Synthèse totale, révision structurale et histoire naturelle des cytochalasines de petite taille : les périconiasines

Cytochalasins are secondary metabolites born from fungal PKS-NRPS which possess a characteristic tricyclic core and display a large variety of biological properties. This document exposes the strategies elaborated toward total syntheses of small cytochalasins periconiasins A-C, isolated from Periconia sp. F-31 and sharing a 9/6/5 backbone, and periconiasin G which possesses the smallest macrocyclic ring so far in this family with a 7/6/5 tricyclic ring. Several analogues of natural product periconiasin C, including isomer bis-iso-périconiasin C, are described, as well as their bioassays on HeLa and MDA cell lines which allowed identification of a highly toxic lead. Moreover, the total synthesis of periconiasin G led us to the revise the structure published by Dai et al. and carry out pertinent bioassays on gram-positives bacteria Micrococcus luteus and Staphylococcus aureus, and on the phytopathogen Botrytis cinerea responsible of the gray mold disease throughout the world. A specificity of periconiasin G against the phytopathogen was discovered, leading us to consider the protective role of endophytes in the plant-fungus mutualism.Les cytochalasines, métabolites secondaires issus de PKS-NRPS fongiques, représentent une large famille de composés bioactifs intéressants de par leur système tricyclique. Ce document expose les stratégies de synthèse vers l’obtention de cytochalasines de petite taille, les périconiasines A-C, isolées de Periconia sp. F-31, qui partagent un système 9/6/5 et des cytotoxicités intéressantes envers l’adénocarcinome du colon, et la synthèse totale de la périconiasine G qui possède le plus petit macrocycle rencontré jusqu’à présent dans cette famille avec un système 7/6/5. Plusieurs analogues du produit naturel dont l’bis-iso-périconiasine C qui se caractérise par une isomérisation des alcènes initiaux sont décrits, ainsi que leurs tests sur des cellules HeLa et MDA ce qui a permis l’identification d’un composé hautement cytotoxique. D’autre part, la synthèse totale de la périconiasine G a conduit à réviser la structure initialement attribuée par Dai et al. et réaliser des tests biologiques pertinents sur les bactéries gram-négatives Micrococcus luteus et Staphylococcus aureus ainsi que sur le phytopathogène Botrytis cinerea responsable de la « pourriture grise » des cultures à travers le monde. Une spécificité de la périconiasine G contre le phytopathogène a pu être découverte ce qui amène à considérer le rôle protecteur des endophytes dans le mutualisme plante-champignon

Total synthesis, structural revision and natural history of small cytochalasins, periconiasins

Les cytochalasines, métabolites secondaires issus de PKS-NRPS fongiques, représentent une large famille de composés bioactifs intéressants de par leur système tricyclique. Ce document expose les stratégies de synthèse vers l’obtention de cytochalasines de petite taille, les périconiasines A-C, isolées de Periconia sp. F-31, qui partagent un système 9/6/5 et des cytotoxicités intéressantes envers l’adénocarcinome du colon, et la synthèse totale de la périconiasine G qui possède le plus petit macrocycle rencontré jusqu’à présent dans cette famille avec un système 7/6/5. Plusieurs analogues du produit naturel dont l’bis-iso-périconiasine C qui se caractérise par une isomérisation des alcènes initiaux sont décrits, ainsi que leurs tests sur des cellules HeLa et MDA ce qui a permis l’identification d’un composé hautement cytotoxique. D’autre part, la synthèse totale de la périconiasine G a conduit à réviser la structure initialement attribuée par Dai et al. et réaliser des tests biologiques pertinents sur les bactéries gram-négatives Micrococcus luteus et Staphylococcus aureus ainsi que sur le phytopathogène Botrytis cinerea responsable de la « pourriture grise » des cultures à travers le monde. Une spécificité de la périconiasine G contre le phytopathogène a pu être découverte ce qui amène à considérer le rôle protecteur des endophytes dans le mutualisme plante-champignon.Cytochalasins are secondary metabolites born from fungal PKS-NRPS which possess a characteristic tricyclic core and display a large variety of biological properties. This document exposes the strategies elaborated toward total syntheses of small cytochalasins periconiasins A-C, isolated from Periconia sp. F-31 and sharing a 9/6/5 backbone, and periconiasin G which possesses the smallest macrocyclic ring so far in this family with a 7/6/5 tricyclic ring. Several analogues of natural product periconiasin C, including isomer bis-iso-périconiasin C, are described, as well as their bioassays on HeLa and MDA cell lines which allowed identification of a highly toxic lead. Moreover, the total synthesis of periconiasin G led us to the revise the structure published by Dai et al. and carry out pertinent bioassays on gram-positives bacteria Micrococcus luteus and Staphylococcus aureus, and on the phytopathogen Botrytis cinerea responsible of the gray mold disease throughout the world. A specificity of periconiasin G against the phytopathogen was discovered, leading us to consider the protective role of endophytes in the plant-fungus mutualism

