Preclinical and clinical evaluation of German-sourced ONC201 for the treatment of H3K27M-mutant diffuse intrinsic pontine glioma

Background Diffuse intrinsic pontine glioma (DIPG) is a fatal childhood brainstem tumor for which radiation is the only treatment. Case studies report a clinical response to ONC201 for patients with H3K27M-mutant gliomas. Oncoceutics (ONC201) is only available in the United States and Japan; however, in Germany, DIPG patients can be prescribed and dispensed a locally produced compound-ONC201 German-sourced ONC201 (GsONC201). Pediatric oncologists face the dilemma of supporting the administration of GsONC201 as conjecture surrounds its authenticity. Therefore, we compared GsONC201 to original ONC201 manufactured by Oncoceutics Inc. Methods Authenticity of GsONC201 was determined by high-resolution mass spectrometry and nuclear magnetic resonance spectroscopy. Biological activity was shown via assessment of on-target effects, in vitro growth, proliferation, and apoptosis analysis. Patient-derived xenograft mouse models were used to assess plasma and brain tissue pharmacokinetics, pharmacodynamics, and overall survival (OS). The clinical experience of 28 H3K27M+ mutant DIPG patients who received GsONC201 (2017-2020) was analyzed. Results GsONC201 harbored the authentic structure, however, was formulated as a free base rather than the dihydrochloride salt used in clinical trials. GsONC201 in vitro and in vivo efficacy and drug bioavailability studies showed no difference compared to Oncoceutics ONC201. Patients treated with GsONC201 (n = 28) showed a median OS of 18 months (P = .0007). GsONC201 patients who underwent reirradiation showed a median OS of 22 months compared to 12 months for GsONC201 patients who did not (P = .012). Conclusions This study confirms the biological activity of GsONC201 and documents the OS of patients who received the drug; however, GsONC201 was never used as a monotherapy

Computational study of the thermochemical aspects of hydrogen atom donating antioxidants using the ab initio Hartree–Fock method

Despite the extensive and intensive investigations so far, there are still significant gaps in our knowledge and understanding of the chemical and biological mechanisms of antioxidants. For instance, studies aimed at prevention or intervention of diseases with common exogenous antioxidants have shown mixed outcomes. In relation to this also there does not seem to be a general consensus about the actual biological mechanisms of many compounds including dietary polyphenols, which have been classically considered as antioxidants. Even somewhat surprisingly, antioxidants in general and radical scavengers in particular were never properly described in thermodynamical terms. One of the most commonly studied aspects of antioxidants is their ability to neutralize free radicals by donating electrons or hydrogen atoms. However, upon perusal of the ever-increasing literature on the subject, it would not be long before one is confronted with the fact that the thermodynamics and kinetics of hydrogen atom transfer (HAT) reactions of antioxidants are often either confused with each other or lumped together in perplexity. A detailed understanding of the chemical aspects of antioxidant molecules is deemed crucial as it may enable unravelling some of the controversies and uncertainties surrounding them. The detailed chemical knowledge of antioxidants may also serve as a foundation upon which more complex and biologically relevant predictive models could be built. With this in mind and being inspired by a couple of intriguing observations from my related previous studies, I have attempted in the present PhD study to investigate the thermochemical aspects of the HAT reactions of common antioxidant molecules using quantum molecular computations. In summary, the thermodynamic basis of the radical scavenging activities of antioxidants was shown to be their abilities to donate two hydrogen atoms with relative enthalpy changes below 104.206 kcal mol−1. The important kinetic parameters BDE and BDFE were reliably estimated as the relative energy changes accompanying the formation of suitable DSs. Depending on the class of compounds, DSs were proposed to be electronically and/or vibrationally excited species. Moreover, ab initio UHF method was shown to be remarkably adequate for the study of HAT reactions of antioxidants. The above findings may warrant further investigation as they may not only contribute to our general understanding of antioxidants but also have far-reaching implications on several fundamental aspects of antioxidants’ HAT reactions and the computational tools recommended for their study. Furthermore, the findings of this PhD study can form the basis for robust and inclusive quantitative structure-activity relationships of antioxidants

Computation of the bond dissociation enthalpies and free energies of hydroxylic antioxidants using the ab initio Hartree-Fock method

