Influence of N-amino protecting group on aldolase-catalyzed aldol additions of dihydroxyacetone phosphate to amino aldehydes

Calveras, Jordi; Bujons, Jordi; Parella, Teodor; Crehuet, Ramón; Espelt, Laia; Joglar, Jesús; Clapés, Pere

doi:10.1016/j.tet.2005.12.031

Cited by 22 publications

(11 citation statements)

References 31 publications

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“…Thus, an exhaustive conformational analysis was carried out for the syn and anti adducts derived from the (S)-2 c, (R)-2 c, (S)-2 d, and (R)-2 d aldehydes, as representative examples, using a combination of the systematic and stochastic conformational search algorithms implemented in the program MOE (Chemical Computing Group, Montreal), as previously described. [24,40] ) and the corresponding geometries are reported in the Supporting Information. From these values it is clear that the syn adducts are thermodynamically favored, assuming similar entropic contributions to DG, by À3.3 kcal mol À1 on average for the compounds considered.…”

Section: Resultsmentioning

confidence: 99%

“…Similar results were already reported by us for a small set of aldol adducts derived from N-protected 3-aminopropanal. [40] We also looked at the complexes of the above adducts in the active center of RhuA. Figure 5 shows the lowest energy conformers obtained for the syn and anti adducts from aldehydes (S)-2 c and (S)-2 d bound in the active center of RhuA.…”

Section: Resultsmentioning

confidence: 99%

“…The protocols used to determine the lowest energy conformations for the aldol adducts in free state and as complexes with the RhuA active center were the same as those previously reported. [24,40] For the free adducts, starting from an initially optimized structure, a systematic conformational search was run in which every non-terminal single bond was rotated in 60-1208 steps. The conformations generated for each compound were then minimized and ranked according to their energy.…”

Section: Kinetics Of Inhibitionmentioning

confidence: 99%

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Dihydroxyacetone Phosphate Aldolase Catalyzed Synthesis of Structurally Diverse Polyhydroxylated Pyrrolidine Derivatives and Evaluation of their Glycosidase Inhibitory Properties

Calveras

Egido‐Gabás

Gómez

et al. 2009

Chemistry A European J

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The chemoenzymatic synthesis of a collection of pyrrolidine-type iminosugars generated by the aldol addition of dihydroxyacetone phosphate (DHAP) to C-alpha-substituted N-Cbz-2-aminoaldehydes derivatives, catalyzed by DHAP aldolases is reported. L-fuculose-1-phosphate aldolase (FucA) and L-rhamnulose-1-phosphate aldolase (RhuA) from E. coli were used as biocatalysts to generate configurational diversity on the iminosugars. Alkyl linear substitutions at C-alpha were well tolerated by FucA catalyst (i.e., 40-70 % conversions to aldol adduct), whereas no product was observed with C-alpha-alkyl branched substitutions, except for dimethyl and benzyl substitutions (20 %). RhuA was the most versatile biocatalyst: C-alpha-alkyl linear groups gave the highest conversions to aldol adducts (60-99 %), while the C-alpha-alkyl branched ones gave moderate to good conversions (50-80 %), with the exception of dimethyl and benzyl substituents (20 %). FucA was the most stereoselective biocatalyst (90-100 % anti (3R,4R) adduct). RhuA was highly stereoselective with (S)-N-Cbz-2-aminoaldehydes (90-100 % syn (i.e., 3R,4S) adduct), whereas those with R configuration gave mixtures of anti/syn adducts. For iPr and iBu substituents, RhuA furnished the anti adduct (i.e., FucA stereochemistry) with high stereoselectivity. Molecular models of aldol products with iPr and iBu substituents and as complexes with the RhuA active site suggest that the anti adducts could be kinetically preferred, while the syn adducts would be the equilibrium products. The polyhydroxylated pyrrolidines generated were tested as inhibitors against seven glycosidases. Among them, good inhibitors of alpha-L-fucosidase (IC50=1-20 microM), moderate of alpha-L-rhamnosidase (IC50=7-150 microM), and weak of alpha-D-mannosidase (IC50=80-400 microM) were identified. The apparent inhibition constant values (Ki) were calculated for the most relevant inhibitors and computational docking studies were performed to understand both their binding capacity and the mode of interaction with the glycosidases.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Kinetics Of Inhibitionmentioning

confidence: 99%

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Dihydroxyacetone Phosphate Aldolase Catalyzed Synthesis of Structurally Diverse Polyhydroxylated Pyrrolidine Derivatives and Evaluation of their Glycosidase Inhibitory Properties

Calveras

Egido‐Gabás

Gómez

et al. 2009

Chemistry A European J

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“…Computational methods : Conformational searches on aldol adduct derivatives were conducted as previously described4, 6, 47 with use of the program MOE (v. 2008.10, Chemical Computing Group, Montreal). The implemented MMFF94x force field, a modified version of the MMFF94s force field,48 was used for energy calculations.…”

Section: Methodsmentioning

confidence: 99%

Structure‐Guided Minimalist Redesign of the L‐Fuculose‐1‐Phosphate Aldolase Active Site: Expedient Synthesis of Novel Polyhydroxylated Pyrrolizidines and their Inhibitory Properties Against Glycosidases and Intestinal Disaccharidases

