- Two chromone-secoiridoid glycosides and three indole alkaloid glycosides from Neonauclea sessilifolia
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From the dried roots of Neonauclea sessilifolia, two new chromone-secoiridoid glycosides, sessilifoside and 7″-O-β-D-glucopyranosylsessilifoside, and three novel indole alkaloid glycosides, neonaucleosides A, B, and C, were isolated along with the main known glycosides, 5-hydroxy-2-methylchromone-7-O-β-D-apiofuranosyl-(1→6)- β-D-glucopyranoside, sweroside, loganin, grandifloroside, and quinovic acid 3β-O-β-D-quinovopyranoside-28-O-β-D-glucopyranoside. The structures of these new glycosides were determined by spectroscopic and chemical means. Neonaucleoside A and its C-3 epimer were prepared from secologanin and tryptamine.
- Itoh, Atsuko,Tanahashi, Takao,Nagakura, Naotaka,Nishi, Toyoyuki
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- A facile chemoenzymatic approach: One-step syntheses of monoterpenoid indole alkaloids
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Facile chemoenzymatic syntheses of cytotoxic monoterpenoid indole alkaloids with novel skeletons and multiple chiral centers are described. Synthesis of these alkaloids was achieved by a simple one-step reaction using strictosidine and 12-aza-strictosidine as the key intermediates. Strictosidines were prepared by coupling of secologanin with tryptamine and 7-aza-tryptamine, respectively, using the immobilized recombinant Rauvolfia strictosidine synthase. A detailed stereochemical analysis is presented herein. The results provide an opportunity for a chemoenzymatic approach that leads to an increased diversification of complex alkaloids with improved structures and activities.
- Zou, Hong-Bin,Zhu, Hua-Jian,Zhang, Liang,Yang, Liu-Qing,Yu, Yong-Ping,Stoeckigt, Joachim
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- Synthesis and biochemical evaluation of des-vinyl secologanin aglycones with alternate stereochemistry
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Based on the X-ray structure of the enzyme strictosidine synthase, the glucose moiety of the seco-iridoid glucoside, secologanin, appears to be the key for orienting the substrate. We hypothesized that removing the glucose moiety would allow alternate stereoisomers of secologanin to be turned over. A convenient synthesis to prepare stereoisomers of des-vinyl secologanin is presented. The choice of protective group was the key to access this series of compounds. The analogs were assayed with strictosidine synthase and, interestingly, both the natural 2,4-trans diastereomer and the unnatural 2,4-cis diastereomer are turned over. The trans/cis selectivity increases with increased acetal substituent size. The results add to our understanding of how strictosidine synthase discriminates among stereoisomers.
- Bernhardt, Peter,O'Connor, Sarah E.
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- Strictosidine Synthase Triggered Enantioselective Synthesis of N-Substituted (S)-3,14,18,19-Tetrahydroangustines as Novel Topoisomerase i Inhibitors
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Monoterpenoid indole alkaloids (MIAs) comprise an important class of molecules for drug discovery, and they have variant carbon skeletons with prominent bioactivities. For instance, in spite of limitations to their use, camptothecins are the only clinically approved topoisomerase I (Top1) inhibitors. The enzyme strictosidine synthase, which is key for MIA biosynthesis, was applied to the enantioselective preparation of three N-substituted (S)-3,14,18,19-tetrahydroangustine (THA) derivatives. These non-camptothecin MIAs were shown to have moderate in vitro HepG2 cytotoxicity and Top1 inhibition activities. The (S)-configured MIAs had stronger cytotoxicity and Top1 inhibition than their chemically synthesized (R)-enantiomers, which aligned with the results of molecular dynamics simulations. A series of N-substituted (S)-THAs were then chemoenzymatically synthesized to investigate structure-activity relationships. The most active analogue observed was the N-(2-Cl benzoyl)-substituted derivative (7i). Insight into the binding mode of 7i and a Top1-DNA covalent complex was investigated by molecular dynamics simulations, which will facilitate future efforts to optimize the Top1 inhibitory activities of non-camptothecin MIAs.
- Cai, Yunrui,Zhu, Huajian,Alperstein, Zaccary,Yu, Wenjun,Cherkasov, Artem,Zou, Hongbin
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- Deeper insights into the stereostructure of strictosamide tetraacetate and methylisoalangiside tetraacetate, the key reference molecules in monoterpenoid indole- and isoquinoline glucoalkaloids
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The highly shifted acetyl NMR signal of strictosamide tetraacetate, one of the most important reference molecules in the glucoindole alkaloid fields, is that on C2 of the glucose moiety. The signal that behaves similarly in methylisoalangiside tetraacetate was also confirmed to he that on C2.
