Chiroptical studies on brevianamide B : vibrational and electronic circular dichroism confronted

Chiroptical spectroscopy, such as electronic circular dichroism (ECD) and vibrational circular dichroism (VCD) are highly sensitive techniques to probe molecular conformation, configuration, solvation and aggregation. Here we report the application of these techniques to study the fungal metabolite brevianamide B. Comparison of the experimental ECD and VCD spectra with the density functional theory (DFT) simulated counterparts establishes that VCD is the more reliable technique to assign absolute configuration due to the larger functional and dispersion dependence of computed ECD spectra. Despite a low amount of available material, and a relatively unusual example of using VCD carbonyl multiplets, the absolute configuration could be reliably predicted, strengthening the case for application of VCD in the study of complex natural products. Spectral and crystallographic evidence for or against the formation of a dimeric aggregate is discussed; in solution the VCD spectra strongly suggest only monomeric species are present

A French multicentric prospective prognostic cohort with epidemiological, clinical, biological and treatment information to improve knowledge on lymphoma patients: study protocol of the "REal world dAta in LYmphoma and survival in adults" (REALYSA) cohort.

BACKGROUND: Age-adjusted lymphoma incidence rates continue to rise in France since the early 80's, although rates have slowed since 2010 and vary across subtypes. Recent improvements in patient survival in major lymphoma subtypes at population level raise new questions about patient outcomes (i.e. quality of life, long-term sequelae). Epidemiological studies have investigated factors related to lymphoma risk, but few have addressed the extent to which socioeconomic status, social institutional context (i.e. healthcare system), social relationships, environmental context (exposures), individual behaviours (lifestyle) or genetic determinants influence lymphoma outcomes, especially in the general population. Moreover, the knowledge of the disease behaviour mainly obtained from clinical trials data is partly biased because of patient selection. METHODS: The REALYSA ("REal world dAta in LYmphoma and Survival in Adults") study is a real-life multicentric cohort set up in French areas covered by population-based cancer registries to study the prognostic value of epidemiological, clinical and biological factors with a prospective 9-year follow-up. We aim to include 6000 patients over 4 to 5 years. Adult patients without lymphoma history and newly diagnosed with one of the following 7 lymphoma subtypes (diffuse large B-cell, follicular, marginal zone, mantle cell, Burkitt, Hodgkin, mature T-cell) are invited to participate during a medical consultation with their hematologist. Exclusion criteria are: having already received anti-lymphoma treatment (except pre-phase) and having a documented HIV infection. Patients are treated according to the standard practice in their center. Clinical data, including treatment received, are extracted from patients' medical records. Patients' risk factors exposures and other epidemiological data are obtained at baseline by filling out a questionnaire during an interview led by a clinical research assistant. Biological samples are collected at baseline and during treatment. A virtual tumor biobank is constituted for baseline tumor samples. Follow-up data, both clinical and epidemiological, are collected every 6 months in the first 3 years and every year thereafter. DISCUSSION: This cohort constitutes an innovative platform for clinical, biological, epidemiological and socio-economic research projects and provides an opportunity to improve knowledge on factors associated to outcome of lymphoma patients in real life. TRIAL REGISTRATION: 2018-A01332-53, ClinicalTrials.gov identifier: NCT03869619

Synthesis and biological evaluation of histone lysine methyltransferase inhibitors

The epigenetic component of cancer is now well-established and epigenetic therapeutics targeting histone deacetylase and DNA methyltransferase enzymes have received FDA approval. Histone lysine methyltransferases (HKMTs) are a new and promising epigenetic target class for cancer treatment, but the search for HKMT inhibitors is still in its infancy. First, chaetocin, a fungal metabolite belonging to the 3,6 epidithio-diketopiperazine (ETP) class, was previously described as a specific inhibitor of the HKMT SU(VAR)3 9. Like other ETP molecules however, it exhibits a broad cytotoxicity due to the presence of the disulfide bridge. The requirement of this moiety for HKMT inhibition has been questioned. We reasoned that access to semi-synthetic analogues devoid of such functionality would provide valuable insight into its reported HKMT inhibitory activity. Our results revealed a total loss in inhibitory potency upon modification of the disulfide bridge. In addition, we conducted biochemical and mass spectroscopy studies on the mechanism of action of chaetocin. Our results demonstrated the ETP functionality of chaetocin to be responsible for its reported HKMT inhibitory activity and suggest that chaetocin is a non-specific inhibitor. The stereochemical course of ETP desulfurisation by triphenylphosphine has also been investigated by comparison of experimental and computationally simulated chiroptical spectra. Our data showed that all ETPs are desulfurised with retention of stereochemistry. Second, BIX-01294 has been identified as an inhibitor of G9a/GLP HKMTs. In light of the expected structural similarities of EZH2’s peptide binding site with that of G9a, we felt we could use this molecule as a starting point for the reversal of H3K27-mediated gene silencing. We anticipated that upon derivatisation of BIX 01294, it might be possible to expand the biological activities of the parent compound and gain EZH2 inhibitory activity. A library of analogues has been prepared in collaboration with co-workers in the Fuchter group and has been assessed in biological assays. Three compounds have been identified in a cell-based assay to lead to re-expression of EZH2 target genes and their biological activities have been further assessed.Open Acces

