Wolfgang DohleHannah AsikiWojciech GruchotPaul A. Foster...
11页
查看更多>>摘要：Abstract 2‐Difluoromethoxyestratriene derivatives were designed to improve potency and in?vivo stability of the drug candidate 2‐methoxyestradiol (2ME2). Compound evaluation in?vitro against the proliferation of MCF‐7 and MDA MB‐231 breast cancer cells, as inhibitors of tubulin polymerisation and also steroid sulfatase (STS) both in cell lysates and in whole cells, showed promising activities. In antiproliferative assays 2‐difluoromethoxyestradiol was less potent than 2ME2, but its sulfamates were often more potent than their corresponding non‐fluorinated analogues. The fluorinated bis‐sulfamate is a promising antiproliferative agent in MCF‐7 cells (GI50 0.28?μM) vs the known 2‐methoxyestradiol‐3,17‐O,O‐bissulfamate (STX140, GI50 0.52?μM), confirming the utility of our approach. Compounds were also evaluated in the NCI 60‐cell line panel and the fluorinated bis‐sulfamate derivative displayed very good overall activities with a sub‐micromolar average GI50. It was a very potent STS inhibitor in whole JEG‐3 cells (IC50 3.7?nM) similar to STX140 (4.2?nM) and additionally interferes with tubulin assembly in?vitro and colchicine binding to tubulin. An X‐ray study of 2‐difluoromethoxy‐3‐benzyloxyestra‐1,3,5(10)‐trien‐17‐one examined conformational aspects of the fluorinated substituent. The known related derivative 2‐difluoromethyl‐3‐sulfamoyloxyestrone was evaluated for STS inhibition in whole JEG‐3 cells and showed an excellent IC50 of 55?pM.
Anne Sophie CzerniakKevin KretschmerTina Wei?Annette G. Beck‐Sickinger...
9页
查看更多>>摘要：Abstract To study the binding mode of the adipokine chemerin as well as the short peptide agonist chemerin‐9 (C9) to its two receptors chemokine‐like receptor 1 (CMKLR1) and G protein‐coupled receptor 1 (GPR1), we generated 5‐carboxytetramethylrhodamine (TAMRA) modified variants of both ligands. In addition, we labeled GPR1 and CMKLR1 with a nanoluciferase at the N‐terminus to perform NanoBRET binding assays. For GPR1, both ligands show high affinity and comparable binding. Significant differences were found for CMKLR1, whereby only full‐length chemerin binds with high affinity in saturation and displacement assays. For TAMRA‐C9 a biphasic binding consisting of two binding states has been found and no displacement studies could be performed. Thus, we conclude that CMKLR1 requires full‐length chemerin for stable binding in contrast to GPR1. This work demonstrates the NanoBRET binding assay as a new tool for binding studies at chemerin receptors and it enables deeper insights into the ligand binding parameters.
查看更多>>摘要：Abstract The efficacy of platinum drugs is limited by severe side effects, drug resistance, and poor pharmacokinetic properties. Utilizing long‐lasting blood components as drug carriers is a promising strategy to improve the circulation half‐lives and tumor accumulation of platinum drugs. Non‐immunogenic blood cells such as erythrocytes and blood proteins such as albumins, which have long lifespans, are suitable for the delivery of platinum drugs. In this concept, we briefly summarize the strategies of applying blood components as promising carriers to deliver small‐molecule platinum drugs for cancer treatment. Examples of platinum drugs that are encapsulated, non‐covalently attached, and covalently bound to erythrocytes and plasma proteins such as albumin and apoferritin are introduced. The potential methods to increase the stability of platinum‐based thiol–maleimide conjugates involved in these delivery systems are also discussed. This concept may enlighten researchers with more ideas on the future development of novel platinum drugs that have excellent pharmacokinetic properties and antitumor performance in?vivo.
查看更多>>摘要：Abstract Repurposing of antiviral drugs affords a rapid and effective strategy to develop therapies to counter pandemics such as COVID‐19. SARS‐CoV‐2 replication is closely linked to the metabolism of cytosine‐containing nucleotides, especially cytidine‐5′‐triphosphate (CTP), such that the integrity of the viral genome is highly sensitive to intracellular CTP levels. CTP synthase (CTPS) catalyzes the rate‐limiting step for the de novo biosynthesis of CTP. Hence, it is of interest to know the effects of the 5′‐triphosphate (TP) metabolites of repurposed antiviral agents on CTPS activity. Using E. coli CTPS as a model enzyme, we show that ribavirin‐5′‐TP is a weak allosteric activator of CTPS, while sofosbuvir‐5′‐TP and adenine?arabinofuranoside‐5′‐TP are both substrates. β‐d‐N4‐Hydroxycytidine‐5′‐TP is a weak competitive inhibitor relative to CTP, but induces filament formation by CTPS. Alternatively, sofosbuvir‐5′‐TP prevented CTP‐induced filament formation. These results reveal the underlying potential for repurposed antivirals to affect the activity of a critical pyrimidine nucleotide biosynthetic enzyme.
