Synthesis of New L-Ascorbic Ferulic Acid Hybrids

A feasibility and chemical study of the coupling conditions of L-ascorbic acidwith ferulic acid derivatives are described on the basis of the known synergistic effects ofmixtures of various antioxidants. Novel L-ascorbic ferulic hybrids linked at the C-3hydroxyl group were prepared with the aim to protect the alcohol function and the enediolsystem

Strategies to Reduce the On-Target Platelet Toxicity of Bcl-xL Inhibitors: PROTACs, SNIPERs and Prodrug-Based Approaches

lisään tiedoston kun full VoR julkaistuApoptosis is a highly regulated cellular process. Aberration in apoptosis is a common characteristic of various disorders. Therefore, proteins involved in apoptosis are prime targets in multiple therapies. Bcl-xL is an antiapoptotic protein. Compared to other antiapoptotic proteins, the expression of Bcl-xL is common in solid tumors and, to an extent, in some leukemias and lymphomas. The overexpression of Bcl-xL is also linked to survival and chemoresistance in cancer and senescent cells. Therefore, Bcl-xL is a promising anticancer and senolytic target. Various nanomolar range Bcl-xL inhibitors have been developed. ABT-263 was successfully identified as a Bcl-xL/Bcl-2 dual inhibitor. But it failed in the clinical trial (phase-II) because of its on-target platelet toxicity, which also implies an essential role of Bcl-xL protein in the survival of human platelets. Classical Bcl-xL inhibitor designs utilize occupancy-driven pharmacology with typical shortcomings (such as dose-dependent off-target and on-target platelet toxicities). Hence, event-driven pharmacology-based approaches, such as proteolysis targeting chimeras (PROTACs) and SNIPERs (specific non-genetic IAP-based protein erasers) have been developed. The development of Bcl-xL based PROTACs was expected, as 600 E3-ligases are available in humans, while some (such as cereblon (CRBN), von Hippel-Lindau (VHL)) are relatively less expressed in platelets. Therefore, E3 ligase ligand-based Bcl-xL PROTACs (CRBN: XZ424, XZ739; VHL: DT2216, PZ703b, 753b) showed a significant improvement in platelet therapeutic index than their parent molecules (ABT-263: DT2216, PZ703b, 753b, XZ739, PZ15227; A1155463: XZ424). Other than their distinctive pharmacology, PROTACs are molecularly large, which limits their cell permeability and plays a role in improving their cell selectivity. We also discuss prodrug-based approaches, such as antibody-drug conjugates (ABBV-155), phosphate prodrugs (APG-1252), dendrimer conjugate (AZD0466), and glycosylated conjugates (Nav-Gal). Studies of in-vitro, in-vivo, structure-activity relationships, biophysical characterization, and status of preclinical/clinical inhibitors derived from these strategies are also discussed in the review.Peer reviewe

The use of halo (het) arylboronic acids and esters to achieve syntheses of garlands as mimics of alpha helices able to disrupt protein-protein interactions.

International audienc

Impact de l'activité physique et sportive sur l'organisme féminin

CAEN-BU Médecine pharmacie (141182102) / SudocLYON1-BU Santé (693882101) / SudocSudocFranceF

Conception et synthèse de nouveaux ligands des récepteurs alpha7 nicotiniques de structure pyridinique

CAEN-BU Médecine pharmacie (141182102) / SudocLYON1-BU Santé (693882101) / SudocSudocFranceF

Synthèse, étude physicochimique et évaluation biologique de nouvelles pyrazoloquinazolinones comme inhibiteurs de rho kinases

CAEN-BU Médecine pharmacie (141182102) / SudocLYON1-BU Santé (693882101) / SudocSudocFranceF

Tau protein aggregation in Alzheimer's disease: An attractive target for the development of novel therapeutic agents

International audienceAlzheimer's Disease (AD) is a neurodegenerative brain disorder in which many biological dysfunctions are involved. Among them, two main types of lesions were discovered and widely studied: the amyloid plaques and the neurofibrillary tangles (NFTs). These two lesions are caused by the dysfunction and the accumulation of two proteins which are, respectively, the beta-amyloid peptide and the tau protein. The process that leads these two proteins to aggregate is complex and is the subject of current studies. After a brief description of the aggregation mechanisms, we will provide an overview of new therapeutic agents targeting the different dysfunctions and toxic species found during aggregatio

Etude de la synthèse et recherche des propriétés biologiques de nouveaux acides et esters pyridinylboroniques

CAEN-BU Médecine pharmacie (141182102) / SudocSudocFranceF

Azobenzene Photoswitches in Proteolysis Targeting Chimeras

Publisher Copyright: © 2022 The Authors. ChemistrySelect published by Wiley-VCH GmbH.The photoswitchable-PROTACs have photoswitches that work as an actual ON/OFF switch for any particular bioactivity. In reported studies, the ON/OFF activity correlates with the photostationary state and quantum yield of a specific isomer under a definite wavelength of light, providing a spatiotemporal control over protein degradation (an example of photochemistry-based precision medicine). The studies reported the role of azobenzenes as photoswitches (ortho-tetramethoxybenzenes, ortho-tetraflurobenzenes as push-pull and push-push) to develop light-controlled PROTACs. This paper discussed the photophysical properties of photoswitchable-PROTACs (such as photoisomerization, quantum yield, and thermal relaxation states) and correlated their photochemical-based structural bioactivity relationships. The proteins studied under photoswitchable-PROTACs are kinase proteins: BCR-ABL fusion protein, ABL; Bromodomain proteins: BRD2, 3, 4; Immunophilins: FKBP12.Peer reviewe

Estrogen Receptor-alpha Targeting: PROTACs, SNIPERs, Peptide-PROTACs, Antibody Conjugated PROTACs and SNIPERs

Targeting selective estrogen subtype receptors through typical medicinal chemistry approaches is based on occupancy-driven pharmacology. In occupancy-driven pharmacology, molecules are developed in order to inhibit the protein of interest (POI), and their popularity is based on their virtue of faster kinetics. However, such approaches have intrinsic flaws, such as pico-to-nanomolar range binding affinity and continuous dosage after a time interval for sustained inhibition of POI. These shortcomings were addressed by event-driven pharmacology-based approaches, which degrade the POI rather than inhibit it. One such example is PROTACs (Proteolysis targeting chimeras), which has become one of the highly successful strategies of event-driven pharmacology (pharmacology that does the degradation of POI and diminishes its functions). The selective targeting of estrogen receptor subtypes is always challenging for chemical biologists and medicinal chemists. Specifically, estrogen receptor alpha (ER-alpha) is expressed in nearly 70% of breast cancer and commonly overexpressed in ovarian, prostate, colon, and endometrial cancer. Therefore, conventional hormonal therapies are most prescribed to patients with ER + cancers. However, on prolonged use, resistance commonly developed against these therapies, which led to selective estrogen receptor degrader (SERD) becoming the first-line drug for metastatic ER + breast cancer. The SERD success shows that removing cellular ER-alpha is a promising approach to overcoming endocrine resistance. Depending on the mechanism of degradation of ER-alpha, various types of strategies of developed.Peer reviewe