528812-92-2Relevant articles and documents
Rapid Model-Based Optimization of a Two-Enzyme System for Continuous Reductive Amination in Flow
Citoler, Joan,Cosgrove, Sebastian C.,Finnigan, William,Turner, Nicholas J.
, p. 1969 - 1977 (2020)
Enzymes are increasingly combined into multienzyme systems for cost and productivity benefits. Further advantages can be gained through the use of immobilized enzymes, allowing continuous biotransformations in flow. However, the optimization of such multienzyme systems is challenging, particularly where immobilized enzymes are used. Here, we meet this challenge using both mechanistic and empirical modeling to optimize a reaction involving a reductive aminase and a glucose dehydrogenase for continuous biocatalytic reductive amination in flow. Crucially, the construction of the mechanistic model was achieved quickly, with only a few important parameters determined experimentally, and ensemble modeling used to facilitate the use of estimates or literature values. Upon reaching the limits of the mechanistic model's capabilities, we show that solution space can be further explored using a definitive screening design to generate an empirical model of the reaction, using the mechanistic model's prediction as a starting point. We demonstrate the use of this empirical model to design optimal processes for either high productivity or to minimize necessary cofactor and cosubstrate concentrations. Our results demonstrate that the synergistic use of both mechanistic and empirical modeling offers a route for rapid optimization of multienzyme systems of immobilized enzymes in flow with minimal experimental effort.
Design and synthesis of 14 and 15-membered macrocyclic scaffolds exhibiting inhibitory activities of hypoxia-inducible factor 1α
Shimizu, Takahiro,Takahashi, Norihito,Huber, Vincent J.,Asawa, Yasunobu,Ueda, Hiroki,Yoshimori, Atsushi,Muramatsu, Yukiko,Seimiya, Hiroyuki,Kouji, Hiroyuki,Nakamura, Hiroyuki,Oguri, Hiroki
, (2021)
Inspired by the privileged molecular skeletons of 14- and 15-membered antibiotics, we adopted a relatively unexplored synthetic approach that exploits alkaloidal macrocyclic scaffolds to generate modulators of protein–protein interactions (PPIs). As mimetics of hot-spot residues in the α-helices responsible for the transcriptional regulation, three hydrophobic sidechains were displayed on each of the four distinct macrocyclic scaffolds generating diversity of their spatial arrangements. Modular assembly of the building blocks followed by ring-closing olefin metathesis reaction and subsequent hydrogenation allowed concise and divergent synthesis of scaffolds 1–4. The 14-membered alkaloidal macrocycles 2–4 demonstrated similar inhibition of hypoxia-inducible factor (HIF)-1α transcriptional activities (IC50 between 8.7 and 10 μM), and 4 demonstrated the most potent inhibition of cell proliferation in vitro (IC50 = 12 μM against HTC116 colon cancer cell line). A docking model suggested that 4 could mimic the LLxxL motif in HIF-1α, in which the three sidechains are capable of matching the spatial arrangements of the protein hot-spot residues. Unlike most of the stapled peptides, the 14-membered alkaloidal scaffold has a similar size to the α-helix backbone and does not require additional atoms to induce α-helix mimetic structure. These experimental results underscore the potential of alkaloidal macrocyclic scaffolds featuring flexibly customizable skeletal, stereochemical, substitutional, and conformational properties for the development of non-peptidyl PPI modulators targeting α-helix-forming consensus sequences responsible for the transcriptional regulation.
Integrated Electro-Biocatalysis for Amine Alkylation with Alcohols
Pe?afiel, Itziar,Dryfe, Robert A. W.,Turner, Nicholas J.,Greaney, Michael F.
, p. 864 - 867 (2021/01/21)
The integration of electro and bio-catalysis offers new ways of making molecules under very mild, environmentally benign conditions. We show that TEMPO mediated electro-catalytic oxidation of alcohols can be adapted to work in aqueous buffers, with minimal organic co-solvent, enabling integration with biocatalytic reductive amination using the AdRedAm enzyme. The combined process offers a new approach to amine alkylation with native alcohols, a key bond formation in the chemical economy that is currently achieved via precious metal-catalyzed hydrogen-borrowing technologies. The electrobio transformation is effective for primary and secondary alcohols undergoing coupling with allyl, propargyl, benzyl, and cyclopropyl amines, and has been adapted for use with solid-supported AdRedAm for ease of operation.
PRODUCTION OF AMINES VIA A HYDROAMINOALKYLATION REACTION
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Page/Page column 64-65; 73, (2019/12/04)
Provided is a process for producing an amine via a hydroaminoalkylation reaction of a non-aromatic C-C double bond or C-C triple bond, said process comprising a step of reacting a compound comprising a non-aromatic C-C double bond or C-C triple bond with a reactive component which is obtainable by combining an aminal or a hemiaminal ether with an acidic medium comprising trifluoroacetic acid, wherein the aminal contains two amino groups independently selected from a secondary and a tertiary amino group that are linked by a methylene group wherein one hydrogen atom may be replaced by a further substituent, and at least one of the amino groups carries a hydrogen atom at a carbon atom bound in α-position to its nitrogen atom, and the hemiaminal ether contains a secondary or a tertiary amino group which carries a hydrogen atom at a carbon atom bound in α-position to its nitrogen atom, and the secondary or tertiary amino group is linked to an alkoxy group by a methylene group wherein one hydrogen atom may be replaced by a further substituent.
