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1.
J Org Chem ; 88(17): 12802-12807, 2023 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-37606513

RESUMO

The mechanism of the 1,2-spin-center shift in carbohydrate systems was studied with a fluorenylcyclopropyl radical clock. The 1,2-rearrangement of the acyl fluorenylcyclopropane group without opening of the cyclopropane ring provides the strongest evidence that the 1,2-spin-center shift in carbohydrate systems occurs through a concerted transition state without the intermediacy of a 1,3-dioxolanyl radical.

2.
Org Lett ; 24(37): 6722-6727, 2022 09 23.
Artigo em Inglês | MEDLINE | ID: mdl-36095147

RESUMO

The alkylations of chiral seven-membered rings fused to tetrazoles are highly diastereoselective. The diastereoselectivity depended on the placement and the size of the substituent on the ring and on the electrophile. Subsequent alkylations occurred with high stereoselectivity, allowing for the construction of quaternary stereocenters. Computational studies revealed that torsional effects are responsible for the observed diastereoselectivities. Substituted products can be reduced to the corresponding secondary amines, thus providing an approach for synthesizing diastereomerically enriched azepanes.


Assuntos
Aminas , Azepinas , Alquilação , Ânions , Estereoisomerismo , Tetrazóis
3.
Angew Chem Int Ed Engl ; 61(14): e202114183, 2022 03 28.
Artigo em Inglês | MEDLINE | ID: mdl-35076978

RESUMO

Unlike many reactions of their six-membered-ring counterparts, the reactions of chiral seven-membered-ring enolates are highly diastereoselective. Diastereoselectivity was observed for a range of substrates, including lactam, lactone, and cyclic ketone derivatives. The stereoselectivity arises from torsional and steric interactions that develop when electrophiles approach the diastereotopic π-faces of the enolates, which are distinguished by subtle differences in the orientation of nearby atoms of the ring.


Assuntos
Ácidos Carboxílicos , Cetonas , Estereoisomerismo
4.
Plant Physiol ; 180(4): 1848-1859, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31138623

RESUMO

Though they are rare in nature, anthropogenic 1,3,5-triazines have been used in herbicides as chemically stable scaffolds. Here, we show that small 1,3,5-triazines selectively target ascorbate peroxidases (APXs) in Arabidopsis (Arabidopsis thaliana), tomato (Solanum lycopersicum), rice (Oryza sativa), maize (Zea mays), liverwort (Marchantia polymorpha), and other plant species. The alkyne-tagged 2-chloro-4-methyl-1,3,5-triazine probe KSC-3 selectively binds APX enzymes, both in crude extracts and in living cells. KSC-3 blocks APX activity, thereby reducing photosynthetic activity under moderate light stress, even in apx1 mutant plants. This suggests that APX enzymes in addition to APX1 protect the photosystem against reactive oxygen species. Profiling APX1 with KCS-3 revealed that the catabolic products of atrazine (a 1,3,5-triazine herbicide), which are common soil pollutants, also target APX1. Thus, KSC-3 is a powerful chemical probe to study APX enzymes in the plant kingdom.


Assuntos
Arabidopsis/enzimologia , Arabidopsis/metabolismo , Ascorbato Peroxidases/metabolismo , Arabidopsis/genética , Ascorbato Peroxidases/genética , Atrazina/metabolismo , Regulação da Expressão Gênica de Plantas/genética , Regulação da Expressão Gênica de Plantas/fisiologia , Hepatófitas/genética , Hepatófitas/metabolismo , Solanum lycopersicum/genética , Solanum lycopersicum/metabolismo , Oryza/genética , Oryza/metabolismo , Plantas Geneticamente Modificadas/genética , Plantas Geneticamente Modificadas/metabolismo , Zea mays/genética , Zea mays/metabolismo
5.
Biochemistry ; 57(13): 2035-2043, 2018 04 03.
Artigo em Inglês | MEDLINE | ID: mdl-29521097

RESUMO

Protein disulfide isomerase A1 (PDIA1) is an endoplasmic reticulum (ER)-localized thiol-disulfide oxidoreductase that is an important folding catalyst for secretory pathway proteins. PDIA1 contains two active-site domains (a and a'), each containing a Cys-Gly-His-Cys (CGHC) active-site motif. The two active-site domains share 37% sequence identity and function independently to perform disulfide-bond reduction, oxidation, and isomerization. Numerous inhibitors for PDIA1 have been reported, yet the selectivity of these inhibitors toward the a and a' sites is poorly characterized. Here, we identify a potent and selective PDIA1 inhibitor, KSC-34, with 30-fold selectivity for the a site over the a' site. KSC-34 displays time-dependent inhibition of PDIA1 reductase activity in vitro with a kinact/ KI of 9.66 × 103 M-1 s-1 and is selective for PDIA1 over other members of the PDI family, and other cellular cysteine-containing proteins. We provide the first cellular characterization of an a-site selective PDIA1 inhibitor and demonstrate that KSC-34 has minimal sustained effects on the cellular unfolded protein response, indicating that a-site inhibition does not induce global protein folding-associated ER stress. KSC-34 treatment significantly decreases the rate of secretion of a destabilized, amyloidogenic antibody light chain, thereby minimizing pathogenic amyloidogenic extracellular proteins that rely on high PDIA1 activity for proper folding and secretion. Given the poor understanding of the contribution of each PDIA1 active site to the (patho)physiological functions of PDIA1, site selective inhibitors like KSC-34 provide useful tools for delineating the pathological role and therapeutic potential of PDIA1.


Assuntos
Inibidores Enzimáticos/química , Pró-Colágeno-Prolina Dioxigenase/antagonistas & inibidores , Pró-Colágeno-Prolina Dioxigenase/química , Isomerases de Dissulfetos de Proteínas/antagonistas & inibidores , Isomerases de Dissulfetos de Proteínas/química , Dobramento de Proteína , Domínio Catalítico , Humanos , Pró-Colágeno-Prolina Dioxigenase/genética , Isomerases de Dissulfetos de Proteínas/genética
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