5437-45-6Relevant academic research and scientific papers
Fmoc-based synthesis of glycolate ester peptides for the assembly of de novo designed multimeric proteins using subtiligase
Suich, Daniel J.,Ballinger, Marcus D.,Wells, James A.,DeGrado, William F.
, p. 6653 - 6656 (1996)
An automated method utilizing Fmoc-protected amino acids has been developed for the synthesis of glycolate ester peptides as substrates for subtiligase. As a test of this methodology, peptide esters containing α-helical sequences that specify the association into 3- and 4-helix bundles were synthesized, and used to explore the suitability of subtiligase as a tool, for the generation of covalently linked bundles. The feasibility of creating de novo designed, single-chain or cyclic structures from simple, readily-synthesized modules has been demonstrated.
Engineering Dirhodium Artificial Metalloenzymes for Diazo Coupling Cascade Reactions**
Bultman, Max J.,Huang, Rui,Lewis, Jared C.,Li, Ying,Roux, Benoit,Upp, David M.
supporting information, p. 23672 - 23677 (2021/08/23)
Artificial metalloenzymes (ArMs) are commonly used to control the stereoselectivity of catalytic reactions, but controlling chemoselectivity remains challenging. In this study, we engineer a dirhodium ArM to catalyze diazo cross-coupling to form an alkene that, in a one-pot cascade reaction, is reduced to an alkane with high enantioselectivity (typically >99 % ee) by an alkene reductase. The numerous protein and small molecule components required for the cascade reaction had minimal effect on ArM catalysis. Directed evolution of the ArM led to improved yields and E/Z selectivities for a variety of substrates, which translated to cascade reaction yields. MD simulations of ArM variants were used to understand the structural role of the cofactor on ArM conformational dynamics. These results highlight the ability of ArMs to control both catalyst stereoselectivity and chemoselectivity to enable reactions in complex media that would otherwise lead to undesired side reactions.
Visible-Light-Induced Oxidative α-Alkylation of Glycine Derivatives with Ethers under Metal-Free Conditions
Song, Yang,Zhang, Hao,Guo, Jiabao,Shao, Yifei,Ding, Yuzhou,Zhu, Li,Yao, Xiaoquan
, p. 5914 - 5921 (2021/11/22)
In this work, a visible-light-induced oxidative α-alkylation of glycine derivatives with ethers has been developed in the presence of catalytic Eosin Y. Under the blue light of a 3 W LED, a range of α-etherized glycine derivatives, including α-amino esters, α-amino ketones and α-amino amides, were achieved with good to excellent yields and functional group tolerance with tert-butyl hydroperoxide (TBHP) as oxidant at ambient temperature. The operationally easy procedure provides an economical, metal-free, and mild alternative for the synthesis of the α-etherized glycine derivatives.
1,5-Disubstituted 1,2,3-Triazoles as Amide Bond Isosteres Yield Novel Tumor-Targeting Minigastrin Analogs
Grob, Nathalie M.,Schibli, Roger,Béhé, Martin,Valverde, Ibai E.,Mindt, Thomas L.
supporting information, p. 585 - 592 (2021/04/12)
1,5-Disubstituted 1,2,3-triazoles (1,5-Tz) are considered bioisosteres of cis-amide bonds. However, their use for enhancing the pharmacological properties of peptides or proteins is not yet well established. Aiming to illustrate their utility, we chose the peptide conjugate [Nle15]MG11 (DOTA-dGlu-Ala-Tyr-Gly-Trp-Nle-Asp-Phe-NH2) as a model compound since it is known that the cholecystokinin-2 receptor (CCK2R) is able to accommodate turn conformations. Analogs of [Nle15]MG11 incorporating 1,5-Tz in the backbone were synthesized and radiolabeled with lutetium-177, and their pharmacological properties (cell internalization, receptor binding affinity and specificity, plasma stability, and biodistribution) were evaluated and compared with [Nle15]MG11 as well as their previously reported analogs bearing 1,4-disubstituted 1,2,3-triazoles. Our investigations led to the discovery of novel triazole-modified analogs of [Nle15]MG11 with nanomolar CCK2R-binding affinity and 2-fold increased tumor uptake. This study illustrates that substitution of amides by 1,5-disubstituted 1,2,3-triazoles is an effective strategy to enhance the pharmacological properties of biologically active peptides.
E- and chemoselective thia-Michael addition to benzyl allenoate
Bibi, Rifhat,Murtaza, Amna,Khan, Khalid Mohammed,Rehman, Zia ur,Saeed, Aamer,Tahir, Muhammad Nawaz,Hassan, Abbas
supporting information, p. 969 - 975 (2020/08/05)
Different thiols were successfully reacted with benzyl allenoate resulting in E-selective thia-Michael addition product with α,β-unsaturation as confirmed by single crystal x-ray crystallographic analysis. The thia-Michael addition is chemoselective and free amine and alcohol groups were well tolerated. Catalytic triethylamine was required for high conversion. Fair to excellent yields were obtained for a variety of aliphatic, aryl and heteroaryl thiols.
