Correction: Modified minimal-size fragments of heparan sulfate as inhibitors of endosulfatase-2 (Sulf-2).

Correction for 'Modified minimal-size fragments of heparan sulfate as inhibitors of endosulfatase-2 (Sulf-2)' by Alice Kennett et al., Chem. Commun., 2024, 60, 436-439, https://doi.org/10.1039/D3CC02565A.

Sperm Toolbox-A selection of small molecules to study human spermatozoa.

Male contraceptive options and infertility treatments are limited, and almost all innovation has been limited to updates to medically assisted reproduction protocols and methods. To accelerate the development of drugs that can either improve or inhibit fertility, we established a small molecule library as a toolbox for assay development and screening campaigns using human spermatozoa. We have profiled all compounds in the Sperm Toolbox in several automated high-throughput assays that measure stimulation or inhibition of sperm motility or the acrosome reaction. We have assayed motility under non-capacitating and capacitating conditions to distinguish between pathways operating under these different physiological states. We also assayed cell viability to ensure any effects on sperm function are specific. A key advantage of our studies is that all compounds are assayed together in the same experimental conditions, which allows quantitative comparisons of their effects in complementary functional assays. We have combined the resulting datasets to generate fingerprints of the Sperm Toolbox compounds on sperm function. The data are included in an on-line R-based app for convenient querying.

Modified minimal-size fragments of heparan sulfate as inhibitors of endosulfatase-2 (Sulf-2).

Sulf-2 has been identified as a putative target for anticancer therapies. Here we report the design and synthesis of sulfated disaccharide inhibitors based on IdoA(2S)-GlcNS(6S). Trisulfated disaccharide inhibitor IdoA(2S)-GlcNS(6Sulfamate) demonstrated potent Sulf-2 inhibition. The IC50 value was determined to be 39.8 µM ± 18.3, which is comparable to a tetrasaccharide inhibitor of HSulf-1 reported in the literature. We propose that the disaccharide IdoA(2S)-GlcNS(6S) is the shortest fragment size required for effective inhibition of the Sulfs.

Male contraceptive development: A medicinal chemistry perspective.

There is a need for non-hormonal contraceptives. One area that needs further investigation is the development of male contraceptives. Comparatively little is understood about potential drug targets in men to achieve a reversible contraceptive effect. In this article, we review the need for male contraceptives and some thoughts around the characteristics of a male contraceptive and the potential development pathway. We then discuss different potential approaches to discovering male contraceptives and then highlight potential targets that have been discussed in the literature.

Monitoring Health Inequalities in 12 European Countries: Lessons Learned from the Joint Action Health Equity Europe.

To raise awareness about health inequalities, a well-functioning health inequality monitoring system (HIMS) is crucial. Drawing on work conducted under the Joint Action Health Equity Europe, the aim of this paper is to illustrate the strengths and weaknesses in current health inequality monitoring based on lessons learned from 12 European countries and to discuss what can be done to strengthen their capacities. Fifty-five statements were used to collect information about the status of the capacities at different steps of the monitoring process. The results indicate that the preconditions for monitoring vary greatly between countries. The availability and quality of data are generally regarded as strong, as is the ability to disaggregate data by age and gender. Regarded as poorer is the ability to disaggregate data by socioeconomic factors, such as education and income, or by other measures of social position, such as ethnicity. Few countries have a proper health inequality monitoring strategy in place and, where in place, it is often regarded as poorly up to date with policymakers' needs. These findings suggest that non-data-related issues might be overlooked aspects of health inequality monitoring. Structures for stakeholder involvement and communication that attracts attention from policymakers are examples of aspects that deserve more effort.

Refolding of lid subdomain of SARS-CoV-2 nsp14 upon nsp10 interaction releases exonuclease activity.

During RNA replication, coronaviruses require proofreading to maintain the integrity of their large genomes. Nsp14 associates with viral polymerase complex to excise the mismatched nucleotides. Aside from the exonuclease activity, nsp14 methyltransferase domain mediates cap methylation, facilitating translation initiation and protecting viral RNA from recognition by the innate immune sensors. The nsp14 exonuclease activity is modulated by a protein co-factor nsp10. While the nsp10/nsp14 complex structure is available, the mechanistic basis for nsp10-mediated modulation remains unclear in the absence of the nsp14 structure. Here, we provide a crystal structure of nsp14 in an apo-form. Comparative analysis of the apo- and nsp10-bound structures explain the modulatory role of the co-factor protein and reveal the allosteric nsp14 control mechanism essential for drug discovery. Further, the flexibility of the N-terminal lid of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) nsp14 structure presented in this study rationalizes the recently proposed idea of nsp14/nsp10/nsp16 ternary complex.

