Sodium borohydride: A versatile reagent in the reductive <i>N</i>-monoalkylation of α-amino acids and α-amino methyl esters

Drug discovery strategies include from broad random screening to focussed target-based approaches. Structure and substrate information greatly enables target-based design, but this is limited to relatively few targets; cell-based screening can identify new targets but often suffers from low hit rates and difficult hit optimization. Thus, newer approaches are needed that can improve the efficiency of screening and hit optimization. Here, we describe an efficient approach for hit generation, which may be called "biofocussed chemoprospecting." With bio-likeness and ease of synthesis as priority criteria, libraries may be constructed with good optimization potential, physicochemical diversity, drug likeness and low cost. Following this approach, two libraries based on linear and cyclic dipeptide scaffolds were designed, first as virtual libraries comprising of more than 30000 compounds, and after subsequent filtering, as a small library of a total of 51 compounds. These provided good diversity at low cost, and were tested for bioactivities. The discovery of six active compounds demonstrates a hit rate greater than 10%. This is comparable to target-based approaches, but the "chemoprospecting" method described here has the additional potential to identify new targets and mechanisms.

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“…As per a reported protocol, an aldehyde (1.4 equiv.) was added to a stirred solution of an amino acid (1 equiv.)…”

Section: Methodsmentioning

confidence: 99%

Biofocussed chemoprospecting: An efficient approach for drug discovery

et al. 2017

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“…2.2 Synthesis of N a -dodecyl-L-Histidine (NDH) NDH surfactant was synthesized by a modification of published procedures as described in Scheme 1 [32]: lauraldehyde (3.11 ml, 14 mmol) was dissolved in hot absolute ethanol (30 ml), then it was added into 30 ml absolute methanol solution of L-histidine (1.5516 g, 10 mmol) with NaOH powder (0.52 g, 13 mmol). The mixture was heated to 45°C and stirred for 10 h, then the solution was cooled with an ice bath and NaBH 4 (0.49 g, 13.0 mmol) was added in small portions.…”

Section: Introductionmentioning

confidence: 99%

Effective Cleavage of β-1,4-Glycosidic Bond by Functional Micelle with l-Histidine Residue

Liao¹,

Liu

Xiao³

et al. 2016

Catal Lett

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A novel functional surfactant N a -dodecyl-Lhistidine (NDH) was synthesized and its micelle was used as mimic of b-1,4-endoglucanase to catalyzed the hydrolysis of methyl-b-D-cellobioside (MCB) under relatively low temperatures (80-110°C). The results showed that the micelle of NDH displayed excellent catalytic activity for the cleavage of b-1,4-glycosidic bond and the formation ofThe micelle-catalyzed first-order reaction rate constant k m of degradation of MCB was calculated. The conversion of MCB and selectivity of reducing sugars (glucose and fructose) could reach 58.9 and 87.1 %, respectively, for a reaction time of 10 h at pH 4.0 and 110°C. In NDH micelle-catalyzed reaction sugar ester was deduced as the chief product. The reaction pathways of MCB hydrolysis were proposed and the activation energy Ea for the hydrolysis was calculated. Graphical AbstractO OCR OH OH HO HO pH4.0, 90 o C Selectivity>97% O O OH OH HO HO O OH OH OCH 3 HO Glucose Fructose + p H 1 2 . 0 , 2 5 o C O N N H NH HOOC C 12 H 25

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“…Iron-catalyzed N-alkylation of unprotected amino acids ( 1a to 1c ) with long-chain aliphatic alcohols ( 2 ) to produce surfactants. Spectral data of isolated compounds Determination of the optical purity of products HPLC traces 1 H and 13 C NMR spectra References ( 33 – 45 )…”

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confidence: 99%