A General Acid-Mediated Hydroaminomethylation of Unactivated Alkenes and Alkynes
Kaiser, Daniel,Tona, Veronica,Gon?alves, Carlos R.,Shaaban, Saad,Oppedisano, Alberto,Maulide, Nuno
supporting information, p. 14639 - 14643 (2019/09/17)
In comparison to the extensively studied metal-catalyzed hydroamination reaction, hydroaminomethylation has received significantly less attention despite its considerable potential to streamline amine synthesis. State-of-the-art protocols for hydroaminomethylation of alkenes rely largely on transition-metal catalysis, enabling this transformation only under highly designed and controlled conditions. Here we report a broadly applicable, acid-mediated approach to the hydroaminomethylation of unactivated alkenes and alkynes. This methodology employs cheap, readily available, and bench-stable reactants and affords the desired amines with excellent functional group tolerance and impeccable regioselectivity. The broad scope of this transformation, as well as mechanistic investigations and in situ domino functionalization reactions are reported.
Biocatalytic N-Alkylation of Amines Using Either Primary Alcohols or Carboxylic Acids via Reductive Aminase Cascades
Ramsden, Jeremy I.,Heath, Rachel S.,Derrington, Sasha R.,Montgomery, Sarah L.,Mangas-Sanchez, Juan,Mulholland, Keith R.,Turner, Nicholas J.
, p. 1201 - 1206 (2019/01/21)
The alkylation of amines with either alcohols or carboxylic acids represents a mild and safe alternative to the use of genotoxic alkyl halides and sulfonate esters. Here we report two complementary one-pot systems in which the reductive aminase (RedAm) from Aspergillus oryzae is combined with either (i) a 1° alcohol/alcohol oxidase (AO) or (ii) carboxylic acid/carboxylic acid reductase (CAR) to affect N-alkylation reactions. The application of both approaches has been exemplified with respect to substrate scope and also preparative scale synthesis. These new biocatalytic methods address issues facing alternative traditional synthetic protocols such as harsh conditions, overalkylation and complicated workup procedures.
Direct Alkylation of Amines with Primary and Secondary Alcohols through Biocatalytic Hydrogen Borrowing
Montgomery, Sarah L.,Mangas-Sanchez, Juan,Thompson, Matthew P.,Aleku, Godwin A.,Dominguez, Beatriz,Turner, Nicholas J.
supporting information, p. 10491 - 10494 (2017/08/22)
The reductive aminase from Aspergillus oryzae (AspRedAm) was combined with a single alcohol dehydrogenase (either metagenomic ADH-150, an ADH from Sphingobium yanoikuyae (SyADH), or a variant of the ADH from Thermoanaerobacter ethanolicus (TeSADH W110A)) in a redox-neutral cascade for the biocatalytic alkylation of amines using primary and secondary alcohols. Aliphatic and aromatic secondary amines were obtained in up to 99 % conversion, as well as chiral amines directly from the racemic alcohol precursors in up to >97 % ee, releasing water as the only byproduct.
Structure and property based design, synthesis and biological evaluation of γ-lactam based HDAC inhibitors
Choi, Eunhyun,Lee, Chulho,Park, Jung Eun,Seo, Jeong Jea,Cho, Misun,Kang, Jong Soon,Kim, Hwan Mook,Park, Song-Kyu,Lee, Kiho,Han, Gyoonhee
scheme or table, p. 1218 - 1221 (2011/04/16)
Histone deacetylases (HDACs) are involved in post-translational modification and gene expression. Cancer cells recruited amounts of HDACs for their survival by epi-genetic down regulation of tumor suppressor genes. HDACs have been the promising targets for treatment of cancer, and many HDAC inhibitors have been investigated nowadays. In previous study, we synthesized δ-lactam core HDAC inhibitors which showed potent HDAC inhibitory activities as well as cancer cell growth inhibitory activities. Through QSAR study of the δ-lactam based inhibitors, the smaller core is suggested as more active than larger one because it fits better in narrow hydrophobic tunnel of the active pocket of HDAC enzyme. The smaller γ-lactam core HDAC inhibitors were designed and synthesized for biological and property optimization. Phenyl, naphthyl and thiophenyl groups were introduced as the cap groups. Hydrophobic and bulky cap groups increase potency of HDAC inhibition because of hydrophobic interaction between HDAC and inhibitors. In overall, γ-lactam based HDAC inhibitors showed more potent than δ-lactam analogues.
Cerium ammonium nitrate (CAN) for mild and efficient reagent to remove hydroxyethyl units from 2-hydroxyethyl ethers and 2-hydroxyethyl amines
Fujioka, Hiromichi,Hirose, Hideki,Ohba, Yusuke,Murai, Kenichi,Nakahara, Kenji,Kita, Yasuyuki
, p. 625 - 637 (2007/10/03)
Cerium ammonium nitrate (CAN) removed hydroxyethyl units from 2-hydroxyethyl ethers and 2-hydroxyethyl amines to produce alcohols and amines in good yields. Especially, removal of the 2-hydroxyethyl ethers from C2-symmetric diols, chiral 2,3-butanediol and chiral hydrobenzoin, was very useful for asymmetric syntheses using C2-symmetric diols. The reactions using dual abilities of CAN, i.e.,?the ability for removal of the 2-hydroxyethyl unit and the ability for acetal hydrolysis by a single electron transfer, were also achieved successfully. The reaction conditions were very mild and efficient, and many functional groups, which can be affected under normal conditions, were unaffected during the reaction.
A new versatile linker for the solid-phase synthesis of secondary amines
Glatz, Heiko,Bannwarth, Willi
, p. 149 - 152 (2007/10/03)
A novel linker for the solid-phase synthesis of secondary amines based on an intramolecular cyclization was developed. The linker allows for a stepwise built-up of the secondary amines on the support. The feasibility was demonstrated in the parallel synthesis of a small set of different secondary amines.
