Background: Acute myeloid leukemia is the collective name for different types of leukemias of myeloid origin affecting blood and bone marrow. The overproduction of immature myeloblasts (white blood cells) is the characteristic feature of AML, thus flooding the bone marrow and reducing its capacity to produce normal blood cells. USFDA on August 1, 2017, approved a drug named Enasidenib formerly known as AG-221 which is being marketed under the name Idhifa to treat R/R AML with IDH2 mutation. The present review depicts the broad profile of enasidenib including various aspects of chemistry, preclinical, clinical studies, pharmacokinetics, mode of action and toxicity studies. Methods: Various reports and research articles have been referred to summarize different aspects related to chemistry and pharmacokinetics of enasidenib. Clinical data was collected from various recently published clinical reports including clinical trial outcomes. Result: The various findings of enasidenib revealed that it has been designed to allosterically inhibit mutated IDH2 to treat R/R AML patients. It has also presented good safety and efficacy profile along with 9.3 months overall survival rates of patients in which disease has relapsed. The drug is still under study either in combination or solely to treat hematological malignancies. Molecular modeling studies revealed that enasidenib binds to its target through hydrophobic interaction and hydrogen bonding inside the binding pocket. Enasidenib is found to be associated with certain adverse effects like elevated bilirubin level, diarrhea, differentiation syndrome, decreased potassium and calcium levels, etc. Conclusion: Enasidenib or AG-221was introduced by FDA as an anticancer agent which was developed as a first in class, a selective allosteric inhibitor of the tumor target i.e. IDH2 for Relapsed or Refractory AML. Phase 1/2 clinical trial of Enasidenib resulted in the overall survival rate of 40.3% with CR of 19.3%. Phase III trial on the Enasidenib is still under process along with another trial to test its potency against other cell lines. Edasidenib is associated with certain adverse effects, which can be reduced by investigators by designing its newer derivatives on the basis of SAR studies. Hence, it may come in the light as a potent lead entity for anticancer treatment in the coming years.
Gestational diabetes (GDM) is one of the most common complications occurring during pregnancy. Diagnosis is performed by oral glucose tolerance test, but harmonized testing methods and thresholds are still lacking worldwide. Short‐term and long‐term effects include obesity, type 2 diabetes, and increased risk of cardiovascular disease. The identification and validation of sensitidve, selective, and robust biomarkers for early diagnosis during the first trimester of pregnancy are required, as well as for the prediction of possible adverse outcomes after birth. Mass spectrometry (MS)‐based omics technologies are nowadays the method of choice to characterize various pathologies at a molecular level. Proteomics and metabolomics of GDM were widely investigated in the last 10 years, and various proteins and metabolites were proposed as possible biomarkers. Metallomics of GDM was also reported, but studies are limited in number. The present review focuses on the description of the different analytical methods and MS‐based instrumental platforms applied to GDM‐related omics studies. Preparation procedures for various biological specimens are described and results are briefly summarized. Generally, only preliminary findings are reported by current studies and further efforts are required to determine definitive GDM biomarkers.
Limits of Matrix-Assisted Laser Desorption Ionization (MALDI) mass spectrometry (MS) in the study of small molecules are due to matrix-related interfering species in the low m/z range. Single-walled carbon nanohorns (SWCNH) were here evaluated as a specific surface for the rapid analysis of amino acids and lipids by Surface-Assisted Laser Desorption Ionization (SALDI). The method was optimized for detecting twenty amino acids, mainly present as cationized species, with the [M+K]+ response generally 2-time larger than the [M+Na]+ one. The [M+Na]+/[M+K]+ signals ratio was tentatively correlated with the molecular weight, dipole moment and binding affinity, to describe the amino acids’ coordination ability. The SWCNH-based surface was also tested for analyzing triglycerides in olive oil samples, showing promising results in determining the percentage composition of fatty acids without any sample treatment. Results indicated that SWCNH is a promising substrate for the SALDI-MS analysis of low molecular weight compounds with different polarities, enlarging the analytical platforms for MALDI applications.
The current anti-inflammatory drugs are associated with various severe adverse or side effects which mark the question on long term clinical use of such medications. These factors necessitate the development of new heterocyclic molecules having anti-inflammatory potential with minimal to no adverse effect or toxicity. In continuation to our work, in herein report design and synthesis of a series of 15 indole-3-subtituted isoxazoles having potential anti-inflammatory as well as analgesic properties. Most of the compounds exhibited comparable in-vivo anti-inflammatory and analgesic activity in rats to the reference drugs. Compound 9 d, 9 f and 9 i were found to show most significant anti-inflammatory activity and reduced the paw edema by 67.74 %, 61.29 %, and 77.42 % respectively which were comparable to reference drug indomethacin. The COX inhibition studies reveled that these compounds have 2-3 folds selectivity for COX-2 with moderate inhibition activity. In final, molecular docking studies were performed to understand the mechanistic and binding modes at catalytic active sites of COX-2. The results revealed good selectivity of compounds for COX-2 preferably over other inflammatory targets. The compound 9 i is obtained as lead molecule from the current series as promising structural feature for further development of novel anti-inflammatory agent.
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