Click chemistry reactions in medicinal chemistry: applications of the 1,3-dipolar cycloaddition between azides and alkynes

In recent years, there has been an ever-increasing need for rapid reactions that meet the three main criteria of an ideal synthesis: efficiency, versatility, and selectivity. Such reactions would allow medicinal chemistry to keep pace with the multitude of information derived from modern biological screening techniques. The present review describes one of these reactions, the 1,3-dipolar cycloaddition ("click-reaction") between azides and alkynes catalyzed by copper (I) salts. The simplicity of this reaction and the ease of purification of the resulting products have opened new opportunities in generating vast arrays of compounds with biological potential. The present review will outline the accomplishments of this strategy achieved so far and outline some of medicinal chemistry applications in which click-chemistry might be relevant in the future.     

Correction: Water droplet on inclined dusty hydrophobic surface: influence of droplet volume on environmental dust particles removal

Correction for ‘Water droplet on inclined dusty hydrophobic surface: influence of droplet volume on environmental dust particles removal’ by Ghassan Abdelmagid et al., RSC Adv., 2019, 9, 3582–3596.

The authors regret that the name of one of the authors (Ghassan Hassan) was shown incorrectly in the original article. The corrected author list is as shown above.The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers.     

Medicinal chemistry approaches for the treatment and prevention of Alzheimer's disease

Alzheimer's disease (AD) is the most common form of dementia, which is characterised by progressive deterioration of memory and higher cortical functions that ultimately result in total degradation of intellectual and mental activities. Modern strategies in the search of new therapeutic approaches are based on the morphological and biochemical characteristics of AD, and focused on following directions: agents that compensate the hypofunction of cholinergic system, agents that interfere with the metabolism of beta-amyloid peptide, agents that protect nerve cells from toxic metabolites formed in neurodegenerative processes, agents that activate other neurotransmitter systems that indirectly compensate for the deficit of cholinergic functions, agents that affect the process of the formation of neurofibrillary tangles, anti-inflammatory agents that prevent the negative response of nerve cells to the pathological process. The goal of the present review is the validation and an analysis from the point of view of medicinal chemistry of the principles of the directed search of drugs for the treatment and prevention of AD and related neurodegenerative disorders. It is based on systematization of the data on biochemical and structural similarities in the interaction between physiologically active compounds and their biological targets related to the development of such pathologies. The main emphasis is on cholinomimetic, anti-amyloid and anti-metabolic agents, using the data that were published during the last 3 to 4 years, as well as the results of clinical trials presented on corresponding websites.     

Correction: Pharmacophore-based approaches in the rational repurposing technique for FDA approved drugs targeting SARS-CoV-2 Mpro

Correction for ‘Pharmacophore-based approaches in the rational repurposing technique for FDA approved drugs targeting SARS-CoV-2 M^pro’ by Vishal M. Balaramnavar et al., RSC Adv., 2020, 10, 40264–40275, DOI: 10.1039/D0RA06038K.

The authors regret that the name of one of the authors (Talha Jawaid) was shown incorrectly in the original article. The corrected author list is as shown above.The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers.     

Strategies for the synthesis of fluorinated polyesters

In this work we synthetized three fluorinated polyesters from dimethyl tetrafluorosuccinate (DMTFS), dimethyl hexafluoroglutarate (DMHFG), and dimethyl octafluoroadipate (DMOFA) and ethylene glycol. The influence of parameters like monomer''s size, temperature, vacuum, ultrasound and catalyst, on the polyesters synthesis was evaluated. The conversion rates were assessed considering ¹H NMR data and the results disclose the role of ultrasound (US) as crucial to attain high reaction conversion rates (≈20% of increase relatively to the reactions performed in absence of US). The effect of US was more relevant for the higher molecular weight monomers (DMHFG and DMOFA). The use of Candida antarctica lipase (immobilized CALB) marginally favors the synthesis reactions when fixing the other conditions. The size of the starting monomers influenced greatly the reaction conversion rates, as shorter monomers gave rise to high amount of product recovering. All the produced polyesters were isolated and fully characterized by NMR (¹H and ¹⁹F), FTIR, TGA and MALDI-TOF.

In this work we synthetized three fluorinated polyesters from dimethyl tetrafluorosuccinate (DMTFS), dimethyl hexafluoroglutarate (DMHFG), and dimethyl octafluoroadipate (DMOFA) and ethylene glycol.     

From chemistry of life to chemistry of disease: the rise of clinical biochemistry

Any young scientific discipline may experience difficulties in determining its position. For a young discipline placed at the juncture between potent branches of science with a long tradition, as is the case for Clinical Biochemistry, this is especially true. In such a situation, a look backwards to identify first origins and to follow trends of development can be helpful. Moreover, the close relationship between the history and the philosophy of science should provide insight into the nature of our present work and the potential for future work. Our discipline originated with the emergence of modern chemistry at the end of the 18th century. Methods for the chemical analysis of plant and animal material were developed first. The examination of chemical processes in living organisms followed. Only after these successes did chemical investigations of causes and mechanisms of human disease become possible. A few selected milestones in this evolution can illustrate the medical, philosophical, intellectual and social background which has shaped the rise of Clinical Biochemistry.     