Introduction: A new method for calculating theoretical bond dissociation enthalpy (BDE) and bond dissociation free energy (BDFE) of hydroxylic antioxidants is forwarded. BDE and BDFE may be understood as activation energies accompanying the formation of transition states, which may undergo downhill homolytic dissociation. The new method does not involve the complete fission of O-H bonds. Method: Theoretical gas phase BDE values were calculated with the ab initio unrestricted Hartree-Fock (UHF) method, as changes in enthalpy between ground singlet states (GS) and triplet dissociative states (DS). Similarly, gas phase BDFEs were estimated from the corresponding changes in Gibbs free energy. The results were then compared with reliable experimental reports. Results: The proposed theoretical approach of BDE and BDFE determination was tested using 10 simple phenols, 5 flavonoids, and L-ascorbic acid derivatives. The agreement between our calculated gas phase results and the adopted experimental values were generally within 0.5 kcal mol-1, with a very few exceptions. Discussion: Generally, steric interactions as well as intramolecular hydrogen bonding involving the dissociating OH group should be minimized in the GS. The DS are both electronically and vibrationally exited transition states. They have one unpaired electron on the carbon atom, which bears the homolytically dissociating OH group and are second order saddle points with a fixed <C-O-H bond angel of 180°. Conclusion: It was concluded that ab initio UHF was well suited for the estimation of gas phase BDE and BDFE. The method presented has a good potential for application across a range of hydroxylic antioxidants. Currently, work is underway to extend its application in other class of antioxidants

Thermodynamical basis for the radical-scavenging activity of flavonoids revealed with Hartree-Fock computations and thermochemical deduction

Recently, we have established a novel relationship between the enthalpy of reaction for the abstraction of two hydrogen atoms from flavonoids and their reported radical-scavenging activities (RSA), based on Hartree-Fock computations and thermochemical deduction. A brief account of our finding is presented

Computation of the bond dissociation enthalpies and free energies of hydroxylic antioxidants using the ab initio Hartree-Fock method

A new, simple and efficient theoretical approach for the approximation of the bond dissociation enthalpy (BDE) and bond dissociation free energy (BDFE) of hydroxylic antioxidants has been proposed. This method stipulates a unimolecular dissociation mechanism. BDE will be determined by approximating the change in enthalpy associated with the formation of a relevant dissociative state, which may then undergo downhill homolytic dissociation. The dissociative state (DS) is both triplet state of lower energy and a second order saddle point with respect to < C-O-H of the O-H that undergoes homolytic dissociation

A novel relationship between the radicalscavenging activity of flavonoids and enthalpy of formation revealed with Hartree-Fock computations and thermochemical deduction

Objective: The present study aims to establish the relationship between the reported radical-scavenging activities of flavonoids and some enthalpy changes that may occur during flavonoids' reactions with free radicals. Method: Eight flavonoids were chosen for the study on the basis of their structural merits and reported 1,1-diphenyl-2-picryl-hydrazyl scavenging activities. Enthalpy changes accompanying interconversions between selected conformations (including spin multiplicities) and homolytic dissociations were estimated. Results: A novel relationship exists between the total enthalpy of reaction for the abstraction of two hydrogen atoms from flavonoids, their reported radical-scavenging activities and the enthalpy of the homolytic dissociation of hydrogen molecule (104.206 kcal mol -1). Only those flavonoids which could give up two hydrogen atoms with total enthalpy changes well below 104.206 kcal mol -1 were active radical scavengers. Discussion: By appealing to equilibrium dynamics, we demonstrated that, for flavonoids to be able to donate hydrogen atoms, the change in enthalpy accompanying the abstraction of two hydrogen atoms needs to be less than 104.206 kcal mol -1. This condition does not seem to be restricted to flavonoids only but rather generally applicable to chian-breaking antioxidants. Conclusion: Thermodynamical relationships may be the most important factors governing the radicalscavenging reactions of flavonoids and possibly other compounds as well. Nevertheless, a more complete characterization of antioxidants would necessitate kinetic analysis

Estimation of S–H bond dissociation enthalpies and free energies of thiophenols : an ab initio Hartree-Fock study