Bent to Bind: Exploiting the Programmed Cell Death-1 (PD-1) Receptor Plasticity to Design Pembrolizumab H3 Loop Mimics

Checkpoint blockade of the Programmed cell Death-1 (PD-1) immunoreceptor with its ligand 1 (PD-L1) by the monoclonal antibody pembrolizumab provided compelling clinical results among various cancer types, yet the molecular mechanism by which this drug blocks the PD-1:PD-L1 binding interface and reactivates exhausted T cells remains unclear. To address this question, we examined the conformational motion of PD-1 associated with the binding of pembrolizumab. The largely overlooked innate plasticity of both PD-1 C’D and FG loops appears crucial to closing in the receptor edges on the drug. Herein, we describe how PD-1 bends to initiate the formation of a deep binding groove (371 Å3) across several epitopes while engaging pembrolizumab. Our analysis ultimately provided a rational design for mimicking the pembrolizumab H3 loop [RDYRFDMGFD] as a PD-1 inhibitor. A series of H3 loop mimics were synthesized and their folding characterized by CD and NMR spectroscopy. As a result, a first-in-class b-hairpin peptide inhibitor of the PD-1/PD-L1 interface was identified (IC50 of 0.6 ± 0.2 μM). Overall, this study demonstrates that the dynamic groove formed between the C’D and FG loops of PD-1 is an attractive target for the development of peptide-based PD-1 inhibitors

Design, Synthesis, and Organocatalytic Activity of N-Heterocyclic Carbenes Functionalized with Hydrogen-Bond Donors in Enantioselective Reactions of Homoenolates

International audienceA focused library of chiral imidazolinium salts functionalized with urea-type hydrogen-bond donor moieties has been prepared from the chiral pool. The corresponding N-heterocyclic carbenes were evaluated as organocatalysts in three enantioselective reactions involving homoenolate intermediates generated from enals. The catalysts proved competent in enantioselective cyclopentannulation and γ-lactonization reactions, a premiere for imidazoline-based NHCs. This work conveys some new ideas and knowledge on the concepts of bifunctional enantioselective organocatalysis applied to NHCs

Nivolumab to pembrolizumab switch induced a durable melanoma response: A case report

While checkpoint inhibitors have revolutionized the treatment of melanoma, it is not known whether switching from one monoclonal antibody drug to another one would be justified in the case of a treatment failure. Herein, we report a case illustrating a durable response to pembrolizumab after a failure with nivolumab. A 76-year-old white male noticed an enlarging papular lesion on his neck. Malignant melanoma. The patient underwent surgery in December 2013 and was found to have a B-Rapidly Accelerated Fibrosarcoma (BRAF) V600E mutated melanoma. Treatment with BRAF and MAPK/Erk kinase (MEK) inhibitors along with radiation was initiated. After 1 year, the disease progressed, and the treatment was switched to the cytotoxic T-lymphocyte antigen 4 (CTLA-4) blocking antibody, ipilimumab. As the tumor did not respond, the treatment was changed to programmed cell death receptor-1 (PD-1) blockers: nivolumab followed by pembrolizumab. Since the initial diagnosis, the tumor response was monitored by computed tomography (CT) scans. Immunohistochemistry (IHC) was also used for the assessment of programmed death ligand 1 PD-L1) expression in the neck, lung, and spleen lesions. The patient had an initial mixed response to nivolumab, but the disease ultimately progressed as evidenced by new metastases to the spleen, thus the treatment was switched to pembrolizumab. After 46 cycles of treatment, all sites of metastases disappeared, including a substantial shrinkage of the splenic metastasis. To gain understanding about the pharmacological differences between nivolumab and pembrolizumab, the PD-1-ligands interactions and conformational dynamics responsible for the PD-1/PD-L1 checkpoint blockade were investigated. The higher affinity of pembrolizumab might likely arise from a unique and large patch of interactions engaging the C'D loop of PD-1, thus forcing an important motion across the PD-1 immunoreceptor. In this case report, we described the tolerance and response of a melanoma patient to a sequence of various agents, including ipilimumab, nivolumab, and pembrolizumab. To the best of our knowledge, this is the first clinical report highlighting differences between PD-1 blockers, as shown by the unexpected and durable response of the tumor to pembrolizumab, after a treatment failure with nivolumab