20824-29-7Relevant articles and documents
Total Synthesis of (-)-Strictosidine and Interception of Aryne Natural Product Derivatives "strictosidyne" and "strictosamidyne"
Anthony, Sarah M.,Tona, Veronica,Zou, Yike,Morrill, Lucas A.,Billingsley, John M.,Lim, Megan,Tang, Yi,Houk,Garg, Neil K.
supporting information, p. 7471 - 7479 (2021/05/26)
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.
Total Syntheses of (?)-Strictosidine and Related Indole Alkaloid Glycosides
Ishikawa, Hayato,Rakumitsu, Kenta,Sakamoto, Jukiya,Sumimoto, Michinori,Umeda, Yuhei
, p. 13414 - 13422 (2020/06/08)
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.
A (S)- tetrahydro Angustine derivative and its preparation and use (by machine translation)
-
Paragraph 0037; 0038, (2018/05/16)
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)
Strictosidine Synthase Triggered Enantioselective Synthesis of N-Substituted (S)-3,14,18,19-Tetrahydroangustines as Novel Topoisomerase i Inhibitors
Cai, Yunrui,Zhu, Huajian,Alperstein, Zaccary,Yu, Wenjun,Cherkasov, Artem,Zou, Hongbin
, p. 3086 - 3092 (2017/12/26)
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.
Engineering strictosidine synthase: Rational design of a small, focused circular permutation library of the β-propeller fold enzyme
Fischereder, Eva,Pressnitz, Desiree,Kroutil, Wolfgang,Lutz, Stefan
, p. 5633 - 5637 (2015/01/09)
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.
A facile chemoenzymatic approach: One-step syntheses of monoterpenoid indole alkaloids
Zou, Hong-Bin,Zhu, Hua-Jian,Zhang, Liang,Yang, Liu-Qing,Yu, Yong-Ping,Stoeckigt, Joachim
supporting information; experimental part, p. 2400 - 2404 (2011/08/04)
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.
Biocatalytic asymmetric formation of tetrahydro-β-carbolines
Bernhardt, Peter,Usera, Aimee R.,O'Connor, Sarah E.
supporting information; experimental part, p. 4400 - 4402 (2010/09/12)
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.
Synthesis and biochemical evaluation of des-vinyl secologanin aglycones with alternate stereochemistry
Bernhardt, Peter,O'Connor, Sarah E.
scheme or table, p. 7118 - 7120 (2010/01/18)
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.
Bypassing stereoselectivity in the early steps of alkaloid biosynthesis
Bernhardt, Peter,Yerkes, Nancy,O'Connor, Sarah E.
experimental part, p. 4166 - 4168 (2009/12/05)
Total synthesis of glycosylated seco-iridoid stereoisomers allows the identification and bypassing of the stereoselectivity of early steps in monoterpene indole alkaloid biosynthesis.
Substrate specificity and diastereoselectivity of strictosidine glucosidase, a key enzyme in monoterpene indole alkaloid biosynthesis
Yerkes, Nancy,Wu, Jia Xin,McCoy, Elizabeth,Galan, M. Carmen,Chen, Shi,O'Connor, Sarah E.
, p. 3095 - 3098 (2008/12/23)
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.