Ab initio Hartree–Fock method (UHF/6-31G(d)) was used to estimate the gas phase S–H bond dissociation enthalpies (BDEs) and free energies (BDFEs) of thiophenols with a considerable success. This was carried out by identifying the unimolecular dissociative states (DSs) of thiophenols, in a similar way recently described for hydroxylic antioxidants. The DSs of thiophenols forerunning S–H bond homolysis were vibrationally excited singlet or triplet states. In the DS, < C–S–H bond angle was fixed at 180º. The BDE of a given thiophenol was calculated as the relative change in enthalpy accompanying the formation of its DS with respect to a ground state of same multiplicity. BDFE was the corresponding change in Gibbs free energy. The calculated BDEs of thiophenol, its 12 monosubstituted derivatives (2-Me, 3-Me, 4-Me, 2-Cl, 3-Cl, 4-Cl, 4-Br, 3-CF3, 4-NH2, 4-MeO, 4-NO2 and 2-CO2Me) and 2-naphthalenethiol were remarkably similar to literature experimental values. The calculated BDE and BDFE of thiophenol were 79.1 and 80.1 kcal/mol, respectively. The average BDE and BDFE of the 13 thiophenols studied were 79.5±0.8 and 80.5±0.8 kcal/mol, respectively, the lowest and highest BDE/BDFE values being those of 2-methylthiophenol (77.7/78.5 kcal/ mol) and 2-chlorothiophenol (81.3/81.9 kcal/mol). The BDE and BDFE of 2-naphthalenethiol were virtually identical with those of thiophenol’s. The lower literature BDE values of 4-aminothiophenol (-9.3 kcal/mol) and 4-methoxythiophenol (-2.2 kcal/mol) in DMSO were satisfactorily explained by the stabilization of their respective dissociative states with hydrogen bonding of the para substituents with 2 and 1 DMSO molecules

Target priority transboundary animal diseases and zoonoses in the IGAD region for control interventions

Prioritization of transboundary animal diseases (TADs) and zoonoses in the IGAD region was conducted by IGAD Member States, namely, Djibouti, Ethiopia, Eritrea, Somalia, South Sudan and Sudan together with support from ICPALD and AU-IBAR. The main aim of the exercise was to develop clear control strategies and policies for focussing disease control efforts and the limited resources on few diseases in order to achieve efficient and effective disease control. The prioritization methodology for transboundary animal diseases and zoonoses according to Phylum was applied, taking into considerations, economic impact, human health importance, societal impact, environmental impact, feasibility of control methods and the ecological impact of the diseases. Overall, Rift Valley fever had the highest rank, followed by Contagious Bovine  Pleuropneumonia, Newcastle Disease, Highly Pathogenic Avian Influenza, Lumpy Skin Disease, Peste des Petits des Ruminants, Rabies,  Brucellosis, Bovine Tuberculosis, Foot-and Mouth Disease and Sheep and Goat Pox. In conclusion, the IGAD region is encouraged to facilitate systematic efforts  towards rolling forth priority diseases through focused national efforts, harmonized regional strategies and streamlined stakeholder investment in the region.Key words: Target, priority, animal diseases, zoonoses, control, interventions, IGAD region Maladies animales transfrontalières et zoonoses prioritaires Ciblées dans la région IGAD pour les interventions de contrôle Les États membres de l’IGAD, à savoir Djibouti, l’Éthiopie, l’Érythrée, la Somalie, le Soudan du Sud et le Soudan, ont procédé à une définition des maladies animales transfrontières et zoonoses prioritaires dans la région IGAD, avec le soutien de l’ICPALD et de l’UA-BIRA. L’objectif principal de cette priorisation était d’élaborer des stratégies et politiques de contrôle claires visant à concentrer les efforts de contrôle des maladies et les rares ressources disponibles sur certaines maladies afin de parvenir à un contrôle efficace et efficient. La méthodologie de priorisation des maladies animales transfrontalières et des zoonoses selon leur phylum a été appliquée, en prenant en considérations l’impact économique, l’importance pour la santé humaine, l’impact sociétal, l’impact environnemental, la faisabilité des  méthodes de contrôle et l’impact écologique des maladies. Dans l’ensemble, la fièvre de la vallée du Rift a été mise en tête des priorités, suivie de la péripneumonie  contagieuse bovine, la maladie de Newcastle, l’influenza aviaire hautement pathogène, la dermatose nodulaire contagieuse, la peste des petits ruminants, la rage, la brucellose, la tuberculose bovine, la fièvre aphteuse et la clavelée du mouton et la variole caprine. En conclusion, la région IGAD est encouragée à faciliter des efforts systématiques visant à contrôler les maladies prioritaires à travers des activités nationales ciblées, des stratégies régionales harmonisées et une rationalisation des investissements des parties prenantes dans la région.Mots-clés : ciblées, prioritaire, maladies animales, zoonoses, contrôle, interventions, région IGA