SO2 Donors and Prodrugs, and Their Possible Applications: A Review

SO2 is widely recognized as an air pollutant and is a known cause of acid rain. At a sufficiently high level, it also causes respiratory diseases. A much lesser known side of SO2 is its endogenous nature and possible physiological roles. There is mounting evidence that SO2 is produced during normal cellular metabolism and may possibly function as a signaling molecule in normal physiology. The latter aspect is still at the stage of being carefully examined as to the validity of classifying SO2 as a gasotransmitter with endogenous signaling roles. One difficulty in studying the biological and pharmacological roles of SO2 is the lack of adequate tools for its controllable and precise delivery. Traditional methods of using SO2 gas or mixed sulfite salts do not meet research need for several reasons. Therefore, there has been increasing attention on the need of developing SO2 donors or prodrugs that can be used as tools for the elucidation of SO2's physiological roles, pharmacological effects, and possible mechanism(s) of action. In this review, we aim to review basic sulfur chemistry in the context of sulfur signaling and various chemical strategies used for designing SO2 donors. We will also discuss potential pharmacological applications of SO2 donors, lay out desirable features for such donors and possibly prodrugs, analyze existing problems, and give our thoughts on research needs

Hydrogen Sulfide Prodrugs—A review

Abstract Hydrogen sulfide (H2S) is recognized as one of three gasotransmitters together with nitric oxide (NO) and carbon monoxide (CO). As a signaling molecule, H2S plays an important role in physiology and shows great potential in pharmaceutical applications. Along this line, there is a need for the development of H2S prodrugs for various reasons. In this review, we summarize different H2

Prescribed Time Time-varying Output Formation Tracking for Uncertain Heterogeneous Multi-agent Systems

The time-varying output formation tracking for the heterogeneous multi-agent systems (MAS) is investigated in this paper. First, a distributed observer is constructed for followers to estimate the states of the leader, which can ensure that the estimation error converges to the origin in the prescribed time. Then, the local formation controller is designed for each follower based on the estimation of the observer, under which, the formation errors converge to the origin in the prescribed time as well. That is, the settling time of the whole system can be predefined in advance. It's noted that not only the uncertainties in the state matrix but also the uncertainties in the input matrix are considered, which makes the problem more practical. Last, a simulation is performed to show the effectiveness of the proposed approach

Structure of the Product from a Novel Cyclization Reaction Involving a C(6)-Substituted Uridine Analog

This is the publisher's version, also available electronically from http://scripts.iucr.org/cgi-bin/paper?S010827019300412

Evaluation of the Seca Inhibitors as Novel Anti-Microbial Agents

The misuse of conventional antibiotics and natural selection of the infectious bacterial population has produced drug resistance. Thus, novel effective antibiotic compounds that treat bacterial infections resistant to available therapies are needed. SecA is an indispensable ATPase of the protein translocation machinery present in all bacteria. SecA is responsible for the secretion of many essential proteins, some toxins and virulence factors, and is essential for bacterial survival. SecA has no counterpart in mammalian cells, thus provides an ideal target for developing antimicrobial agents. SCA-13 (HO) is a pyrimidine analog derived from virtual screening; it exerts the ability to inhibit SecA translocation ATPase activity with an IC50 of 75 µM. HO showed promising bacteriostatic activities against a vacomycin resistant strain of S. aureus Mu50 and B. anthracis Sterne. No significant difference in antimicrobial activity of HO was observed among efflux pump strains of S. aureus, suggesting that compound HO is not a substrate of NorA or MepA efflux pumps. Resistant mutants of E. coli NR698 selected from HO need to be characterized to gain a better understanding of the resistance mechanisms and subsequently will allow for the identification of the drug target

A Guide for Hiring Mature Employees at Ascentria

This paper will explore existing literature on aspects of an intergenerational workplace in a nonprofit organization and provide recommendations for recruiting and retaining older employees for a human service organization, Ascentria Care Alliance, in Worcester, MA. The paper will review research on trends in the nonprofit industry, a comprehensive breakdown of generational workplace values, reasons people are returning to work and effective marketing strategies that appeal to older generations. Marketing strategies specifically will explore best practices for website design, social media usage, and job descriptions. Additionally, this paper will research case studies of nonprofits with successful intergenerational workforce initiatives, as well as best practices for human resource management. The research concludes that the most effective ways for Ascentria to connect with older employees is by creating a culture of respect in the workplace, targeted marketing approaches, specific benefit programs, and community partnerships

Two-dose-level confirmatory study of the pharmacokinetics and tolerability of everolimus in Chinese patients with advanced solid tumors

<p>Abstract</p> <p>Background</p> <p>This phase I, randomized, multicenter, open-label study investigated the pharmacokinetics, safety, and efficacy of the oral mammalian target of rapamycin inhibitor everolimus in Chinese patients with advanced solid tumors.</p> <p>Methods</p> <p>A total of 24 patients with advanced breast cancer (n = 6), gastric cancer (n = 6), non-small cell lung cancer (n = 6), or renal cell carcinoma (n = 6) who were refractory to/unsuitable for standard therapy were randomized 1:1 to oral everolimus 5 or 10 mg/day. Primary end points were pharmacokinetic parameters and safety and tolerability. Pharmacokinetic 24-h profiles were measured on day 15; trough level was measured on days 2, 8, 15, 16, and 22. Tolerability was assessed continuously. This final analysis was performed after all patients had received 6 months of study drug or had discontinued.</p> <p>Results</p> <p>Everolimus was absorbed rapidly; median T_maxwas 3 h (range, 1-4) and 2 h (range, 0.9-6) in the 5 and 10 mg/day groups, respectively. Pharmacokinetic parameters increased dose proportionally from the 5 and 10 mg/day doses. Steady-state levels were achieved by day 8 or earlier. The most common adverse events suspected to be related to everolimus therapy were increased blood glucose (16.7% and 41.7%) and fatigue (16.7% and 33.3%) in the everolimus 5 and 10 mg/day dose cohorts, respectively. Best tumor response was stable disease in 10 (83%) and 6 (50%) patients in the 5 and 10 mg/day groups, respectively.</p> <p>Conclusions</p> <p>Everolimus 5 or 10 mg/day was well tolerated in Chinese patients with advanced solid tumors. The observed safety and pharmacokinetic profile of everolimus from this study were consistent with previous studies.</p> <p>Trial registration</p> <p>Chinese Health Authorities 2008L09346</p

Design and synthesis of boronic-acid-labeled thymidine triphosphate for incorporation into DNA

The boronic acid moiety is a versatile functional group useful in carbohydrate recognition, glycoprotein pull-down, inhibition of hydrolytic enzymes and boron neutron capture therapy. The incorporation of the boronic-acid group into DNA could lead to molecules of various biological functions. We have successfully synthesized a boronic acid-labeled thymidine triphosphate (B-TTP) linked through a 14-atom tether and effectively incorporated it into DNA by enzymatic polymerization. The synthesis was achieved using the Huisgen cycloaddition as the key reaction. We have demonstrated that DNA polymerase can effectively recognize the boronic acid-labeled DNA as the template for DNA polymerization, that allows PCR amplification of boronic acid-labeled DNA. DNA polymerase recognitions of the B-TTP as a substrate and the boronic acid-labeled DNA as a template are critical issues for the development of DNA-based lectin mimics via in vitro selection