75040-72-1

Upstream product

• 10065-72-2 L-Alanine methyl ester 
• 100-46-9 benzylamine 
• 51814-55-2 tert-butyl (S)-[1-(benzylamino)-1-oxopropan-2-yl]carbamate 
• 2491-20-5 L-alanine methyl ester hydrochloride 
• 15761-38-3 L-N-Boc-Ala 

Downstream Products

• 75040-69-6 (S)-N¹-benzyl-1,2-propanediamine 
• 184956-12-5 [(R)-1-((S)-1-Benzylcarbamoyl-ethylcarbamoyl)-3-methyl-butyl]-carbamic acid tert-butyl ester 
• 637362-79-9 (2S)-2-[(1H-benzotriazol-1-ylmethyl)amino]-N-benzylpropanamide 
• 911289-58-2 C₃₀H₂₉N₃O₄ 
• 911289-29-7 C₁₆H₁₇N₃O₄*ClH 
• 181314-37-4 (2-{(S)-5-Benzyl-3-[2-((S)-3-benzyl-5-methyl-2-oxo-imidazolidin-1-yl)-ethyl]-2-oxo-imidazolidin-1-yl}-2-oxo-ethyl)-carbamic acid 9H-fluoren-9-ylmethyl ester 
• 181314-38-5 [(S)-1-(2-{(S)-5-Benzyl-3-[2-((S)-3-benzyl-5-methyl-2-oxo-imidazolidin-1-yl)-ethyl]-2-oxo-imidazolidin-1-yl}-ethylcarbamoyl)-propyl]-carbamic acid tert-butyl ester 
• 181314-34-1 [2-((S)-3-Benzyl-5-methyl-2-oxo-imidazolidin-1-yl)-2-oxo-ethyl]-carbamic acid 9H-fluoren-9-ylmethyl ester 

Relevant academic research and scientific papers

Discovery of the First-in-Class Dual Histone Deacetylase-Proteasome Inhibitor

Dual- or multitarget drugs have emerged as a promising alternative to combination therapies. Proteasome inhibitors (PIs) possess synergistic activity with histone deacetylase (HDAC) inhibitors due to the simultaneous blockage of the ubiquitin degradation and aggresome pathways. Here, we present the design, synthesis, binding modes, and anticancer properties of RTS-V5 as the first-in-class dual HDAC-proteasome ligand. The inhibition of both targets was confirmed by biochemical and cellular assays as well as X-ray crystal structures of the 20S proteasome and HDAC6 complexed with RTS-V5. Cytotoxicity assays with leukemia and multiple myeloma cell lines as well as therapy refractory primary patient-derived leukemia cells demonstrated that RTS-V5 possesses potent and selective anticancer activity. Our results will thus guide the structure-based optimization of dual HDAC-proteasome inhibitors for the treatment of hematological malignancies.

Mechanistic implications of the enantioselective addition of alkylzinc reagents to aldehydes catalyzed by nickel complexes with α-amino amide ligands

The enantioselective alkylation of aldehydes catalysed by nickel(ii)-complexes derived from α-amino amides was studied by means of density functional theory (DFT) and ONIOM (B3LYP:UFF) calculations. A mechanism was proposed in order to investigate the origin of enantioselectivity. The chirality-determining step for the alkylation was the formation of the intermediate complexes with the involvement of a 5/4/4-fused tricyclic transition state. The predominant products predicted theoretically were of (S)-configuration, in good agreement with experimental observations. The scope of the reaction was examined and high yields and enantioselectivities were observed for the enantioselective addition of Et2Zn and Me2Zn to aromatic and aliphatic aldehydes.

C2 symmetrical nickel complexes derived from α-amino amides as efficient catalysts for the enantioselective addition of dialkylzinc reagents to aldehydes

A series of C2 symmetrical 1:2 Ni:L complexes derived from α-amino amides were studied for the enantioselective addition of dialkylzinc reagents to aldehydes. Different structural elements on the ligands seem to play an important role in determining the observed enantioselectivity. Through optimization of structure and reaction conditions, the best ligand provided secondary alcohols in excellent yields (up to 98%) and enantioselectivity of up to 99% ee for (R)-enantiomer. A transition state model has been proposed to explain the observed enantioselectivities based on computational calculations at the DFT level. Very interestingly, calculations suggest a coordination model of the aldehyde to the metal complex through association of a lone pair of the carbonyl oxygen to the hydrogen atom of an amino group.

