroscopic properties were obtained from the stable acetaldoxim 3a. Furthermore, this oxidation system could be applied to other arylpropenes, thus, safrole, 4-methoxyallylbenzene, allylbenzene, and the corresponding arylacetaldehyde formed.
- Yuasa, Yoshifumi,Shibuya, Shiroshi,Yuasa, Yoko
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p. 3947 - 3952
(2007/10/03)
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- Isotopic changes during the synthesis of amphetamines
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Observed variations in the δ13C and δ15N content of amphetamines are shown to be attributable to kinetic isotope effects during synthesis; chemical degradation and isotopic characterisation provides a means to identify the synthetic origins of illicit MDMA and other amphetamines.
- Carter, James F.,Titterton, Emma L.,Grant, Helen,Sleeman, Richard
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p. 2590 - 2591
(2007/10/03)
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- Synthesis of a biochemically important aldehyde, 3,4- dihydroxyphenylacetaldehyde
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3,4-Dihydroxyphenylacetaldehyde (DOPAL) is an important precursor of the major brain metabolites of dopamine, 3,4-dihydroxyphenylacetic acid and 4- hydroxy-3-methoxyphenylacetic acid. A new method for the synthesis of DOPAL from piperonal is described. We report for the first time the physical and chemical characteristics of DOPAL. Its importance for research in Parkinson's disease and Alzheimer's disease is discussed.
- Li, Shu Wen,Spaziano, Vincent T.,Burke, William J.
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- Total synthesis of isodeoxypodophyllotoxin using the Me3Sn radical initiated carbocyclization
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The lactone portion of the podophylotoxin framework was assembled from a free-radical carbocyclization reaction, and the target structure was constructed based on intramolecular Friedel-Crafts reaction. In addition to isodeoxypodophyllotoxin, there were formed unusual tri- and tetracyclic compounds.The lactone portion of the podophylotoxin framework was assembled from a free-radical carbocyclization reaction, and the target structure was constructed based on intramolecular Friedel-Crafts reaction. In addition to isodeoxypodophyllotoxin, there were formed unusual tri- and tetracyclic compounds.
- Hanessian, Stephen,Ninkovic, Sacha
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p. 1880 - 1888
(2007/10/03)
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- Synthesis and LTB4 receptor antagonist activities of the naturally occurring LTB4 receptor antagonist Leucettamine A and related analogues
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The isolation and structure determination of the naturally occurring LTB4 receptor antagonist Leucettamine A (1) was recently reported. Herein we describe the synthesis of this natural product, the preparation of several analogues, and their effectiveness as antagonists of [3H]LTB4 binding to intact human U-937 cells. Total synthesis of Leucettamine A (1) is achieved by a convergent route which takes advantage of the elements of symmetry within the molecule. Syntheses of analogues of 1, which lacked the same degree of symmetry, are achieved by a different approach starting from α- amino acids. The natural product 1 inhibits [3H]LTB4 binding to its receptors on intact human U-937 cells with a K(i) = 3.5 ± 0.8 μM and is devoid of measurable agonist activity at the concentrations tested. 2-Amino imidazole analogues of 1 lacking the dioxolane groups were prepared. Generally these are significantly less potent than 1. However, one (26), designed on the basis of a putative structural overlay with LTB4, demonstrated potency comparable to that of the natural product (K(i) = 2.4 ± 0.2 μM).
- Boehm,Gleason,Pendrak,Sarau,Schmidt,Foley,Kingsbury
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p. 3333 - 3340
(2007/10/02)
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- A Convenient Strategy for Homologation of p-Oxygenated Benzaldehydes
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It is shown that p-oxygenated benzaldehydes can be conveniently obtained by pyrolysis of the corresponding oxiranes.
- Haridas, K.,Dev, Sukh
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p. 1018 - 1020
(2007/10/02)
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- Transformation of Aromatic Nitroalkanes into Carbonyl Compounds by the Improved Nef Reaction
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An improved two-layer method of the Nef reaction which is effective for the conversion of a variety of aromatic nitroalkanes into carbonyl compounds is described.
- Chikashita, H.,Morita, Y.,Itoh, K.
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p. 677 - 684
(2007/10/02)
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- Method of preparing aldehydes
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A novel method for preparing substituted actaldehydes comprising subjecting a specific sulfoxide derivative to an acidic hydrolysis.
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