Discovery of boronic acid-based potent activators of tumor pyruvate kinase M2 and development of gastroretentive nanoformulation for oral dosing.

Several studies have established that cancer cells explicitly over-express the less active isoform of pyruvate kinase M2 (PKM2) is critical for tumorigenesis. The activation of PKM2 towards tetramer formation may increase affinity towards phosphoenolpyruvate (PEP) and avoidance of the Warburg effect. Herein, we describe the design, synthesis, and development of boronic acid-based molecules as activators of PKM2. The designed molecules were inspired by existing anticancer scaffolds and several fragments were assembled in the derivatives. 6a-6d were synthesized using a multi-step synthetic strategy in 55-70% yields, starting from cheap and readily available materials. The compounds were selectively cytotoxic to kill the cancerous cells at 80 nM, while they were non-toxic to the normal cells. The kinetic studies established the compounds as novel activators of PKM2 and (E/Z)-(4-(3-(2-((4-chlorophenyl)amino)-4-(dimethylamino)thiazol-5-yl)-2-(ethoxycarbonyl)-3-oxoprop-1-en-1-yl) phenyl)boronic acid (6c) emerged as the most potent derivative. 6c was further evaluated using various in silico tools to understand the molecular mechanism of tetramer formation. Docking studies revealed that 6c binds to the PKM2 dimer at the dimeric interface. Further to ascertain the binding site and mechanism of action, rigorous MD (molecular dynamics) simulations were undertaken, which led to the conclusion that 6c stabilizes the center of the dimeric interface that possibly promotes tetramer formation. We further planned to make a tablet of the developed molecule for oral delivery, but it was seriously impeded owing to poor aqueous solubility of 6c. To improve aqueous solubility and retain 6c at the lower gastrointestinal tract, thiolated chitosan-based nanoparticles (TCNPs) were prepared and further developed as tablet dosage form to retain anticancer potency in the excised goat colon. Our findings may provide a valuable pharmacological mechanism for understanding metabolic underpinnings that may aid in the clinical development of new anticancer agents targeting PKM2.

Potassium tert-butoxide mediated C-C, C-N, C-O and C-S bond forming reactions.

Potassium tertiary butoxide (KOtBu) mediated constructions of C-C, C-O, C-N, and C-S bonds are reviewed with special emphasis on their synthetic applications. KOtBu can be used to perform reactions already known to be carried out using transition metals, but it has advantages in terms of environmental congruence and economic cost. KOtBu is widely employed in organic synthesis to mediate the construction of C-C, C-O, C-N, C-S and miscellaneous bonds in good to excellent yields. Synthetic uses of KOtBu in coupling, alkylation, arylation, α-phenylation, cyclization, Heck-type, annulation, photo-arylation, aromatic-substitution, amidation, and silylation reactions are summarized and discussed. The mechanisms through which KOtBu carries out a specific reaction are also discussed. One of the goals of this review is to attract the attention of chemists as to the benefits of using KOtBu as an environmentally benign alternative to transition metals and its applications in the construction of chemical bonds with predominant importance in organic synthesis. This review completely covers the synthetic protocols that have been performed using KOtBu in the last two decades.

Bioanalysis and Quadrupole-Time of Flight-Mass Spectrometry Driven In Vitro Metabolite Profiling of a New Boronic Acid-Based Anticancer Molecule.

(E/Z)-(4-(3-(2-((4-chlorophenyl)amino)-4-(dimethylamino)thiazol-5-yl)-2-(ethoxy carbonyl)-3-oxoprop-1-en-1-yl)phenyl) boronic acid, a newly developed molecule having anticancer activity serves as a potential candidate for the further drug development process. In this study, to ascertain the anticancer potential of the molecule, we screened it against different cell lines and compared the activity against the standard drug doxorubicin. The molecule showed promising activity at a low concentration against almost all cell lines used in the study. Apart from that, the molecule was characterized for its pKa and a precise reverse phase high-performance liquid chromatography bioanalytical method has been developed. The method was validated according to the United States of Food and Drug Administration bioanalytical guideline and was found to produce linear response over the calibration range of 0.8-25 µg/mL. Inter- and intra-day accuracy were found to be in the range of 93.44-99.74%, whereas precision [% coefficient of variation (CV)] for inter- and intra-day was ranged between 1.63 and 5.79%, and 0.87 and 6.96%, respectively. The bioanalytical stability testing was carried out in different conditions including 8 h benchtop, 12 h autosampler and three freeze-thaw cycles. The analyte was stable in all the tested stability conditions. Finally, an in vitro metabolite identification study was conducted using quadrupole-time of flight-mass spectrometer, and two metabolites have been identified.

To Do or Not to Do?-A Review of Cancer Surgery Triage Guidelines in COVID-19 Pandemic.

COVID-19 pandemic has emerged as a global health emergency involving more than 200 countries so far. The number of affected population is on rising, so is the mortality. This crisis has overwhelmed the healthcare infrastructures in many affected countries. Due to overall rising cancer incidence and specific concerns, a cohort of cancer patients forms a distinct subset of the population in whom a correct and timely treatment has a huge impact on the outcome. During this period, oncology care is definitely affected owing to many factors like lockdowns, reduced beds and deferral of elective cases to halt the spread of the pandemic. Surgery remains the best line of defence in many solid organ tumours especially in early stage and is potentially curative. China, the source of this pandemic, has taken more than 3 months to enter the post transitional phase of this pandemic. Deferring cancer surgeries for this long period may have a direct impact on the long-term outcomes of cancer patients. Many surgical oncology associations across the globe have come up with triage guidelines for surgical care of cancer patients; however, these are based on expert opinion rather than actual data. Herein, we intend to review these guidelines with respect to the risk of disease progression in cancer patients. In the absence of actual data on cancer surgery care during this pandemic, clinical decisions should be based on careful consideration of disease-related and patient-related factors. While some of the cancer surgeries can be safely delayed for some time, how long we can delay surgeries safely cannot be answered/ explained by any means. Thorough evaluation and discussion by an expert and experienced multidisciplinary team appears to be the most effective way forward.

Management of ventricular storm with thoracic epidural anesthesia.

The incidence of recurrent ventricular arrhythmias is increasing these days. Ventricular electrical storm can be of three types as follows: monomorphic ventricular tachycardia (VT), polymorphic VT, and ventricular fibrillation. The mechanism of ventricular storm is complex, and its management is quite a challenge for the clinicians due to its life-threatening consequences. We report a case of ventricular storm in whom all the conventional methods for the management of arrhythmias were ineffective, and the case is managed effectively with thoracic epidural anesthesia (TEA). A 60-year-old male patient was admitted to recurrent ventricular arrhythmias. He received defibrillator shocks and other antiarrhythmic drugs, but he was not responding to the treatment. We managed to revert the ventricular arrhythmias to the sinus rhythm with TEA. Ventricular storm is a challenging complication, which can be managed effectively with timely diagnosis and effective management.

Anesthetic management of patent ductus arteriosus in adults.

Patent ductus arteriosus (PDA) is an extracardiac left to right shunt. It should be corrected at an early age, but some patients may survive into adult life even without repair. Anesthetic management for adult patients with PDA poses many challenges for the anesthesiologist due to alterations in the cardiopulmonary physiology. We report successful anesthesia management of a case of an adult patient of PDA with moderate pulmonary artery hypertension with infective endarteritis (two large mobile vegetations at the pulmonary end of the duct).