- Takayama,Ohmori,Subhadhirasakul,Kitajima,Aimi
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- Substrate specificity of strictosidine synthase
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Strictosidine synthase catalyzes a Pictet-Spengler reaction in the first step in the biosynthesis of terpene indole alkaloids to generate strictosidine. The substrate requirements for strictosidine synthase are systematically and quantitatively examined and the enzymatically generated compounds are processed by the second enzyme in this biosynthetic pathway.
- McCoy, Elizabeth,Galan, M. Carmen,O'Connor, Sarah E.
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- First direct and detailed stereochemical analysis of strictosidine
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Using the easy lactamization of vincoside (4), epimer-free strictosidine (1) was prepared from secologanin (2) and tryptamine (3). 2D NMR methods were used to determine unambiguously the 1H- and 13C-NMR chemical shifts, the 1H-1H and 13C-1H coupling constants, and the 1H-1H NOE interactions in strictosidine (1). A minimal number of spectroscopic parameters (11 coupling constants, 3 NOEs) and some theoretical considerations have made it possible to select the single species of the 648 selected stereoisomers and to confirm directly the S configuration at the newly formed C-3 chiral center, the P helicity of the dihydropyran and tetrahydropyridine rings, and the conformations around C-14 and the glycosidic bridge.
- Patthy-Lukats, Agnes,Karolyhazy, Laszlo,Szabo, Laszlo F.,Podanyi, Benjamin
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- Substrate specificity and diastereoselectivity of strictosidine glucosidase, a key enzyme in monoterpene indole alkaloid biosynthesis
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Strictosidine glucosidase (SGD) from Catharanthus roseus catalyzes the deglycosylation of strictosidine, an intermediate from which thousands of monoterpene indole alkaloids are derived. The steady-state kinetics of SGD with a variety of strictosidine analogs revealed the substrate preferences of this enzyme at two key positions of the strictosidine substrate. Additionally, SGD from C. roseus turns over both strictosidine and its stereoisomer vincoside, indicating that although this enzyme prefers the naturally occurring diastereomer, the enzyme is not completely diastereoselective. The implications of the substrate specificity of SGD in metabolic engineering efforts of C. roseus are highlighted.
- Yerkes, Nancy,Wu, Jia Xin,McCoy, Elizabeth,Galan, M. Carmen,Chen, Shi,O'Connor, Sarah E.
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- Bacterial biotransformation of 3α(S)-strictosidine to the monoterpenoid indole alkaloid vallesiachotamine
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3α(S)-Strictosidine produced by heterologously expressed strictosidme synthase from Rauwolfia serpentina was used in biotransformation experiments with a series of 22 bacterial strains.All strains tested were found to deglucosylate and rearrange the alkaloid to vallesiachotamine, thereby providing an example of how gene technology and microbial biotransformation can be combined for the biotechnological production of alkaloidal natural products. - Keywords: Rauwolfia serpentina, Spodoptera frugiperda, baculovirus, strictosidine synthase, vallesiachotamine.
- Shen, Zhengwu,Eisenreich, Wolfgang,Kutchan, Toni M.
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- Engineering strictosidine synthase: Rational design of a small, focused circular permutation library of the β-propeller fold enzyme
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Strictosidine synthases catalyze the formation of strictosidine, a key intermediate in the biosynthesis of a large variety of monoterpenoid indole alkaloids. Efforts to utilize these biocatalysts for the preparation of strictosidine analogs have however been of limited success due to the high substrate specificity of these enzymes. We have explored the impact of a protein engineering approach called circular permutation on the activity of strictosidine synthase from the Indian medicinal plant Rauvolfia serpentina. To expedite the discovery process, our study departs from the usual process of creating a random protein library, followed by extensive screening. Instead, a small, focused library of circular permutated variants of the six bladed β-propeller protein was prepared, specifically probing two regions which cover the enzyme active site. The observed activity changes suggest important roles of both regions in protein folding, stability and catalysis.