Synthesis, antiinflammatory activity, and molecular docking studies of bisphosphonic esters as potential MMP-8 and MMP-9 inhibitors
Cortes-Pacheco, Abimelek,Jiménez-Arellanes, María Adelina,Juárez-Vázquez, María del Carmen,López-Torres, Adolfo,Palacios-Can, Francisco José,Ramírez-Marroquín, Oscar Abelardo,Razo-Hernández, Rodrigo Said,Valcarcel-Gami?o, José Antonio
supporting information, p. 1277 - 1287 (2020/07/10)
Bisphosphonic acids (or bisphosphonates) have been successfully used in the clinic treatment of bone diseases for over decades. Additionally, the antiinflammatory activity of these compounds has been gaining attention. In our previous work, we synthesized and in vivo evaluated the bisphosphonic esters 1 and 2, finding a moderate edema inhibition upon oral and topical administration on BALB/c mice. Thus, in this work, the bioisosteric replacement of an amide functional group for an ester afforded the new bisphosphonates 3–6, which had a moderate oral edema inhibition (25 mg/kg dose) and a significant topical antiinflammatory activity (2 mg/ear) on BALB/c mice, with 6 being the most active hit (55.9% edema inhibition), comparable to the positive control (55.5% edema inhibition) on a TPA topical model. Next, to assess the acute toxicity of the synthesized derivatives, test animals were administered with 50–100 mg/kg of 3–6, respectively, by an oral route, and after 14 days, neither lethality nor a significative weight loss were observed. Finally, a structure–activity relationship (SAR) and a molecular docking analysis of 3–6 helped us to explain the trend observed in biological tests. Considering all these aspects, we propose the inhibition of MMP-8 and MMP-9 as a possible action mechanism of the synthesized derivatives.
Cross coupling of sulfonyl radicals with silver-based carbenes: A simple approach to β-carbonyl arylsulfones
Li, Jingjing,Lian, Pengcheng,Wan, Xiaobing,Wang, Hanghang,Zheng, Yonggao
supporting information, p. 2163 - 2169 (2020/03/27)
A coupling reaction between sulfonyl radicals and silver-based carbenes has been well established. This simple radical-carbene coupling (RCC) process provided an efficient approach to a variety of β-carbonyl arylsulfones from sodium arylsulfinates and diazo compounds, and was characterized by wide substrate scope, easy scale-up, simple manipulation, accessible starting materials, and mild reaction conditions.
Enantioselective Allenoate-Claisen Rearrangement Using Chiral Phosphate Catalysts
Ellwart, Mario,Gensch, Tobias,Han, Seo-Jung,Lin, Hsin-Hui,Miró, Javier,Sigman, Matthew S.,Toste, F. Dean
supporting information, p. 6390 - 6399 (2020/04/27)
Herein we report the first highly enantioselective allenoate-Claisen rearrangement using doubly axially chiral phosphate sodium salts as catalysts. This synthetic method provides access to β-amino acid derivatives with vicinal stereocenters in up to 95percent ee. We also investigated the mechanism of enantioinduction by transition state (TS) computations with DFT as well as statistical modeling of the relationship between selectivity and the molecular features of both the catalyst and substrate. The mutual interactions of charge-separated regions in both the zwitterionic intermediate generated by reaction of an amine to the allenoate and the Na+-salt of the chiral phosphate leads to an orientation of the TS in the catalytic pocket that maximizes favorable noncovalent interactions. Crucial arene-arene interactions at the periphery of the catalyst lead to a differentiation of the TS diastereomers. These interactions were interrogated using DFT calculations and validated through statistical modeling of parameters describing noncovalent interactions.
Visible-Light-Assisted Gold-Catalyzed Fluoroarylation of Allenoates
Feng, Chao,Tang, Hai-Jun,Zhang, Xinggui,Zhang, Yu-Feng
supporting information, p. 5242 - 5247 (2020/02/28)
A strategically novel synthetic method for the fluoroarylation of allenic ester was developed that enables the expedient construction of a host of β-fluoroalkyl-containing cinnamate derivatives. The reaction proceeds through visible-light-promoted gold redox catalysis, occurs smoothly under very mild reaction conditions, accommodates a large variety of functional groups, and more importantly allows the incorporation of fluorine and aryl groups with excellent regio- and stereoselectivity. The concomitant activation mode for both the allene motif and the hydrogen fluoride is key for the success of the reaction.
Virtual Screening Identifies Irreversible FMS-like Tyrosine Kinase 3 Inhibitors with Activity toward Resistance-Conferring Mutations
Bensinger, Dennis,Stubba, Daniel,Cremer, Anjali,Kohl, Vanessa,Wa?mer, Theresa,Stuckert, Johanna,Engemann, Victoria,Stegmaier, Kimberly,Schmitz, Katja,Schmidt, Boris
supporting information, p. 2428 - 2446 (2019/03/11)
The use of covalent irreversible binding inhibitors is an established concept for drug development. Usually, the discovery of new irreversible kinase inhibitors occurs serendipitously, showing that efficient rational approaches for the rapid discovery of new drugs are needed. Herein, we report a virtual screening strategy that led to the discovery of irreversible inhibitors of FMS-like tyrosine kinase 3 (FLT3) involved in the pathogenesis of acute myeloid leukemia. A virtual screening library was designed to target the highly conserved Cys828 residue preceding the DFG motif by modification of reported reversible inhibitors with chemically reactive groups. Prospective covalent docking allowed the identification of two lead series, resulting in a massive increase in inhibition of kinase activity and cell viability by irreversible inhibitors compared to the corresponding reversible scaffolds. Lead compound 4b (BSc5371) displays superior cytotoxicity in FLT3-dependent cell lines to compounds in recent clinical trials and overcomes drug-resistant mutations.
