Theoretical study of the formation of α-bromoglycidic esters in aliphatic series using the DFT quantum mechanical method with B3LYP/6-311G (d, p)

In the present work we used density functional theory (DFT) with B3LYP/6-311G (d, p) to describe the reaction between isopropyl dibromoacetate and isobutyraldehyde. We calculated the optimized geometry of the two reactants, the transition states and the products obtained. We determined the energies corresponding to the reactants and the products as well as electron density, isodensity surfaces of the HOMO and LUMO and the localization of the transition states, and calculated the electrophilic and nucleophilic character of the reactants, the condensed local softness and some thermodynamic quantities (enthalpy, entropy and Gibbs free energy). We used natural population analysis (NPA) to determine Fukui indices, atomic electronic populations and reactivity indices. Finally, we analyzed the potential energy surface and studied the reaction mechanism.

The regio- and stereoselective addition of dibromocarbene and dichlorocarbene onto β-himachalene

In this work we used DFT B3LYP/6-31G (d) to study the mechanism, the regio- and stereoselectivity of the [1+2] cycloaddition reaction between β-himachalene and dihalogenocarbene. Analysis of the reactivity indices and calculation of the activation energies of the transition states showed that this reaction is stereoselectives, the treatment of β-himachalene with one equivalent of dibromocarbene leads via an exothermic reaction to the formation of a single product P1 resulting from the attack of the most substituted double bond C6=C7 of β-himachalene. Treatment of product P1 with one equivalent of dichlorocarbene leads, again via an exothermic reaction, to formation of the two products P3 and P4, but dibromocarbene does not react with the product P1 due to the high activation energy of this reaction

A DFT study of the mechanism and regioselectivity of the reaction between diethyl trichloro-methyl phosphonate and diphenyl methyl phosphinite

The reaction of diethyl trichloro-methyl phosphonate (C1) with diphenyl methyl phosphinite (C2), has been scrutinized within the Density Function Theory at the B3LYP/6-311(d,p) computational level. The regiosomeric reaction paths involving the two center of compound (C1) have been studied. DFT calculations account for the high regioselectivity in the chlorine atom, in complete agreement with the experimental outcomes

A theoretical investigation of the reactivity and regioselectivity of triterpene derivatives using difference local index, Parr functions.

A theoretical study of the reactivity and regioselectivity of thiosemicarbazide (TSC) condensation toward some carbonyl triterpenes was carried out using density functional theory with B3LYP/6-31G(d,p). The relative reactivity of these systems was rationalized by means of the global electrophilicity index. Positional selectivity, namely C3, C7 and C11, were evaluated using difference index Rk, Parr functions and difference of Parr function. The present study showed that the experimental results of the relative reactivity and regioselectivity of these reactions were correctly predicted using difference index Rk, Parr functions and difference of Parr function

The mechanism, the chemoselectivity and the regioselectivity of the 1-Benzyl-4-ethynyl-1H-[1,2,3]triazole and 1-Azidomethyl-4-tert-butyl-benzene in [3+2] cycloaddition reactions: a DFT study

The [3 + 2] cycloaddition (32CA) reaction between the 1-Benzyl-4-ethynyl-1H-[1,2,3]triazole and 1-Azidomethyl-4-tert-butyl-benzen has been studied within the Density Functional Theory (DFT) B3LYP/6-311G(d,p) computational level. Analysis of the conceptual DFT reactivity indices allows the explanation of the reactivity, and the chemo- and regioselectivity experimentally observed. The possible chemoselective channels and ortho/meta regioselective channels were explored and characterized. Analysis of the energies associated with the different reaction pathways indicates that the 32CA reactions of the between the 1-benzyl-4-ethynyl-1H-[1,2,3]triazole and 1-azidomethyl-4-tert-butyl-benzene is highly chemioselective and meta regioselectivitie, in agreement with the experimental outcomes

Understanding the Regioselectivity and Reactivity of Friedel–Crafts benzoylation Using Parr Functions