- Fischereder, Eva,Pressnitz, Desiree,Kroutil, Wolfgang,Lutz, Stefan
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- Total Synthesis of (-)-Strictosidine and Interception of Aryne Natural Product Derivatives "strictosidyne" and "strictosamidyne"
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Monoterpene indole alkaloids are a large class of natural products derived from a single biosynthetic precursor, strictosidine. We describe a synthetic approach to strictosidine that relies on a key facially selective Diels-Alder reaction between a glucosyl-modified alkene and an enal to set the C15-C20-C21 stereotriad. DFT calculations were used to examine the origin of stereoselectivity in this key step, wherein two of 16 possible isomers are predominantly formed. These calculations suggest the presence of a glucosyl unit, also inherent in the strictosidine structure, guides diastereoselectivity, with the reactive conformation of the vinyl glycoside dienophile being controlled by an exo-anomeric effect. (-)-Strictosidine was subsequently accessed using late-stage synthetic manipulations and an enzymatic Pictet-Spengler reaction. Several new natural product analogs were also accessed, including precursors to two unusual aryne natural product derivatives termed "strictosidyne"and "strictosamidyne". These studies provide a strategy for accessing glycosylic natural products and a new platform to access monoterpene indole alkaloids and their derivatives.
- Anthony, Sarah M.,Tona, Veronica,Zou, Yike,Morrill, Lucas A.,Billingsley, John M.,Lim, Megan,Tang, Yi,Houk,Garg, Neil K.
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supporting information
p. 7471 - 7479
(2021/05/26)
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- Total Syntheses of (?)-Strictosidine and Related Indole Alkaloid Glycosides
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A collective synthesis of glycosylated monoterpenoid indole alkaloids is reported. A highly diastereoselective Pictet–Spengler reaction with α-cyanotryptamine and secologanin tetraacetate as substrates, followed by a reductive decyanation reaction, was developed for the synthesis of (?)-strictosidine, which is an important intermediate in biosynthesis. This two-step chemical method was established as an alternative to the biosynthetically employed strictosidine synthase. Furthermore, after carrying out chemical and computational studies, a transition state for induction of diastereoselectivity in our newly discovered Pictet–Spengler reaction is proposed. Having achieved the first enantioselective total synthesis of (?)-strictosidine in just 10 steps, subsequent bioinspired transformations resulted in the concise total syntheses of (?)-strictosamide, (?)-neonaucleoside A, (?)-cymoside, and (?)-3α-dihydrocadambine.
- Ishikawa, Hayato,Rakumitsu, Kenta,Sakamoto, Jukiya,Sumimoto, Michinori,Umeda, Yuhei
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p. 13414 - 13422
(2020/06/08)
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- A (S)- tetrahydro Angustine derivative and its preparation and use (by machine translation)
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The present invention provides a (S)- tetrahydro Angustine derivatives and their pharmaceutically acceptable salts, the use of nucleotide synthetase catalytic tryptamine and crack link vomica alkali synthetic nucleotide as the initiator, obtained through a series of structural modification. The invention synthesizes the traditional medicinal chemistry to a sole chiral synthesis of a plurality of works and nuclear compound, such compound has outstanding in vitro topoisomerase I inhibitory activity HepG2 with the in vitro anti-tumor activity, can be in the preparation topoisomerase I inhibitor anti-tumor drug in the application. With the following formula (I) structure of the general formula: . (by machine translation)
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Paragraph 0037; 0038
(2018/05/16)
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- Biocatalytic asymmetric formation of tetrahydro-β-carbolines
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Strictosidine synthase triggers the formation of strictosidine from tryptamine and secologanin, thereby generating a carbon-carbon bond and a new stereogenic center. Strictosidine contains a tetrahydro-β-carboline moiety - an important N-heterocyclic framework found in a range of natural products and synthetic pharmaceuticals. Stereoselective methods to produce tetrahydro-β-carboline enantiomers are greatly valued. We report that strictosidine synthase from Ophiorrhiza pumila utilizes a range of simple achiral aldehydes and substituted tryptamines to form highly enantioenriched (ee >98%) tetrahydro-β-carbolines via a Pictet-Spengler reaction. This is the first example of aldehyde substrate promiscuity in the strictosidine synthase family of enzymes and represents a first step toward developing a general biocatalytic strategy to access chiral tetrahydro-β-carbolines.
- Bernhardt, Peter,Usera, Aimee R.,O'Connor, Sarah E.