Garrabou

Gómez

Joglar

et al. 2010

Chemistry A European J

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A minimalist active site redesign of the L-fuculose-1-phosphate aldolase from E. coli FucA was envisaged, to extend its tolerance towards bulky and conformationally restricted N-Cbz-amino aldehyde acceptor substrates (Cbz=benzyloxycarbonyl). Various mutants at the active site of the FucA wild type were obtained and screened with seven sterically demanding N-Cbz-amino aldehydes including N-Cbz-prolinal derivatives. FucA F131A showed an aldol activity of 62 μmol h(-1) mg(-1) with (R)-N-Cbz-prolinal, whereas no detectable activity was observed with the FucA wild type. For the other substrates, the F131A mutant gave aldol activities from 4 to about 25 times higher than those observed with the FucA wild type. With regard to the stereochemistry of the reactions, the (R)-amino aldehydes gave exclusively the anti configured aldol adducts whereas their S counterparts gave variable ratios of anti/syn diastereoisomers. Interestingly, the F131A mutant was highly stereoselective both with (R)- and with (S)-N-Cbz-prolinal, exclusively producing the anti and syn aldol adducts, respectively. Molecular models suggest that this improved activity towards bulky and more rigid substrates, such as N-Cbz-prolinal, could arise from a better fit of the substrate into the hydrophobic pocket created by the F131A mutation, due to an additional π-cation interaction with the residue K205' and to efficient contact between the substrate and the mechanistically important Y113' and Y209' residues. An expedient synthesis of novel polyhydroxylated pyrrolizidines related to the hyacinthacine and alexine types was accomplished through aldol additions of dihydroxyacetone phosphate (DHAP) to hydroxyprolinal derivatives with the hyperactive FucA F131A as catalyst. The iminocyclitols obtained were fully characterised and found to be moderate to weak inhibitors (relative to 1,4-dideoxy-1,4-imino-L-arabinitol (LAB) and 1,4-dideoxy-1,4-imino-D-arabinitol (DAB)) against glycosidases and rat intestinal saccharidases.

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“…Moreover, docking simulations of N-protected 3-aminopropionaldehyde into RhuA suggested that the protecting group cannot get into the catalytic site and therefore cannot drive any preferred orientation. [22] Hence, the loss of interaction points between the RhuA and the N-Cbz-prolinal may lead to less restricted rotation around C-7a/C-1.…”

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Chemoenzymatic Synthesis and Inhibitory Activities of Hyacinthacines A₁ and A₂ Stereoisomers

et al. 2007

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A novel straightforward chemoenzymatic procedure for the synthesis of hyacinthacine stereoisomers based on the aldol addition of dihydroxyacetone phosphate (DHAP) to N-Cbz-prolinal under catalysis by l-rhamnulose 1-phosphate aldolase from E. coli is presented. The synthesis is complemented by a simple and effective purification protocol consisting of ion-exchange chromatography on CM-sepharose. As examples, (À)-hyacinthacine A 2 [the enantiomer of (+)-hyacinthacine A 2 ], 7-deoxy-2-epialexine (the enantiomer of 3-epihyacinthacine A 2 ), ent-7-deoxyalexine (the enantiomer of 7-deoxyalexine) and 2-epihyacinthacine A 2 were synthesized by these procedures and characterized for the first time. These new isomers were assayed as inhibitors of glycosidases. As a result, (À)-hyacinthacine A 2 demonstrated to be a good inhibitor of a-d-glucosidase from rice whereas the natural enantiomer, hyacinthacine A 2 , was not. Moreover, a new family of inhibitors of a-l-rhamnosidase was uncovered.

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Influence of N-amino protecting group on aldolase-catalyzed aldol additions of dihydroxyacetone phosphate to amino aldehydes

Cited by 22 publications

References 31 publications

Dihydroxyacetone Phosphate Aldolase Catalyzed Synthesis of Structurally Diverse Polyhydroxylated Pyrrolidine Derivatives and Evaluation of their Glycosidase Inhibitory Properties

Dihydroxyacetone Phosphate Aldolase Catalyzed Synthesis of Structurally Diverse Polyhydroxylated Pyrrolidine Derivatives and Evaluation of their Glycosidase Inhibitory Properties

Structure‐Guided Minimalist Redesign of the L‐Fuculose‐1‐Phosphate Aldolase Active Site: Expedient Synthesis of Novel Polyhydroxylated Pyrrolizidines and their Inhibitory Properties Against Glycosidases and Intestinal Disaccharidases

Chemoenzymatic Synthesis and Inhibitory Activities of Hyacinthacines A₁ and A₂ Stereoisomers

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Influence of N-amino protecting group on aldolase-catalyzed aldol additions of dihydroxyacetone phosphate to amino aldehydes

Cited by 22 publications

References 31 publications

Dihydroxyacetone Phosphate Aldolase Catalyzed Synthesis of Structurally Diverse Polyhydroxylated Pyrrolidine Derivatives and Evaluation of their Glycosidase Inhibitory Properties

Dihydroxyacetone Phosphate Aldolase Catalyzed Synthesis of Structurally Diverse Polyhydroxylated Pyrrolidine Derivatives and Evaluation of their Glycosidase Inhibitory Properties

Structure‐Guided Minimalist Redesign of the L‐Fuculose‐1‐Phosphate Aldolase Active Site: Expedient Synthesis of Novel Polyhydroxylated Pyrrolizidines and their Inhibitory Properties Against Glycosidases and Intestinal Disaccharidases

Chemoenzymatic Synthesis and Inhibitory Activities of Hyacinthacines A1 and A2 Stereoisomers

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Chemoenzymatic Synthesis and Inhibitory Activities of Hyacinthacines A₁ and A₂ Stereoisomers