Pilot Study to Quantify Palladium Impurities in Lead-like Compounds Following Commonly Used Purification Techniques.

Palladium-catalyzed reactions are among the most commonly used procedures in organic synthesis. The products have a range of uses, including as intermediates in total synthesis and as screening compounds for drug discovery or agrochemical projects. Despite the known and potentially deleterious effects of low-level metal impurities in biological assays, the quantification of metal remaining in reaction products to verify the effective removal of the transition element is rarely reported. Using palladium as an exemplar, we describe a pilot study that for the first time quantifies residual metal levels in reaction products following increasingly rigorous purification protocols. Our results demonstrate that significant levels of residual palladium can remain in isolated reaction products following chromatographic purification, and only by using a subsequent metal scavenging step are they reliably reduced to a low level. Finally, we provide a set of simple guidelines that should minimize the potential for issues associated with residual palladium in reaction products.

Remote AI Supported E-Multidisciplinary Oncology Conference in Breast Cancer as a Technology and Method to Optimize Outcomes in the Peripheries.

AIM: Feasibility-reliability control of Telemedicine Systems (TS) integrated with Multimedia Systems (MS) and Artificial intelligence (AI) for remote e-Multidisciplinary Oncology Conference in Breast Cancer. MATERIAL AND METHODS: Forty (n1=40) patients suffering from breast surgical oncology malignant (n2=32) and non-malignant (n3=8) diseases classified to seven categories: Nipple Discharge, Dominant Breast Mass, Occult Breast Lesion, Early Breast Carcinoma, Advanced Breast Carcinoma, Recurrent Breast Carcinoma) and treated clinically with the standard diagnostic (Mammography, US, MRI, Cytology, Pathology, BRCA1/2 Mutation Predisposition and Breast Cancer Risk Analysis) surgical, auxiliary therapeutic methods. Then clinical decisions compared to those proposed remotely by the virtual AI supported e-Oncology Conference for each patient. RESULTS: In four (n4=4) out of forty patients (TS, MS and AI) supported decision making and surgical treatment proposal including postoperative Radiotherapy proposal was not as clear as expected. Non-output answer for non-malignant breast pathologies (n3=8) was accurately indicated by (MS and AI). Mean accuracy of (TS, MS and AI) for: 1.Surgical Operative Planning including Rad=94.1%, 2.Chem=96.8%, 3.Horm=96.7% [In 95%, (Confidence interval: 85-99%)]. CONCLUSION: High feasibility-reliability of the virtual AI supported e-Multidisciplinary Oncology Conference for remote decision making and surgical planning and for optimum outcomes in Breast Cancer treatment makes it a clinical necessity especially for the periphery of Hellas.

Compounds enhancing human sperm motility identified using a high-throughput phenotypic screening platform.