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supporting information; experimental part
p. 4400 - 4402
(2010/09/12)
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- Bypassing stereoselectivity in the early steps of alkaloid biosynthesis
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Total synthesis of glycosylated seco-iridoid stereoisomers allows the identification and bypassing of the stereoselectivity of early steps in monoterpene indole alkaloid biosynthesis.
- Bernhardt, Peter,Yerkes, Nancy,O'Connor, Sarah E.
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experimental part
p. 4166 - 4168
(2009/12/05)
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- Strictosidine synthase: Mechanism of a Pictet-Spengler catalyzing enzyme
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The Pictet-Spengler reaction, which yields either a β-carboline or a tetrahydroquinoline product from an aromatic amine and an aldehyde, is widely utilized in plant alkaloid biosynthesis. Here we deconvolute the role that the biosynthetic enzyme strictosidine synthase plays in catalyzing the stereoselective synthesis of a β-carboline product. Notably, the rate-controlling step of the enzyme mechanism, as identified by the appearance of a primary kinetic isotope effect (KIE), is the rearomatization of a positively charged intermediate. The KIE of a nonenzymatic Pictet-Spengler reaction indicates that rearomatization is also rate-controlling in solution, suggesting that the enzyme does not significantly change the mechanism of the reaction. Additionally, the pH dependence of the solution and enzymatic reactions provides evidence for a sequence of acid-base catalysis steps that catalyze the Pictet-Spengler reaction. An additional acid-catalyzed step, most likely protonation of a carbinolamine intermediate, is also significantly rate controlling. We propose that this step is efficiently catalyzed by the enzyme. Structural analysis of a bisubstrate inhibitor bound to the enzyme suggests that the active site is exquisitely tuned to correctly orient the iminium intermediate for productive cyclization to form the diastereoselective product. Furthermore, ab initio calculations suggest the structures of possible productive transition states involved in the mechanism. Importantly, these calculations suggest that a spiroindolenine intermediate, often invoked in the Pictet-Spengler mechanism, does not occur. A detailed mechanism for enzymatic catalysis of the β-carboline product is proposed from these data.
- Maresh, Justin J.,Giddings, Lesley-Ann,Friedrich, Anne,Loris, Elke A.,Panjikar, Santosh,Trout, Bernhardt L.,Stoeckigt, Joachim,Peters, Baron,O'Connor, Sarah E.
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p. 710 - 723
(2008/09/20)
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- Chemoselective derivatization of alkaloids in periwinkle
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The terpene indole alkaloid biosynthetic pathway can utilize a secologanin substrate analog containing a handle for functionalization, and the resulting non-natural alkaloids can be chemoselectively derivatized in crude extracts of plant tissue. The Royal Society of Chemistry.
- Galan, M. Carmen,McCoy, Elizabeth,O'Connor, Sarah E.
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p. 3249 - 3251
(2008/02/13)
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- Con figurative correlation and conformational analysis of strictosidine and vincoside derivatives
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On the basis of the configuration of C-15 of the secologanin unit, using detailed NMR analysis, the configuration of C-3, the solution conformation around C-14, and the glucosidic bridge, as well as those of the dihydropyran and tetrahydropyridine rings, were determined in the vincosamide and strictosamide derivatives 4b and 5b. The stereochemical analysis was extended by chemical correlation to the 4-benzylated strictosidine and vincoside derivatives 3c and 3d. Experimental proof was presented for the interpretation of the 'anomalous' chemical shift of acetylated strictosamide derivatives.
- Patthy-Lukats, Agnes,Kocsis, Akos,Szabo, Laszlo F.,Podanyi
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p. 1492 - 1499
(2007/10/03)
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- Final solution on the long-standing structural arguments on the c-3 stereochemistries of three glucoindole alkaloids: Palicoside, dolichantoside, and isodolichantoside - Through chemical conversions and spectroscopic studies
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Three natural strictosidine/vincoside-class glucoindole alkaloids have been chemically correlated with strictosidinic acid possessing a rigorously established stereostructure. The C-3 stereochemistry of palicoside, dolichantoside, and isodolichantoside has been firmly proved to be (S), (S), and (R), respectively.
- Ohmori, Osamu,Kumazawa, Kyoko,Hoshino, Hiroyuki,Suzuki, Takako,Morishima, Yuka,Kohno, Hiroko,Kitajima, Mariko,Sakai, Shin-Ichiro,Takayama, Hiromitsu,Aimi, Norio
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p. 7737 - 7740
(2007/10/03)
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