Synthesis, physical-chemical characterisation and biological evaluation of novel 2-amido-3-hydroxypyridin-4(1H)-ones: Iron chelators with the potential for treating Alzheimer's disease

A novel class of 2-amido-3-hydroxypyridin-4-one iron chelators is described. These compounds have been designed to behave as suitable molecular probes which will improve our knowledge of the role of iron in neurodegenerative conditions. Neurodegenerative disorders, such as Alzheimer's disease (AD) and Parkinson disease (PD), can be considered as diverse pathological conditions sharing critical metabolic processes such as protein aggregation and oxidative stress. Interestingly, both these metabolic alterations seem to be associated with the involvement of metal ions, including iron. Iron chelation is therefore a potential therapeutic approach. The physico-chemical (pKa, pFe 3+ and log P) and biological properties (inhibition of iron-containing enzymes) of these chelators have been investigated in order to obtain a suitable profile for the treatment of neurodegenerative conditions. Studies with neuronal cell cultures confirm that the new iron chelators are neuroprotective against β-amyloid-induced toxicity.

Crystallisation-induced asymmetric transformation (CIAT) for the synthesis of dipeptides containing homophenylalanine

A novel synthesis of highly enantioenriched dipeptides containing homophenylalanine is described. The process involves a crystallisation-induced asymmetric transformation (CIAT) in a Michael addition followed by exhaustive reduction. A unique example of a formally stereodivergent CIAT in conjugate addition of an achiral N-nucleophile to enantiomerically pure Michael acceptor has been discovered.

BACE-1 inhibition by a series of ψ[CH2NH] reduced amide isosteres

A series of β-site amyloid precursor protein cleaving enzyme (BACE-1) inhibitors containing a ψ(CH2NH) reduced amide bond were synthesized. Incorporation of this reduced amide isostere as a non-cleavable peptide surrogate afforded inhibitors possessing low nanomolar potencies in both an enzymatic and cell-based assay.

Facile N-Derivatization of α-Amino Esters and Amides via Benzotriazolylmethyl Derivatives

α-(N-Substituted amino)esters were prepared in a two-step procedure from available unsubstituted α-amino esters. α-Amino esters are first converted into the corresponding N-benzotriazolylmethyl derivatives; in the second step, the benzotriazole group is substituted by various nucleophiles with or without the presence of a Lewis acid to give substituted α-amino esters in high overall yield under mild conditions with no signs of racemization. Boc-protected amino acids were converted into α-amino amides; subsequent deprotection allowed the conversion into N-substituted derivatives analogously to the α-amino esters, without racemization in high yields under mild conditions.

Derivatives of tetramethylcyclopropane

The present invention relates to derivatives of 2,2,3,3-tetramethylcyclopropane carboxylic acid (TMCA) of general formula (I), STR1 wherein R is lower alkyl group (C1 -C6), an aryl group, an aralkyl group or an amide of general formula (II), STR2 where R1 and R2 are the same or different and may be hydrogen, a alkyl group (C1 -C6), an aryl group or an aralkyl group, and n=0-3, to their racemic mixtures and the D and L enantiomers. The invention also relates to processes for the preparation of said compounds and for pharmaceutical preparations comprising the same. The new compounds show improved activity against epilepsy.

Synthesis of a cyclic urea as a nonnatural biopolymer scaffold

A cyclic urea trimer was synthesized from readily available amino acid derivatives using a simple, iterative approach. A selective amide reduction using borane (BH3-THF) and a triphosgene-mediated cyclization are the key features in a synthesis of the cyclic urea trimer 2.

Chymotrypsin inhibitory conformation induced by amino acid side chain-side chain intramolecular CH/π interaction

Dipeptide amides H-D-Leu-Phe-NH-R have been found to assume a conformation induced by the CH/π interaction and to inhibit chymotrypsin strongly. A series of benzyl amide derivatives H-D-Leu-Phe-NH-[CH2]n-C6H5 (n = 0-4) have been assayed for chymotrypsin. They inhibit the enzyme in a competitive manner and the highest inhibition is achieved by the amide of n = 1 (Ki = 3.6 × 10-6 M). The activity enhancement is dependent upon the length of methylene chain, not upon the increase in molecular hydrophobicity, indicating the presence of an optimal distance between dipeptide backbone and C-terminal phenyl group for chymotrypsin inhibition. The C-terminal phenyl group has been found to interact with chymotrypsin stereospecifically. The R-isomer of H-D-Leu-Phe-NH-CH(CH3)-C6H5 is as active as the benzyl amide, while the S-isomer is about twenty-fold less active. When the fluorine atom is introduced at a para-position of the C-terminal phenyl group, the resulting dipeptide H-D-Leu-Phe-NH-CH2-C6H4F-p exhibits about six-times increased inhibitory activity (Ki = 6.1 × 107 M; this dipeptide is one of the most potent chymotrypsin inhibitors to date). 1H NMR conformational analyses of these dipeptide amide derivatives show the CH/π interaction between D-Leu-isobutyl and Phe-phenyl as a key structural element for chymotrypsin inhibition. These structural examinations strongly suggest that in the inhibitory conformation the C-terminal phenyl group fits the chymotrypsin S1 site, while the hydrophobic core constructed by D-Leu-Phe CH/π interaction fits the chymotrypsin S2 or S1′ site.