Solution‐phase submonomer diversification of aza‐dipeptide building blocks and their application in aza‐peptide and aza‐DKP synthesis

Aza‐peptides have been used as tools for studying SARs in programs aimed at drug discovery and chemical biology. Protected aza‐dipeptides were synthesized by a solution‐phase submonomer approach featuring alkylation of N‐terminal benzophenone semicarbazone aza‐Gly‐Xaa dipeptides using different alkyl halides in the presence of potassium tert‐butoxide as base. Benzophenone protected aza‐dipeptide tert‐butyl ester 31c was selectively deprotected at the C‐terminal ester or N‐terminal hydrazone to afford, respectively, aza‐dipeptide acid and amine building blocks 36c and 40c, which were introduced into longer aza‐peptides. Alternatively, removal of the benzophenone semicarbazone protection from aza‐dipeptide methyl esters 29a–c led to intramolecular cyclization to produce aza‐DKPs 39a–c. In light of the importance of aza‐peptides and DKPs as therapeutic agents and probes of biological processes, this diversity‐oriented solution‐phase approach may provide useful tools for studying peptide science. Copyright © 2010 European Peptide Society and John Wiley & Sons, Ltd.     

Synthesis of Base Substituted 2-Hydroxy-3-(purin-9-yl)-propanoic Acids and 4-(Purin-9-yl)-3-butenoic Acids

Abstract

Alkylation of 6-chloropurine and 2-amino-6-chloropurine with bromoacetaldehyde diethyl acetal afforded 6-chloro-9-(2,2-diethoxyethyl)purine (3a) and its 2-amino congener (3b). Treatment of compounds 3 with primary and secondary amines gave the N⁶-substituted adenines (5a–5c) and 2,6-diaminopurines (5d–5f). Hydrolysis of 3 resulted in hypoxanthine (6a) and guanine (6b) derivatives, while their reaction with thiourea led to 6-sulfanylpurine (7a) and 2-amino-6-sulfanylpurine (7b) compounds. Treatment with diluted acid followed by potassium cyanide treatment and acid hydrolysis afforded 6-substituted 3-(purin-9-yl)- and 3-(2-aminopurin-9-yl)-2-hydroxypropanoic acids (8–10). Reaction of compounds 3 with malonic acid in aqueous solution gave exclusively the product of isomerisation, 6-substituted 4-(purin-9-yl)-3-butenoic acids (15).     

Asymmetric total synthesis of (+)- and (-)-clusianone and (+)- and (-)-clusianone methyl enol ether via ACC alkylation and evaluation of their anti-HIV activity

The total asymmetric synthesis of (+)- and (−)-clusianone and (+)- and (−)-clusianone methyl enol ether is reported. Asymmetric induction is achieved through the use of ACC alkylation, providing the key intermediates with an er of 99:1. The four synthetic compounds were evaluated for their anti-HIV activity. Both (+)- and (−)-clusianone displayed significant anti-HIV activity.     

Synthesis and Antioxidant Capacity of Some Derivatives of Sesamol at the C-6 Position

Several synthetic approaches (aminomethylation, alkylation, condensation, etc.) have been used to synthesize derivatives based on the sesamol ( 1 ), natural phenol. The set of methods, including the study of antioxidant activity (AOA) by the ability to inhibit the initiated oxidation of animal lipids, radical scavenging activity, Fe²⁺-chelation ability, as well as a comparative assessment of membrane-protective activity under the conditions of H₂O₂-induced hemolysis of mice red blood cells (RBCs), was used to analyze the antioxidant potential of the synthesized compounds. The synthesized derivatives have demonstrated different activity in the listed test systems, and we have identified compounds which appear to be most promising for a detailed study of their pharmacological properties.     

The effect of ligand donor atoms on the regioselectivity in the palladium catalyzed allylic alkylation

The regioselectivity of the palladium catalyzed allylic alkylation was studied systematically using bidentate ligands based on a xanthene backbone, bearing different donor atoms. The nature of the ligand donor atoms has a pronounced influence on the regioselectivity of the reaction. The results can be explained by a mechanism that distinguishes two ‘stages’ in the alkylation reaction. Ligands bearing strong π-acceptor donor atoms induce the formation of branched products (60% for the PP derivative), whereas the use of ligands with weak π-acceptor donor atoms mainly yields linear products (>99% for the NN derivative).     

Ribosome quality control antagonizes the activation of the integrated stress response on colliding ribosomes

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Synthesis and characterization of 2,3-di-O-alkylated amyloses: hydrophobic substitution destabilizes helical conformation

Amylose was selectively alkylated in the 2,3-O position of each anhydroglucose unit after trityl protection of the 6-OH groups. Alkyl iodides of varying chain length (C(2), C(5), C(8)) were coupled to amylose, and degrees of substitution (DSs) were varied between 0.3 and 1.8, as assessed by NMR analysis. Increasing amounts of methyl groups per anhydroglucose unit increased solubility in nonaqueous media, while at the same time reducing the ability of modified amylose to form a complex with iodine. The tendency to form inclusion complexes with the surfactant N-dodecyl pyridinium bromide decreased in the order beta-cyclodextrin > amylose approximately solubilized starch, indicating that the frozen macrocycle of beta-cyclodextrin was the most efficient inclusion host. Introduction of the bulky trityl group abolished the helical amylose conformation, which is not readily reassumed in the presence of hydrophobic substitution of the C2 and C3 positions. These results indicated that a polar outer surface is necessary but not sufficient for the formation of a stable amylose helix.     

Polymethylene Derivatives of Nucleic Bases with ω-Functional Groups. III.1 N-[7-(2-Oxocyclohexyl)-7-oxoheptyl]-Substituted Pyrimidines

New polymethylene derivatives of nucleic bases containing a -dioxo function at the -position were synthesized by alkylation of uracil, thymine, and cytosine with 1-(7-chloroheptanoyl)cyclohexan-2-one, and their physicochemical properties were studied.     

Novel Gly building units for backbone cyclization: synthesis and incorporation into model peptides

We report the preparation of novel building units for backbone cyclization that have the general formula Fmoc-N[CH(R)CO₂Al]Gly-OH. These building units were prepared by the reductive alkylation method using allyl esters of several amino acids as starting material and hence, respectively, contain the side chain of these amino acids. These N-alkylated Gly building units were incorporated in model backbone cyclic peptides. The resulting crude backbone cyclic peptides were obtained in high degree of purity according to HPLC and mass spectrometric analyses.     

Generation of C5-desoxy analogs of tetrahydroisoquinoline alkaloids exhibiting potent DNA alkylating ability

C5-desoxy analogs of tetrahydroisoquinoline (THIQ) alkaloids were designed and synthesized as hitherto unexplored structural variants for evaluation of their DNA alkylating activities. While chemical synthesis of the C5-desoxy analogs bearing a phenolic hydroxyl group in the A-ring of the saframycins was assumed to be laborious based on semi-synthetic modifications, a chemo-enzymatic approach allowed for concise access to the analogs. The C5-desoxy analog 7 exhibited greater DNA alkylating ability with a wider tolerance for the sequence variations compared to cyanosafracin B. The C5-desoxy A-ring having a C8 phenolic hydroxyl group, and a C1 substituent in the vicinity of the C21 aminonitrile responsible for DNA alkylation, were demonstrated to play pivotal roles in the interaction between the THIQ alkaloids and DNA.