A theoretical study of the reactivity and regioselectivity of some aromatic compounds in electrophilic aromatic substitution is carried out at the B3LYP/6-31G(d) computational level. The relative reactivity of these systems is rationalized by means of the global nucleophilicity index proposed by Domingo’s group. The positional selectivity, namely o, m or p, is predicted by means of the local nucleophilicity indices [Parr fonctions]. The present study shows that the experimental trends of the relative reactivities and regioselectivities of these reactions are correctly predicted using Parr fonctions

Tislelizumab versus chemotherapy as second-line treatment for European and North American patients with advanced or metastatic esophageal squamous cell carcinoma: a subgroup analysis of the randomized phase III RATIONALE-302 study

Esophageal squamous cell carcinoma; TislelizumabCarcinoma de células escamosas de esófago; TislelizumabCarcinoma de cèl·lules escamoses d'esòfag; TislelizumabBackground The phase III RATIONALE-302 study evaluated tislelizumab, an anti-programmed cell death protein 1 antibody, as second-line (2L) treatment for advanced/metastatic esophageal squamous cell carcinoma (ESCC). This prespecified exploratory analysis investigated outcomes in patients from Europe and North America (Europe/North America subgroup). Patients and methods Patients with tumor progression during/after first-line systemic treatment were randomized 1 : 1 to open-label tislelizumab or investigator’s choice of chemotherapy (paclitaxel, docetaxel, or irinotecan). Results The Europe/North America subgroup comprised 108 patients (tislelizumab: n = 55; chemotherapy: n = 53). Overall survival (OS) was prolonged with tislelizumab versus chemotherapy (median: 11.2 versus 6.3 months), with a hazard ratio (HR) of 0.55 [95% confidence interval (CI) 0.35-0.87]; HR was similar irrespective of programmed death-ligand 1 score [≥10%: 0.47 (95% CI 0.18-1.21); <10%: 0.55 (95% CI 0.30-1.01)]. Median progression-free survival was 2.3 versus 2.7 months with tislelizumab versus chemotherapy [HR: 0.97 (95% CI 0.64-1.47)]. Overall response rate was greater with tislelizumab (20.0%) versus chemotherapy (11.3%), with more durable response (median duration of response: 5.1 versus 2.1 months). Tislelizumab had a favorable safety profile versus chemotherapy, with fewer patients experiencing ≥grade 3 treatment-related adverse events (13.0% versus 51.0%). Those on tislelizumab experienced less deterioration in health-related quality of life, physical functioning, and/or disease- and treatment-related symptoms (i.e. fatigue, pain, and eating problems) as compared to those on chemotherapy, per the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (QLQ-C30) and QLQ-OES18 scores. Conclusions As a 2L therapy for advanced/metastatic ESCC, tislelizumab improved OS and had a favorable safety profile as compared to chemotherapy in European/North American ESCC patients in the randomized phase III RATIONALE-302 study.This work was supported by BeiGene, Ltd. In collaboration with the academic authors, the sponsor participated in the study design, in the collection, analysis and interpretation of data, and in the writing of the report. The authors led the writing of the report, with professional medical writing assistance funded by the sponsor, and the authors were responsible for the decision to submit the article for publication

O-15 Randomized, phase 3 study of second-line tislelizumab vs chemotherapy in advanced or metastatic esophageal squamous cell carcinoma (RATIONALE 302) in the overall population and Europe/North America subgroup