Mechanistic and chiroptical studies on the desulfurization of epidithiodioxopiperazines reveal universal retention of configuration at the bridgehead carbon atoms

The stereochemistry of the desulfurization products of chiral natural and synthetic 3,6-epidithiodiketopiperazines (ETPs) is specified inconsistently in the literature. Qualitative mechanisms have been put forward to explain apparently divergent stereochemical pathways, however the quantita-tive feasibility of such mechanistic pathways has not been assessed. We report a computational study which reveals that desulfurization of ETPs should occur universally with retention of configuration. While the majority of stereochemically assigned and reassigned cases fit this model, until now desulfu-rization of a synthetic gliotoxin analogue (7) has remained assigned as proceeding via inversion of con-figuration. Through detailed chiroptical studies, comparing experimentally obtained optical rotation val-ues, electronic circular dichroism spectra, and vibrational circular dichroism spectra to their computa-tionally simulated counterparts, as well as using chemical derivatization studies, we have unambiguous-ly demonstrated that, contrary to its current assignment in the literature, the desulfurization of a synthet-ic ETP (7) also proceeds with retention of configuration

Mechanistic and chiroptical studies on the desulfurization of epidithiodioxopiperazines reveal universal retention of configuration at the bridgehead carbon atoms.

<p>2,3,10,10-Tetramethyl-2,3-dihydro-1H-3,10a-epithiopyrazino[1,2-a]indole-1,4(10H)-dione (<strong>8</strong>). To a solution of gliotoxin analogue (7, 33 mg, 0.10 mmol) in dioxane (8 mL) was added PPh3 (33 mg, 0.16 mmol) and the resulting mixture was stirred overnight at room temperature. The solvent was then re-moved under reduced pressure and the pink residue was purified by column chromatography [PEEtOAc (100:0 to 95:5)] to afford a colorless oil (19 mg, 64%) which was recrystallized from CH2Cl2 to give a white solid: m.p. 58 60 C; IR (neat) 1720, 1456, 1387, 1288, 1134 cm-1; 1H NMR (400 MHz, CDCl3) 8.54 (app-d, J = 7.8 Hz, 1H), 7.25 (td, J = 7.8, 1.0 Hz, 1H), 7.20 (dd, J = 7.8, 1.0 Hz, 1H), 7.13 (td, J = 7.8, 1.0 Hz, 1H), 2.96 (s, 3H), 1.83 (s, 3H), 1.75 (s, 3H), 1.48 (s, 3H); 13C NMR (100 MHz, CDCl3) 172.5, 172.0, 139.7, 138.1, 128.1, 124.7, 122.4, 113.6, 86.6, 75.1, 43.5, 27.2, 26.3, 25.7, 13.3; MS (CI) m/z 289 (M+H)+, 306 (M+NH4)+; HRMS (CI) m/z calcd for C15H17N2O2S [(M+H)+] 289.1011, found: 289.1026. The obtained enantiomers could be separated by chiral HPLC (OD+ semiprep column, Hexane : Isopropanol, 90:10): First peak: [α]25D -47.5 (c 1.12, CH2Cl2), Second peak: [α]25D +34.4 (c 1.12, CH2Cl2).</p

Mechanistic and Chiroptical Studies on the Desulfurization of Epidithiodioxopiperazines Reveal Universal Retention of Configuration at the Bridgehead Carbon Atoms

The stereochemistry of the desulfurization products of chiral natural and synthetic 3,6-epidithiodiketopiperazines (ETPs) is specified inconsistently in the literature. Qualitative mechanisms have been put forward to explain apparently divergent stereochemical pathways, but the quantitative feasibility of such mechanistic pathways has not been assessed. We report a computational study revealing that desulfurization of ETPs should occur universally with retention of configuration. While the majority of stereochemically assigned and reassigned cases fit this model, until now desulfurization of the synthetic gliotoxin analogue shown has remained assigned as proceeding via inversion of configuration. Through detailed chiroptical studies comparing experimentally obtained optical rotation values, electronic circular dichroism spectra, and vibrational circular dichroism spectra to their computationally simulated counterparts as well as chemical derivatization studies, we have unambiguously demonstrated that contrary to its current assignment in the literature, the desulfurization of this synthetic ETP also proceeds with retention of configuration