Unprecedented rhodium-mediated catalytic transfer hydrogenation of a phosphonate functionalized olefin in ecofriendly media

RhCl₃ · xH₂O catalyst-mediated hydrogenation reactions of vinyl phosphonic diethyl ester H₂CCH-P(O)(OEt)₂ (1) have been investigated. Results demonstrate that the hydrogenation of H₂CCH-P(O)(OEt)₂ (1) to CH₃CH₂-P(O)(OEt)(OH) (2) proceeds in the presence of RhCl₃ · xH₂O catalyst, without any external hydrogen source and ancillary ligands, to near qualitative yields in ethanol and water media. ³¹P, ¹³C and ¹H NMR and deuterium-labeling experiments provide evidence for the non-concerted mechanistic pathway associated with the hydrogenation of 1 to 2.     

Conformationally constrained peptides target the allosteric kinase dimer interface and inhibit EGFR activation

Although EGFR is a highly sought-after drug target, inhibitor resistance remains a challenge. As an alternative strategy for kinase inhibition, we sought to explore whether allosteric activation mechanisms could effectively be disrupted. The kinase domain of EGFR forms an atypical asymmetric dimer via head-to-tail interactions and serves as a requisite for kinase activation. The kinase dimer interface is primarily formed by the H-helix derived from one kinase monomer and the small lobe of the second monomer. We hypothesized that a peptide designed to resemble the binding surface of the H-helix may serve as an effective disruptor of EGFR dimerization and activation. A library of constrained peptides was designed to mimic the H-helix of the kinase domain and interface side chains were optimized using molecular modeling. Peptides were constrained using peptide “stapling” to structurally reinforce an alpha-helical conformation. Peptide stapling was demonstrated to notably enhance cell permeation of an H-helix derived peptide termed EHBI2. Using cell-based assays, EHBI2 was further shown to significantly reduce EGFR activity as measured by EGFR phosphorylation and phosphorylation of the downstream signaling substrate Akt. To our knowledge, this is the first H-helix-based compound targeting the asymmetric interface of the kinase domain that can successfully inhibit EGFR activation and signaling. This study presents a novel, alternative targeting site for allosteric inhibition of EGFR.     

Therapeutic potential of meso 2,3-dimercaptosuccinic acid or 2,3-dimercaptopropane 1-sulfonate in chronic arsenic intoxication in rats

The therapeutic efficacy of two thiol chelators, meso 2,3-dimercaptosuccinic acid (DMSA) or 2,3-dimercaptopropane sulfonate (DMPS) in treating chronic arsenic intoxication was investigated in male rats. Both the chelators were effective in promoting urinary arsenic excretion and restoring arsenic induced inhibition of blood -aminolevulinic acid dehydratase activity and hepatic glutathione level. Elevation of urinary -aminolevulinic acid excretion and arsenic concentration in blood, liver and kidneys were reduced significantly by both the chelators. Histopathological lesions induced by arsenic were also effectively reduced by the above chelators. DMSA being more effective than DMPS. The results suggest DMSA and DMPS to be effective antidotes for treating chronic arsenic toxicity in experimental animals.     

Effects of salbutamol on intracellular calcium oscillations in porcine airway smooth muscle

Prakash, Y. S., H. F. M. van der Heijden, M. S. Kannan, andG. C. Sieck. Effects of salbutamol on intracellular calcium oscillations in porcine airway smooth muscle. J. Appl.Physiol. 82(6): 1836-1843, 1997.Relaxation ofairway smooth muscle (ASM) by -adrenoceptor agonists involvesreduction of intracellular Ca²⁺concentration([Ca²⁺]_i).In porcine ASM cells, acetylcholine induces[Ca²⁺]_ioscillations that display frequency modulation by agonist concentration and basal[Ca²⁺]_i.We used real-time confocal microscopy to examine the effect ofsalbutamol (1 nM to 1 µM), a₂-adrenoceptor agonist, on[Ca²⁺]_ioscillations in freshly dissociated porcine ASM cells. Salbutamol decreased the frequency of[Ca²⁺]_ioscillations in a concentration-dependent fashion, completely inhibiting the oscillations at 1 µM. These effects were mimicked by acell-permeant analog of adenosine 3,5-cyclicmonophosphate. The inhibitory effect of salbutamol was partiallyreversed by BAY K 8644. Salbutamol reduced[Ca²⁺]_ieven when sarcoplasmic reticulum (SR)Ca²⁺ reuptake andCa²⁺ influx were blocked.Lanthanum blockade of Ca²⁺ effluxattenuated the inhibitory effect of salbutamol on[Ca²⁺]_i.The[Ca²⁺]_iresponse to caffeine was unaffected by salbutamol. On the basis ofthese results, we conclude that₂-adrenoceptor agonists have little effect on SR Ca²⁺ releasein ASM cells but reduce[Ca²⁺]_iby inhibiting Ca²⁺ influx throughvoltage-gated channels and by enhancingCa²⁺ efflux.

