- Exploiting a C–N Bond Forming Cytochrome P450 Monooxygenase for C–S Bond Formation
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C–S bond formation reactions are widely distributed in the biosynthesis of biologically active molecules, and thus have received much attention over the past decades. Herein, we report intramolecular C–S bond formation by a P450 monooxygenase, TleB, which normally catalyzes a C?N bond formation in teleocidin biosynthesis. Based on the proposed reaction mechanism of TleB, a thiol-substituted substrate analogue was synthesized and tested in the enzyme reaction, which afforded the unprecedented sulfur-containing thio-indolactam V, in addition to an unusual indole-fused 6/5/8-tricyclic product whose structure was determined by the crystalline sponge method. Interestingly, conformational analysis revealed that the SOFA conformation is stable in thio-indolactam V, in sharp contrast to the major TWIST form in indolactam V, resulting in differences in their biological activities.
- Abe, Ikuro,Fujita, Makoto,Hoshino, Shotaro,Kikuchi, Takashi,Mitsuhashi, Takaaki,Mori, Takahiro,Morita, Iori,Nagae, Kei,Nasu, Norihiro,Ohwada, Tomohiko,Taniguchi, Yoshimasa
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supporting information
p. 3988 - 3993
(2020/02/05)
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- The Synthesis and Biological Evaluation of Indolactam Alkaloids
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In this work, we execute a general synthetic strategy to access novel indolactam alkaloids, which are agonists of protein kinase C. This protocol allowed for the most efficient reported syntheses of indolactam V (ILV) stereoisomers, while also affording t
- Billingsley, Kelvin L.,Eom, Ryan,Haynes-Smith, Jeremy,Mendoza, Manuel,Salas, Celeste
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p. 4443 - 4451
(2019/11/21)
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- 11-Step Total Synthesis of Teleocidins B-1-B-4
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A unified and modular approach to the teleocidin B family of natural products is presented that proceeds in 11 steps and features an array of interesting strategies and methods. Indolactam V, the known biosynthetic precursor to this family, was accessed through electrochemical amination, Cu-mediated aziridine opening, and a remarkable base-induced macrolactamization. Guided by a desire to minimize concession steps, the tactical combination of C-H borylation and a Sigman-Heck transform enabled the convergent, stereocontrolled synthesis of the teleocidins.
- Nakamura, Hugh,Yasui, Kosuke,Kanda, Yuzuru,Baran, Phil S.
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p. 1494 - 1497
(2019/01/26)
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- Synthetic Indolactam V Analogues as Inhibitors of PAR2-Induced Calcium Mobilization in Triple-Negative Breast Cancer Cells
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Human proteinase-activated receptor 2 (PAR2), a transmembrane G-protein-coupled receptor (GPCR), is an attractive target for a novel anticancer therapy, as it plays a critical role in cell migration and invasion. Selective PAR2 inhibitors therefore have potential as anti-metastatic drugs. Knowing that the natural product teleocidin A2 is able to inhibit PAR2 in tumor cells, the goal of the present study was to elaborate structure–activity relationships and to identify potent PAR2 inhibitors with lower activity against the adverse target, protein kinase C (PKC). For this purpose, an efficient gram-scale total synthesis of indolactam V (i.e., the parent structure of all teleocidins) was developed, and a library of derivatives was prepared. Some compounds were indeed found to exhibit high potency as PAR2 inhibitors at low nanomolar concentrations with improved selectivity (relative to teleocidin A2). The pseudopeptidic fragment bridging the C3 and C4 positions of the indole core proved to be essential for target binding, whereas activity and target selectivity depends on the substituents at N1 or C7. This study revealed novel derivatives that show high efficacy in PAR2 antagonism combined with increased selectivity.