STUDY QUESTION: Can a high-throughput screening (HTS) platform facilitate male fertility drug discovery? SUMMARY ANSWER: An HTS platform identified a large number of compounds that enhanced sperm motility. WHAT IS KNOWN ALREADY: Several efforts to find small molecules modulating sperm function have been performed but none have used high-throughput technology. STUDY DESIGN, SIZE, DURATION: Healthy donor semen samples were used and samples were pooled (3-5 donors per pool). Primary screening was performed singly; dose-response screening was performed in duplicate (using independent donor pools). PARTICIPANTS/MATERIALS, SETTING, METHODS: Spermatozoa isolated from healthy donors were prepared by density gradient centrifugation and incubated in 384-well plates with compounds (6.25 µM) to identify those compounds with enhancing effects on motility. Approximately 17 000 compounds from the libraries, ReFRAME, Prestwick, Tocris, LOPAC, CLOUD and MMV Pathogen Box, were screened. Dose-response experiments of screening hits were performed to confirm the enhancing effect on sperm motility. Experiments were performed in a university setting. MAIN RESULTS AND THE ROLE OF CHANCE: From our primary single concentration screening, 105 compounds elicited an enhancing effect on sperm motility compared to dimethylsulphoxide-treated wells. Confirmed enhancing compounds were grouped based on their annotated targets/target classes. A major target class, phosphodiesterase inhibitors, were identified, in particular PDE10A inhibitors as well as number of compounds not previously known to enhance human sperm motility, such as those related to GABA signalling. LARGE SCALE DATA: N/A. LIMITATIONS, REASONS FOR CAUTION: Although this approach provides data about the activity of the compound, it is only a starting point. For example, further substantive experiments are necessary to provide a more comprehensive picture of each compound's activity, the effect on the kinetics of the cell populations and subpopulations, and their potential mechanisms of action. Compounds have been tested with prepared donor spermatozoa, incubated under non-capacitating conditions, and only incubated with compounds for a relatively short period of time. Therefore, the effect of compounds under different conditions, for example in whole semen, for longer incubation times, or using samples from patient groups, may be different and require further study. All experiments were performed in vitro. WIDER IMPLICATIONS OF THE FINDINGS: This phenotypic screening assay identified a large number of compounds that increased sperm motility. In addition to furthering our understanding of human sperm function, for example identifying new avenues for discovery, we highlight potential compounds as promising start-point for a medicinal chemistry programme for potential enhancement of male fertility. Moreover, with disclosure of the results of screening, we present a substantial resource to inform further work in the field. STUDY FUNDING/COMPETING INTEREST(S): This study was supported by the Bill and Melinda Gates Foundation, Scottish Funding Council and Scottish Universities Life Science Alliance. C.L.R.B. is Editor for RBMO. C.L.R.B. receives funding from Chief Scientists Office (Scotland), ESHRE and Genus PLC, consulting fees from Exscientia and lecture fees from Cooper Surgical and Ferring. S.M.d.S. is an Associate Editor of Human Reproduction, and an Associate Editor of Reproduction and Fertility. S.M.d.S. receives funding from Cooper Surgical and British Dietetic Society. No other authors declared a COI.

Identification and Preliminary Structure-Activity Relationship Studies of 1,5-Dihydrobenzo[e][1,4]oxazepin-2(3H)-ones That Induce Differentiation of Acute Myeloid Leukemia Cells In Vitro.

Acute myeloid leukemia (AML) is the most aggressive type of blood cancer, and there is a continued need for new treatments that are well tolerated and improve long-term survival rates in patients. Induction of differentiation has emerged as a promising alternative to conventional cytotoxic chemotherapy, but known agents lack efficacy in genetically distinct patient populations. Previously, we established a phenotypic screen to identify small molecules that could stimulate differentiation in a range of AML cell lines. Utilising this strategy, a 1,5-dihydrobenzo[e][1,4]oxazepin-2(3H)-one hit compound was identified. Herein, we report the hit validation in vitro, structure-activity relationship (SAR) studies and the pharmacokinetic profiles for selected compounds.

Asymmetric Synthesis of Pyrrolidine-Containing Chemical Scaffolds via Tsuji-Trost Allylation of N-tert-Butanesulfinyl Imines.

A simple and efficient asymmetric synthesis of novel sp3 -rich pyrrolidine chemical scaffolds over five steps starting from simple ketones is described. Key steps involve the use of tert-butanesulfinamide as a chiral auxiliary to perform an asymmetric Tsuji-Trost allylation, with subsequent cross-metathesis with an acrylate ester and reduction of the sulfinimine/cyclisation of the resulting amine giving the pyrrolidine scaffolds in high yields and diastereoselectivites. By removing the chiral auxiliary and functionalising the ester group, the resulting scaffold core can be further derivatised.

Versatile Self-Adapting Boronic Acids for H-Bond Recognition: From Discrete to Polymeric Supramolecules.

