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All total 111 Articles be foundTopology-Controlled Selective Fe3+ Binding in Water by -Peptides with a Dihydropyrimidinone-Containing Amino Acid
Ghorai, Pradip Kumar,Haldar, Debasish,Konar, Sukanya,Podder, Debasish,Sasmal, Supriya
, p. 1760 - 1770 (2020)
The effect of topology on the structure, self-assembly, and selective Fe3+ binding of -peptides has been investigated. A series of -peptides with an amino acid containing dihydropyrimidinone and o-, m-, and p-aminobenzoic acids have been designed to study the structure-function relationship. A new amino acid containing dihydropyrimidinone was synthesized by the Biginelli reaction of ethyl acetoacetate, urea, and o-nitrobenzaldehyde followed by reduction with iron powder and acetic acid. X-ray crystallography sheds some light on the conformations, self-assembly, and the diverse degrees of -πstacking of adjacent -peptide molecules. Peptides with o- or m-aminobenzoic acid form eight-membered intramolecular hydrogen-bonded turn conformations and self-assemble through intermolecular hydrogen bonds between dihydropyrimidinone units to form a butterfly-like structure. However, the -peptide containing p-aminobenzoic acid forms a water-mediated cage-like structure. Irrespective of the presence of the same functional groups, only the -peptide with o-aminobenzoic acid can selectively bind Fe3+ in methanol as well as in water. The topology plays a crucial role in the selective Fe3+ ion binding by the -peptide.
Development of potent dual PDK1/AurA kinase inhibitors for cancer therapy: Lead-optimization, structural insights, and ADME-Tox profile
Bacci, Andrea,Chiarugi, Sara,Gado, Francesca,Garau, Gianpiero,Gul, Sheraz,Huguet, Samuel,Manera, Clementina,Margheritis, Eleonora,Rapposelli, Simona,Rezai, Keyvan,Riveiro, Maria E.,Runfola, Massimiliano,Sestito, Simona,Vazquez, Ramiro
supporting information, (2021/10/08)
We report the synthesis of novel first-in-class 2-oxindole-based derivatives as dual PDK1-AurA kinase inhibitors as a novel strategy to treat Ewing sarcoma. The most potent compound 12 is suitable for progression to in vivo studies. The specific attributes of 12 included nanomolar inhibitory potency against both phosphoinositide-dependent kinase-1 (PDK1) and Aurora A (AurA) kinase, with acceptable in vitro ADME-Tox properties (cytotoxicity in 2 healthy and 14 hematological and solid cancer cell-lines; inhibition of PDE4C1, SIRT7, HDAC4, HDAC6, HDAC8, HDAC9, AurB, CYP1A2, CYP2C9, CYP2C19, CYP2D6, and hERG). X-ray crystallography and docking studies led to the identification of the key AurA and PDK1/12 interactions. Finally, in vitro drug-intake kinetics and in vivo PK appear to indicate that these compounds are attractive lead-structures for the design and synthesis of PDK1/AurA dual-target molecules to further investigate the in vivo efficacy against Ewing Sarcoma.
Palladium-Catalyzed Chlorocarbonylation of Aryl (Pseudo)Halides Through In Situ Generation of Carbon Monoxide
Bismuto, Alessandro,Boehm, Philip,Morandi, Bill,Roediger, Sven
supporting information, p. 17887 - 17896 (2020/08/19)
An efficient palladium-catalyzed chlorocarbonylation of aryl (pseudo)halides that gives access to a wide range of carboxylic acid derivatives has been developed. The use of butyryl chloride as a combined CO and Cl source eludes the need for toxic, gaseous carbon monoxide, thus facilitating the synthesis of high-value products from readily available aryl (pseudo)halides. The combination of palladium(0), Xantphos, and an amine base is essential to promote this broadly applicable catalytic reaction. Overall, this reaction provides access to a great variety of carbonyl-containing products through in situ transformation of the generated aroyl chloride. Combined experimental and computational studies support a reaction mechanism involving in situ generation of CO.