- Stein, Jan,Stahn, Sonja,Neud?rfl, J?rg-M.,Sperlich, Julia,Schmalz, Hans-Günther,Teusch, Nicole
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p. 147 - 154
(2018/02/06)
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- Modular Total Synthesis of Protein Kinase C Activator (-)-Indolactam v
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A concise, eight-step total synthesis of (-)-indolactam V, a nanomolar agonist of protein kinase C, is reported. The synthesis relies upon an efficient copper-catalyzed amino acid arylation to establish the indole C4-nitrogen bond. This cross-coupling met
- Haynes-Smith, Jeremy,Diaz, Italia,Billingsley, Kelvin L.
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p. 2008 - 2011
(2016/06/01)
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- A concise total synthesis of (-)-indolactam v
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One-pot synthesis of tryptophanol derivative from N-Boc-aziridine and indole has been developed. The ring opening reaction of the aziridine takes place smoothly at -30°C in a regioselective manner and tolerates a wide range of functional groups including
- Noji, Toshiharu,Okano, Kentaro,Tokuyama, Hidetoshi
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supporting information
p. 3833 - 3837
(2015/06/02)
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- Total syntheses of indolactam alkaloids (-)-indolactam V, (-)-pendolmycin, (-)-lyngbyatoxin A, and (-)-teleocidin A-2
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We report the total syntheses of (-)-indolactam V and the C7-substituted indolactam alkaloids (-)-pendolmycin, (-)-lyngbyatoxin A, and (-)-teleocidin A-2. The strategy for preparing indolactam V relies on a distortion-controlled indolyne functionalization reaction to establish the C4-N linkage, in addition to an intramolecular conjugate addition to build the conformationally-flexible nine-membered ring. The total synthesis of indolactam V then sets the stage for the divergent synthesis of the other targeted alkaloids. Specifically, late-stage sp2-sp3 cross-couplings on an indolactam V derivative are used to introduce the key C7 substituents and the necessary quaternary carbons. These challenging couplings, in addition to other delicate manipulations, all proceed in the presence of a basic tertiary amine, an unprotected secondary amide, and an unprotected indole. Thus, our approach not only enables the enantiospecific total syntheses of four indolactam alkaloids, but also serves as a platform for probing complexity-generating and chemoselective transformations in the context of alkaloid total synthesis. This journal is the Partner Organisations 2014.
- Fine Nathel, Noah F.,Shah, Tejas K.,Bronner, Sarah M.,Garg, Neil K.
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p. 2184 - 2190
(2014/05/20)
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- Synthesis of (-)-epi-indolactam v by an intramolecular Buchwald-Hartwig C-N coupling cyclization reaction
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The synthetic efforts toward the concise synthesis of (-)-indolactam V from simple and commercially available starting materials using palladium- and copper-catalyzed intramolecular N-arylation strategy for the elaboration of the requisite nine-membered lactam ring as the key step are described. The incorporation of a turn-inducing structural element along the linear precursor was fundamental to achieve the heterocyclization step as well as obtain the correct regio- and chemoselectivity. The stereoselective nature in the C-N coupling cyclization reaction is interpreted in terms of minimization of allylic strain at the transition state for the palladium-amido complex formation. Meanwhile, the synthesis of the (-)-epi-indolactam V and its enantiomer have been accomplished.
- Mari, Michele,Bartoccini, Francesca,Piersanti, Giovanni
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p. 7727 - 7734
(2013/09/02)
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- Total synthesis of (-)-indolactam v
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The total synthesis of protein kinase C activator (-)-indolactam V (IL-V) has been successfully completed with two separate approaches: From known 4-nitrotryptophan derivative 3 in 8 steps (49% overall yield) and from l-glutamic acid in 12 steps (18% overall yield), where 4-nitrotryptophanol derivative 4 served as a key intermediate. Derivatives 3 and 4, both incorporating indole 4-substitution and the C-9 stereocenter in IL-V, were synthesized via the Pd-catalyzed indole synthesis from 3-nitro-2-iodoaniline 5 with aldehydes 6 and 7, respectively. Aldehyde 7 was, meanwhile, synthesized from l-glutamic acid in 5 steps (68% yield). Lactamization of the 9-membered ring was achieved using HATU in THF in good yield.