Because of the peculiar dynamic covalent reactivity of boronic acids to form tetraboronate derivatives, interest in using their aryl derivatives in materials science and supramolecular chemistry has risen. Nevertheless, their ability to form H-bonded complexes has been only marginally touched. Herein we report the first solution and solid-state binding studies of the first double-H-bonded DD·AA-type complexes of a series of aromatic boronic acids that adopt a syn-syn conformation with suitable complementary H-bonding acceptor partners. The first determination of the association constant (Ka) of ortho-substituted boronic acids in solution showed that Ka for 1:1 association is in the range between 300 and 6900 M-1. Crystallization of dimeric 1:1 and trimeric 1:2 and 2:1 complexes enabled an in-depth examination of these complexes in the solid state, proving the selection of the -B(OH)2 syn-syn conformer through a pair of frontal H-bonds with the relevant AA partner. Non-ortho-substituted boronic acids result in "flat" complexes. On the other hand, sterically demanding analogues bearing ortho substituents strive to retain their recognition properties by rotation of the ArB(OH)2 moiety, forming "T-shaped" complexes. Solid-state studies of a diboronic acid and a tetraazanaphthacene provided for the first time the formation of a supramolecular H-bonded polymeric ribbon. On the basis of the conformational dynamicity of the -B(OH)2 functional group, it is expected that these findings will also open new possibilities in metal-free catalysis or organic crystal engineering, where double-H-bonding donor boronic acids could act as suitable organocatalysts or templates for the development of functional materials with tailored organizational properties.

Synthesis of Tertiary Enamides by Ag2CO3-Promoted Pd-Catalyzed Alkenylation of Acyclic Secondary Amides.

A Pd-catalyzed methodology for the preparation of tertiary enamides from acyclic secondary amides and bromo acrylates under mild reaction conditions has been developed using [Pd2(dba)3], XantPhos, and Ag2CO3 as a base. The reaction occurs through a stereospecific metal-mediated oxidative-insertion mechanism.

Mechanism and optimisation of the homoboroproline bifunctional catalytic asymmetric aldol reaction: Lewis acid tuning through in situ esterification.

The use of homoboroproline as a bifunctional catalyst in the asymmetric aldol reaction has been investigated mechanistically, particularly with respect to tuning the Lewis acidity of boron by in situ esterification with mildly sigma-electron withdrawing diols such as hydrobenzoin and tartrate esters. The stability of simple cyclohexyl and cyclopentyl boronate diol esters shows that the 5-ring boronate esters are more stable, which sheds light on the mode of action of esterified homoboroproline catalyst in the enamine-mediated aldol reaction, which is also studied by NMR. The result is reaction optimisation to provide an efficient aldol reaction and a proposed mechanistic proposal.

Papillary carcinoma of the male breast: report of a case.

Intracystic papillary carcinoma of the male breast represents an extremely rare entity that accounts for less than 1% of all malignancies, and histologically may range from papillary hyperplasia in gynecomastia to invasive papillary carcinoma. This report presents the case of a 61-year-old Caucasian man who presented with a 5-year history of a centrally located painless swelling of his right breast with occasional nipple discharge. Triple assessment was very helpful in establishing the diagnosis. Treatment included a mastectomy and hormonal therapy because the neoplasm expressed hormone receptors. Although male breast carcinomas tend to behave more aggressively than their female counterparts, the prognosis of this neoplasm is excellent.

Synthesis of aminoboronic acids and their applications in bifunctional catalysis.

Amino acids have been known to catalyze organic reactions for many years, but their boronic acid counterparts are much less well-studied. Although there are a number of useful general approaches to the synthesis of protected aminoboronic acids, many practical challenges remain in the isolation and purification of free aminoboronic acids. Despite these issues, now several different chiral and achiral aminoboronic acids show promise as bifunctional organic catalysts. In this Account, we describe both advances in the synthesis of these aminoboronic acids and some of their underdeveloped potential in catalysis. The first aminoboronic acids that demonstrated catalytic properties, such as 8-quinoline boronic acid, enabled the hydrolysis and etherification of chlorohydrins. More recently, aminoboronic acids have effectively catalyzed direct amide formation. In addition, these catalysts can enable the kinetic resolution of racemic amines during the acylation process. Aminoboronic acids can also function as aldol catalysts, acting through in situ boronate enolate formation in water, and have facilitated tunable asymmetric aldol reactions, acting through the formation of an enamine. On the basis of these examples, we expect that these molecules can catalyze an even wider range of reactions. We anticipate many further discoveries in this area.