29511-09-9Relevant articles and documents
Anticancer Activity of Phenolic Acids of Natural or Synthetic Origin: A Structure-Activity Study
Gomes, Catarina A.,Gir?o Da Cruz, Teresa,Andrade, José L.,Milhazes, Nuno,Borges, Fernanda,Marques, M. Paula M.
, p. 5395 - 5401 (2003)
Several phenolic acids-caffeic and gallic acid derivatives-were synthesized and screened for their potential antiproliferative and cytotoxic properties, in different human cancer cell lines: mammary gland and cervix adenocarcinomas and lymphoblastic leukemia. The selected phenols were structurally related, which allowed us to gather important information regarding the structure-activity relationships underlying the biological activity of such compounds. This is proposed to be due to a balance between the antioxidant and pro-oxidant properties of this kind of agent. Distinct effects were found for different cell lines, which points to a significant specificity of action of the drugs tested. It was verified, for the types of cancer investigated, that the trihydroxylated derivatives yielded better results than the dihydroxylated ones. Tests in noncancerous cells, human lung fibroblasts, were also undertaken, in view of determining the toxic side effects of the compounds studied.
Structure-Based Design of High-Affinity Macrocyclic FKBP51 Inhibitors
Bauder, Michael,Meyners, Christian,Purder, Patrick L.,Merz, Stephanie,Sugiarto, Wisely Oki,Voll, Andreas M.,Heymann, Tim,Hausch, Felix
supporting information, p. 3320 - 3349 (2021/04/06)
The FK506-binding protein 51 (FKBP51) emerged as a key player in several diseases like stress-related disorders, chronic pain, and obesity. Linear analogues of FK506 called SAFit were shown to be highly selective for FKBP51 over its closest homologue FKBP52, allowing the proof-of-concept studies in animal models. Here, we designed and synthesized the first macrocyclic FKBP51-selective ligands to stabilize the active conformation. All macrocycles retained full FKBP51 affinity and selectivity over FKBP52 and the incorporation of polar functionalities further enhanced affinity. Six high-resolution crystal structures of macrocyclic inhibitors in complex with FKBP51 confirmed the desired selectivity-enabling binding mode. Our results show that macrocyclization is a viable strategy to target the shallow FKBP51 binding site selectively.
p-Hydroxyphenylacetate 3-Hydroxylase as a Biocatalyst for the Synthesis of Trihydroxyphenolic Acids
Dhammaraj, Taweesak,Phintha, Aisaraphon,Pinthong, Chatchadaporn,Medhanavyn, Dheeradhach,Tinikul, Ruchanok,Chenprakhon, Pirom,Sucharitakul, Jeerus,Vardhanabhuti, Nontima,Jiarpinitnun, Chutima,Chaiyen, Pimchai
, p. 4492 - 4502 (2015/08/18)
Trihydroxyphenolic acids such as 3,4,5-trihydroxycinnamic acid (3,4,5-THCA) 4c and 2-(3,4,5-trihydroxyphenyl)acetic acid (3,4,5-THPA) 2c are strong antioxidants that are potentially useful as medicinal agents. Our results show that p-hydroxyphenylacetate (HPA) 3-hydroxylase (HPAH) from Acinetobacter baumannii can catalyze the syntheses of 3,4,5-THPA 2c and 3,4,5-THCA 4c from 4-HPA 2a and p-coumaric acid 4a, respectively. The wild-type HPAH can convert 4-HPA 2a completely into 3,4,5-THPA 2c within 100 min (total turnover number (TTN) of 100). However, the wild-type enzyme cannot efficiently synthesize 3,4,5-THCA 4c. To improve the efficiency, the oxygenase component of HPAH (C2) was rationally engineered in order to maximize the conversion of p-coumaric acid 4a to 3,4,5-THCA 4c. Results from site-directed mutagenesis studies showed that Y398S is significantly more effective than the wild-type enzyme for the synthesis of 3,4,5-THCA 4c; it can catalyze the complete bioconversion of p-coumaric acid 4a to 3,4,5-THCA 4c within 180 min (TTN ~ 23 at 180 min). The yield and stability of 3,4,5-THPA 2c and 3,4,5-THCA 4c were significantly improved in the presence of ascorbic acid. Thermostability studies showed that the wild-type C2 was very stable and remained active after incubation at 30, 35, and 40 °C for 24 h. Y398S was moderately stable because its activity was retained for 24 h at 30 °C and for 15 h at 35 °C. Transient kinetic studies using stopped-flow spectrophotometry indicated that the key improvement in the reaction of Y398S with p-coumaric acid 4a lies within the protein-ligand interaction. Y398S binds to p-coumaric acid 4a with higher affinity than the wild-type enzyme, resulting in a shift in equilibrium toward favoring the productive coupling path instead of the path leading to wasteful flavin oxidation.