- Xu, Zhengren,Zhang, Fengying,Zhang, Lihe,Jia, Yanxing
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experimental part
p. 2512 - 2517
(2011/05/06)
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- Enzymatic production of (-)-indolactam V by LtxB, a cytochrome P450 monooxygenase
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The P450 cytochrome monooxygenase gene, ltxB, was cloned and overexpressed in Escherichia coli as a 6xHis-tagged protein. The resulting recombinant LtxB was purified by Ni-NTA affinity chromatography and characterized biochemically. Purified LtxB demonstrated typical cytochrome P450 spectroscopic properties including substrate-induced transition from a low-spin (λmax = 414 nm) to high-spin state (λmax = 386 nm) upon incubation with N-methyl-L-valyl-L-tryptophanol. The catalytic activity of LtxB was verified by demonstrating the oxidation/cyclization of N-methyl-L-valyl-L- tryptophanol to (-)-indolactam V. LtxB shows a relaxed specificity for analogue substrates in which the valyl group is substituted for other aliphatic groups. The relaxed substrate specificity of LtxB, along with the relaxed specificity of the prenyltransferase, LtxC, allowed for the enzymatic production of a series of (-)-indolactam V and lyngbyatoxin analogues.
- Huynh, Minh U.,Elston, Matthew C.,Hernandez, Nick M.,Ball, David B.,Kajiyama, Shin-Ichiro,Irie, Kazuhiro,Gerwick, William H.,Edwards, Daniel J.
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experimental part
p. 71 - 74
(2010/04/28)
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- Protein Kinase C Modulators. Indolactams. 1. Efficient and Flexible Routes for the Preparation of (-)-Indolactam V for Use in the Synthesis of Analogs
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Three syntheses of the protein kinase C activator, (-)-indolactam V, are described and are compared for their potential utility in the preparation of ILV analogs.In one route the 4-amino functionality is introduced regiospecifically during the constructio
- Quick, James,Saha, Bijali,Driedger, Paul E.
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p. 8549 - 8552
(2007/10/02)
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- A SYNTHESIS OF (-)-INDOLACTAM V
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(-)-Indolactam V (1) was synthesized in 14 steps from 2,6-dinitrotoluene in 15 percent overall yield via enantiospecific SN2 displacement of a chiral triflate with the 4-amino group of a 4-aminoindole and coupling of 3-bromomethylindole with Schoellkopf's asymmetric bislactim ether.
- Semmelhack, M. F.,Rhee, Hakjune
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p. 1395 - 1398
(2007/10/02)
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- Synthesis of (-)-Indolactam V
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A stereospecific 7-step synthesis of (-)-indolactam V 1 from tryptophan methyl ester is described.The key steps are the photocyclisation of the dichloroamide 6 to give the isomeric 7-hydroxy-7-isopropylpyrrolobenzazocines 16 + 18 and the nitrene-mediated ring expansion of the derived azide 5 to give the 9-membered imine 4.The synthesis is completed by stereoselective reduction of the imine bond and N-methylation.
- Mascal, Mark,Moody, Christopher J.,Slawin, Alexandra M. Z.,Williams, David J.
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p. 823 - 830
(2007/10/02)
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- A Regio- and stereocontrolled total synthesis of (-)-indolactam-V
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(-)-Indolactam-V (IL-V) (1)-was prepared in 10 steps from L-tryptophan methyl ester in 17.1% overall yield. The key steps involve regiospecific thallation of the acylindole intermediate (4), followed by azide displacement and reduction to introduce the 13-amino group. Control of the C-11 stereocenter was achieved by SN2 displacement of the chiral inflate (10), derived from D-valine. The thallium mediated closure of dipeptide (17) did not provide an alternative route to IL-V.
- Kogan, Timothy P.,Somers, Todd C.,Venuti, Michael C.