Digital microfluidics comes of age: high-throughput screening to bedside diagnostic testing for genetic disorders in newborns

Introduction: Digital microfluidics (DMF) is an emerging technology with the appropriate metrics for application to newborn and high-risk screening for inherited metabolic disease and other conditions that benefit from early treatment.

Areas covered: This review traces the development of electrowetting-based DMF technology toward the fulfillment of its promise to provide an inexpensive platform to conduct enzymatic assays and targeted biomarker assays at the bedside. The high-throughput DMF platform, referred to as SEEKER®, was recently authorized by the United States Food and Drug Administration to screen newborns for four lysosomal storage disorders (LSDs) and is deployed in newborn screening programs in the United States. The development of reagents and methods for LSD screening and results from screening centers are reviewed. Preliminary results from a more compact DMF device, to perform disease-specific test panels from small volumes of blood, are also reviewed. Literature for this review was sourced using principal author and subject searches in PubMed.

Expert commentary: Newborn screening is a vital and highly successful public health program. DMF technology adds value to the current testing platforms that will benefit apparently healthy newborns with underlying genetic disorders and infants at-risk for conditions that present with symptoms in the newborn period.     

Correction: DFT/TDDFT insights into the chemistry,biochemistry and photophysics of copper coordination compounds

Correction for ‘DFT/TDDFT insights into the chemistry, biochemistry and photophysics of copper coordination compounds’ by Athanassios C. Tsipis, RSC Adv., 2014, 4, 32504–32529, DOI: 10.1039/C4RA04921G.

RSC Advances is issuing this correction to notify readers that there are portions of text overlap with a number of different sources in this review article. Although the sources have been cited in appropriate locations in this article, the text should have been rewritten to avoid the overlapping text.     

New technologies in chemistry instrumentation: the basis for clinical chemistry automation

The analytical and operational capabilities of clinical chemistry analyzers will continue to evolve as new technologies are developed. This will lead to increasingly greater automation and enhanced ease of use. However, it will be important for the laboratorian to understand these technologies in order to effectively integrate them and interact with them in the health care environment.     

Novel therapies for metastatic renal cell carcinoma: efforts to expand beyond the VEGF/mTOR signaling paradigm

With six agents approved for metastatic renal cell carcinoma (mRCC) within the past 5 years, there has undoubtedly been progress in treating this disease. However, the goal of cure remains elusive, and the agents nearest approval (i.e., axitinib and tivozanib) abide by the same paradigm as existing drugs (i.e., inhibition of VEGF or mTOR signaling). The current review will focus on investigational agents that diverge from this paradigm. Specifically, novel immunotherapeutic strategies will be discussed, including vaccine therapy, cytotoxic T-lymphocyte antigen 4 (CTLA4) blockade, and programmed death-1 (PD-1) inhibition, as well as novel approaches to angiogenesis inhibition, such as abrogation of Ang/Tie-2 signaling. Pharmacologic strategies to block other potentially relevant signaling pathways, such as fibroblast growth factor receptor or MET inhibition, are also in various stages of development. Although VEGF and mTOR inhibition have dramatically improved outcomes for patients with mRCCs, a surge above the current plateau with these agents will likely require exploring new avenues.     

Using droplet digital PCR to screen for rare blood donors: Proof of principle

BackgroundDigital droplet PCR (ddPCR) is a very sensitive high throughput genotyping methodology. To date, the use of ddPCR in immunohematology is restricted to fetal genotyping of red blood cell antigens. Our hypothesis is that this technology could be applied to screen for rare red blood cell genotypes, such as Di(b-).MethodsNucleic acid of 3168 donors was extracted for viral screening routine in pools of 6, which were converted into three types of 48-donor pools: control pools (only DI*B/*B samples), pools with varying amount of DI*A/*B samples (n = 1–5) and a pool with one rare DI*A/*A sample. Pools were genotyped using ddPCR to detect and quantify DI*A and DI*B alleles.ResultsDI*A allele was accurately detected in all pools containing Di(a + b+) samples and in the pool containing one Di(a + b-) sample. No copies were detected in the control pools (n = 60). The ratio between the number of DI*A and DI*B copies varied significantly between the pools and the triplicates.ConclusionThe proposed ddPCR assay was accurate in identifying the rare DI*A allele in large pools of donors and can be applied to screen for Di(b-) phenotype. The strategy can potentially be extended to search for other rare RBC phenotypes.