     

Absorption of Iron by Enzymically Isolated Leaf Cells

Iron uptake was studied using cells enzymically isolated from green tobacco leaves. Absorption was increased both by light and succinate as probable energy sources. Bicarbonate in the incubation mixture was inhibitory, and citrate also reduced absorption presumably by chelation with the metal. Absorption of iron was temperature sensitive and optimal at 25°C. Temperature coefficients and activation energies suggested that absorption was energy mediated. NaN₃ and DNP inhibited uptake at concentrations of 10-³M and 10^?4M, respectively. The inhibition caused by DNP was not negated by an external supply of ATP. The results suggest that iron absorption is an active metabolic process in cells enzymically isolated from green tobacco leaves. Cells from Fe-chlorotic leaves of PI 54619–5–1 soybean absorbed less iron than those derived from healthy leaves of the same variety, while leaf cells from the variety Hawkeye showed no such differences.     

Purification of active matrix metalloproteinase catalytic domains and its use for screening of specific stromelysin-3 inhibitors.

The matrix metalloproteinase (MMP) stromelysin-3 (ST3) has been shown to be involved in malignant tumor progression and therefore represents an attractive therapeutical target. In order to screen for ST3 synthetic inhibitors, we have produced and purified the catalytic domain of ST3, matrilysin, stromelysin-2, and membrane type-1 MMP from inclusion bodies in a bacterial system. Our strategy allowed the purification of MMPs directly in the active form, thereby avoiding in vitro activation. A total of 140,000 synthetic compounds from the Bristol-Myers Pharmaceutical Research Institute chemical deck were tested, using a substrate-based colorimetric enzymatic assay, in which ST3 activity was evaluated through its ability to cleave and inactivate alpha-1 proteinase inhibitor. One ST3 inhibitor belonging to the cephalosporin family of antibiotics was thereby identified.     

The Usefulness and Feasibility of Mobile Interface in Tuberculosis Notification (MITUN) Voice Based System for Notification of Tuberculosis by Private Medical Practitioners – A Pilot Project

Introduction

Tuberculosis (TB) is a notifiable disease and health care providers are required to notify every TB case to local authorities. We conducted a pilot study to determine the usefulness and feasibility of mobile interface in TB notification (MITUN) voice based system for notification of TB cases by private medical practitioners.

Methodology

The study was conducted during September 2013 to October 2014 in three zones of Chennai, an urban setting in South India. Private clinics wherein services are provided by single private medical practitioners were approached. The steps involved in MITUN included: Registration of the practitioners and notification of TB cases by them through voice interactions. Pre and post-intervention questionnaires were administered to collect information on TB notification practices and feasibility of MITUN after an implementation period of 6 months.

Results

A total of 266 private medical practitioners were approached for the study. Of them, 184 (69%) participated in the study; of whom 11 (6%) practitioners used MITUN for TB notification. Reasons for not using MITUN include lack of time, referral of patients to government facility, issues related to patient confidentiality and technical problems. Suggestions for making mobile phone based TB notification process user-friendly included reducing call duration, including only crucial questions and using missed call or SMS options.

Conclusion

The performance (feasibility and usefulness) of MITUN voice based system for TB notification in the present format was sub-optimal. Perceived problems, logistical and practical issues preclude scale–up of notification of TB by private practitioners.