Vassiliki‐Panagiota TassopoulouAriadni TzaraAngeliki P. Kourounakis
23页
查看更多>>摘要：Abstract Multifactorial diseases exhibit a complex pathophysiology with several factors contributing to their pathogenesis and development. Examples of such disorders are neurodegenerative (e.?g. Alzheimer's, Parkinson's) and cardiovascular diseases (e.?g. atherosclerosis, metabolic syndrome, diabetes II). Traditional therapeutic approaches with single‐target drugs have been proven, in many cases, unsatisfactory for the treatment of multifactorial diseases such as diabetes II. The well‐established by now strategy of multitarget drugs is constantly gaining interest and momentum, as a more effective approach. The development of pharmacomolecules able to simultaneously modulate multiple relevant‐to‐the‐disease targets has already several successful examples in various fields and has, as such, inspired the design of multitarget antidiabetic agents; this review highlights the design aspect and efficacy of this approach for improved antidiabetics by presenting several examples of successful pharmacophore combinations in (multitarget) agents that modulate two or more molecular targets involved in diabetes II, resulting in a superior antihyperglycemic profile.
Adrian R. DemeritteWeiwei WangWilliam M. WuestIngrid K. Wilt...
6页
查看更多>>摘要：Abstract Synthetic investigations of natural products has been instrumental in the development of novel antibacterial small molecules. 1‐hydroxyboivinianin A, a lactone containing phenolic bisabolane isolated from marine sediment, has reported antibacterial activity against the aquatic pathogen Vibrio harveyi. The total synthesis of 1‐hydroxyboivinianin A and its enantiomer was completed in a six‐step sequence in 42?% overall yield. The synthesis leveraged a key diastereoselective nucleophilic addition with chiral imidazolidinone to establish the benzylic tertiary alcohol and intramolecular Horner‐Wadsworth Emmons to furnish the lactone. Both enantiomers were found to have negligible antibacterial activity against a panel of gram‐positive and negative bacteria and minimal antifungal activity against phytopathogens. Investigations of a possible in?vitro lactone hydrolysis to produce an inactive linear acid led to the discovery of a spontaneous cyclization, suggesting the lactone is resistant to hydrolysis and the lactone is not degrading to produce an inactive species.
Tiago BozzolaRichard E. JohnssonUlf J. NilssonUlf Ellervik...
10页
查看更多>>摘要：Abstract In search for novel antibacterial compounds, bacterial sialic acid uptake inhibition represents a promising strategy. Sialic acid plays a critical role for growth and colonisation of several pathogenic bacteria, and its uptake inhibition in bacteria was recently demonstrated to be a viable strategy by targeting the SiaT sodium solute symporters from Proteus mirabilis and Staphylococcus aureus. Here we report the design, synthesis and evaluation of potential sialic acid uptake inhibitors bearing 4‐N‐piperidine and piperazine moieties. The 4‐N‐derivatives were obtained via 4‐N‐functionalization with piperidine and piperazine nucleophiles in an efficient direct substitution of the 4‐O‐acetate of Neu5Ac. Evaluation for binding to bacterial transport proteins with nanoDSF and ITC revealed compounds possessing nanomolar affinity for the P. mirabilis SiaT symporter. Computational analyses indicate the engagement of a previously untargeted portion of the binding site.
Eddy E. AlfonsoRogelio TrocheZifang DengThirunavukkarasu Annamalai...
8页
查看更多>>摘要：Abstract Bacterial DNA gyrase, an essential enzyme, is a validated target for discovering and developing new antibiotics. Here we screened a pool of polyphenols and discovered that digallic acid is a potent DNA gyrase inhibitor. We also found that several food additives based on gallate, such as dodecyl gallate, potently inhibit bacterial DNA gyrase. Interestingly, the IC50 of these gallate derivatives against DNA gyrase is correlated with the length of hydrocarbon chain connecting to the gallate. These new bacterial DNA gyrase inhibitors are ATP competitive inhibitors of DNA gyrase. Our results also show that digallic acid and certain gallate derivatives potently inhibit E. coli DNA topoisomerase IV. Several gallate derivatives have strong antimicrobial activities against Staphylococcus aureus and methicillin‐resistant Staphylococcus aureus (MRSA). This study provides a solid foundation for the design and synthesis of gallate‐based DNA gyrase inhibitors that may be used to combat antibacterial resistance.
NSTL
Wiley