Background: The global Phase 3 study RATIONALE 302 (NCT03430843) evaluated the efficacy and safety of second-line tislelizumab, an anti-PD-1 antibody, in patients with advanced or metastatic esophageal squamous cell carcinoma (ESCC). Here, we report data from the overall and Europe/North America (EU/NA) populations. Methods: Eligible adult patients had disease progression during or after first-line systemic therapy, ≥1 evaluable lesion per RECIST v1.1 and an Eastern Cooperative Oncology Group performance score (ECOG PS) of ≤1. Patients were randomized (1:1) to receive tislelizumab 200 mg intravenously Q3W or investigator-chosen chemotherapy (paclitaxel, docetaxel, or irinotecan) and treated until disease progression, intolerable toxicity, or withdrawal. Stratification factors included chemotherapy option, region, and ECOG PS. The primary endpoint was overall survival (OS) in all patients (ITT population). The key secondary endpoint was OS in PD-L1 positive (vCPS ≥10%) patients; other secondary endpoints included progression-free survival (PFS), overall response rate (ORR), duration of response (DoR), health-related quality of life and safety. Results: 512 patients (overall population) were randomized to tislelizumab (n=256) or chemotherapy (n=256), of which 108 (21%) patients were enrolled into EU/NA subgroup (n=55 tislelizumab, n=53 chemotherapy). On 1 December 2020 (data cut-off), median follow-up was 6.9 and 6.8 months in the overall population and EU/NA subgroup, respectively. Tislelizumab improved OS vs chemotherapy in the overall population (median OS 8.6 vs 6.3 months; HR 0.70, 95% CI 0.57–0.85; p=0.0001); survival benefit was consistently observed in the EU/NA subgroup (median OS 11.2 vs 6.3 months; HR 0.55; 95% CI 0.35–0.87). Treatment with tislelizumab was associated with improved ORR (20.3% [95% CI 15.6%–25.8%] vs 9.8% [95% CI 6.4%–14.1%]) and median DoR (7.1 vs 4.0 months; HR 0.42, 95% CI 0.23–0.75) vs chemotherapy in the overall population. Improvement in ORR (20.0% [95% CI 10.4%–33.0%] vs 11.3% [95% CI 4.3%–23.0%]) and median DOR (5.1 vs 2.1 months; HR 0.42, 95% CI 0.13–1.39) was also observed in the EU/NA subgroup. Fewer patients had Grade ≥3 treatment-emergent adverse events (TEAE) with tislelizumab vs chemotherapy in both the overall and EU/NA populations (46% vs 68% and 56% vs 71%, respectively). Of these, fewer Grade ≥3 AEs were treatment-related with tislelizumab vs chemotherapy (overall: 19% vs 56%; EU/NA: 13% vs 51%). AEs leading to death were similar with tislelizumab vs chemotherapy (overall: 14% vs 12%; EU/NA: 6% vs 5%). Conclusions: Second-line tislelizumab demonstrated statistically significant and clinically meaningful improvement in OS versus chemotherapy in patients with advanced or metastatic ESCC. Tislelizumab demonstrated a tolerable safety profile. Efficacy and safety results from the EU/NA subgroup were consistent with the overall population. Clinical trial identification: NCT03430843

T cell-inflamed gene expression profile and PD-L1 expression and pembrolizumab efficacy in advanced esophageal cancer

Aim: Investigate the relationship between response to pembrolizumab and expression of the 18-gene T cell-inflamed gene expression profile (TcellinfGEP) or PD-L1 combined positive score (CPS) in esophageal cancer. Materials & methods: This analysis included heavily pretreated patients with advanced/metastatic esophageal/gastroesophageal junction adenocarcinoma or squamous cell carcinoma who received pembrolizumab in the single-arm, phase II study KEYNOTE-180. PD-L1 CPS was evaluated with PD-L1 IHC 22C3 pharmDx. Results: In patients with squamous cell carcinoma, trends toward enrichment for responders were observed for patients with PD-L1 CPS ≥10 tumors. In patients with adenocarcinoma, a trend was observed for TcellinfGEP but not for PD-L1. Conclusion: TcellinfGEP and PD-L1 CPS may enrich for responders to pembrolizumab in patients with esophageal cancer. Clinical Trial Registration: NCT02559687 (ClinicalTrials.gov

Hartree-Fock and density functional theory studies on tautomerism of 5,5o-diisopropyl-3,3o-bipyrazole in gas phase and solution.

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