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p. 6623 - 6632
(2007/10/02)
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- BIOSYNTHESIS OF (-)-INDOLACTAM V, THE BASIC RING-STRUCTURE OF TUMOR PROMOTERS TELEOCIDINS
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(-)-Indolactam V (1) was shown to be biosynthesized from L-tryptophan, L-valine and L-methionine via N-methyl-L-valyl-L-tryptophanol (3) by feeding experiments with several D or 13C-labelled amino acids and possible biosynthetic precursors.
- Irie, Kazuhiro,Kajiyama, Shin-ichiro,Funaki, Atsushi,Koshimizu, Koichi,Hayashi, Hideo,Arai, Motoo
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p. 101 - 104
(2007/10/02)
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- Efficient Syntheses and Chemistry of Indolactam-V and Its Analogs
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The tumor promoter. indolactam-V (1a), was synthesized in 8 steps and a 15percent overall yield from methyl 4-nitroindole-3-carboxylate (2).Several chemical properties of indolactam-V analogs 10a and 10b were investigated.
- Masuda, Toshiya,Nakatsuka, Shin-ichi,Goto, Toshio
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p. 2257 - 2260
(2007/10/02)
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- Synthesis of (-)-Indolactam V
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A stereospecific seven-step synthesis of (-)-indolactam V (1) from tryptophan methyl ester via the pyrrolobenzazocines (7) and (8) is described.
- Mascal, Mark,Moody, Christopher J.
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p. 589 - 590
(2007/10/02)
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- Synthesis and Stereochemistry of Indolactam-V, An Active Fragment of Teleocidins. Structural Requirements for Tumor-Promoting Activity.
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(-)-Indolactam-V, which is an active fragment of the potent tumor promoters teleocidins and has also been isolated as a Streptoverticillium metabolite, has been synthesized starting from 4-nitrogramine.The absolute stereochemistry of (-)-indolactam-V has been determined to be (9S, 12S), which suggests that teleocidins and related compounds are biosinthesyzed from L-amino acids.Three unnatural diastereoisomers were also synthesized.The NMR spectra of (-)- and (+/-)-indolactam-V and its derivatives showed that they exist in two conformational states in solution.The structures of the two conformers were deduced from the chemical shifts, coupling constants and nuclear Overhauser effects to be SOFA and TWIST from which are characterized by trans and cis amide bonds, respectively.The calculated ratio of the two conformers was consistent with the observed ratio.
- Endo, Yasuyuki,Shudo, Koichi,Itai, Akiko,Hasegawa, Masashi,Sakai, Shin-ichiro
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p. 5905 - 5924
(2007/10/02)
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- SYNTHETIC STUDIES ON TELEOCIDIN IV. AN EFFICIENT SYNTHESIS OF (-)-INDOLACTAM V
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An efficient synthesis of (-)-indolactam V (3) was achieved in 12 steps starting from L-tryptophan.
- Nakatsuka, Shin-ichi,Masuda,Toshiya,Sakai, Kunisaku,Goto, Toshio
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p. 5735 - 5738
(2007/10/02)
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- SYNTHESIS OF OPTICALLY ACTIVE TELEOCIDIN DERIVATIVES. ABSOLUTE CONFIGURATION OF TELEOCIDIN B AND OLIVORETIN A
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Optically active 3,4,5,6,7,8-hexahydro-4(S)-hydroxymethyl-7(S)-isopropyl-8- methyl-6-oxodiazoninoindole was synthesized from N-Boc-4-nitro-L-tryptophanol and a circular dichroism study of the compound shows that the nine-membered ring of teleocidin B and olivoretin A is S,S configuration.KEYWORDS - 3,4,5,6,7,8-hexahydro-6-oxodiazoninoindole; nine-membered lactam; tryptophan; teleocidin B; circular dichroism; absolute configuration; tumor promoter
- Endo, Yasuyuki,Shudo, Koichi,Furuhata, Kimio,Ogura, Haruo,Sakai, Shin-ichiro,et al.
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p. 358 - 361
(2007/10/02)
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