ACS Combinatorial Science最新文献

{"title":"Solution-Phase Fmoc-Based Peptide Synthesis for DNA-Encoded Chemical Libraries: Reaction Conditions, Protecting Group Strategies, and Pitfalls","authors":"Olivier B. C. Monty,&nbsp;Nicholas Simmons,&nbsp;Srinivas Chamakuri,&nbsp;Martin M. Matzuk,&nbsp;Damian W. Young*","doi":"10.1021/acscombsci.0c00144","DOIUrl":"https://doi.org/10.1021/acscombsci.0c00144","url":null,"abstract":"<p >Peptide drug discovery has shown a resurgence since 2000, bringing 28 non-insulin therapeutics to the market compared to 56 since its first peptide drug, insulin, in 1923. While the main method of discovery has been biological display—phage, mRNA, and ribosome—the synthetic limitations of biological systems has restricted the depth of exploration of peptide chemical space. In contrast, DNA-encoded chemistry offers the synergy of large numbers and ribosome-independent synthetic flexibility for the fast and deeper exploration of the same space. Hence, as a bridge to building DNA-encoded chemical libraries (DECLs) of peptides, we have developed substrate-tolerant amide coupling reaction conditions for amino acid monomers, performed a coupling screen to illustrate such tolerance, developed protecting group strategies for relevant amino acids and reported the limitations thereof, developed a strategy for the coupling of α,α-disubstituted alkenyl amino acids relevant to all-hydrocarbon stapled peptide drug discovery, developed reaction conditions for the coupling of tripeptides likely to be used in DECL builds, and synthesized a fully deprotected DNA-decamer conjugate to illustrate the potency of the developed methodology for on-DNA peptide synthesis.</p>","PeriodicalId":14,"journal":{"name":"ACS Combinatorial Science","volume":null,"pages":null},"PeriodicalIF":3.784,"publicationDate":"2020-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1021/acscombsci.0c00144","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"1318158","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"High Entropy and Sluggish Diffusion “Core” Effects in Senary FCC Al–Co–Cr–Fe–Ni–Mn Alloys","authors":"Abhishek Mehta*,&nbsp;Yongho Sohn","doi":"10.1021/acscombsci.0c00096","DOIUrl":"https://doi.org/10.1021/acscombsci.0c00096","url":null,"abstract":"<p >Relative role of enthalpy and entropy in the stabilization of senary FCC Al–Co–Cr–Fe–Ni–Mn high entropy alloys was investigated via a high throughput combinatorial solid-to-solid diffusion couple approach. Many off-equiatomic compositions of FCC Al_<i>p</i>Co_<i>q</i>Cr_<i>r</i>Fe_<i>s</i>Ni_<i>t</i>Mn_<i>u</i> were generated by the diffusing Al and Ni in equiatomic Co₂₀Cr₂₀Fe₂₀Ni₂₀Mn₂₀ alloy, i.e., the Al₄₈Ni₅₂ vs Co₂₀Cr₂₀Fe₂₀Ni₂₀Mn₂₀ diffusion couple, annealed at 900°, 1000°, 1100°, and 1200 °C. Above 1000 °C, the solubility limit of Al in off-equiatomic Al_<i>p</i>Co_<i>q</i>Cr_<i>r</i>Fe_<i>s</i>Ni_<i>t</i>Mn_<i>u</i> alloy was determined to be higher than the solubility limit of Al in equiatomic Al_<i>x</i>CoCrFeNiMn alloy. Compositions corresponding to the highest solubility limit of Al in off-equiatomic Al_<i>p</i>Co_<i>q</i>Cr_<i>r</i>Fe_<i>s</i>Ni_<i>t</i>Mn_<i>u</i> alloy exhibited a lower free energy of mixing, i.e., higher thermodynamic stability, than equiatomic Al_<i>x</i>CoCrFeNiMn compositions, at 1100 °C and above. Therefore, the role of enthalpy was estimated to be significant in achieving higher thermodynamic stability in off-equiatomic alloys, since they always have lower entropy of mixing than their equiatomic counterparts. The magnitude of interdiffusion coefficients of individual elements in Al–Co–Cr–Fe–Ni–Mn alloys were compared to the interdiffusion coefficients in relevant quinary, quaternary, and ternary solvent-based alloys. Interdiffusion coefficients were not necessarily lower in FCC Al–Co–Cr–Fe–Ni–Mn alloys; therefore no sluggish diffusion was observed in FCC HEA, but diffusion of individual elements in BCC Al–Co–Cr–Fe–Ni–Mn alloy followed the sluggish diffusion hypothesis except for Ni. All compositions in the FCC Al–Co–Cr–Fe–Ni–Mn alloy were observed to comply with existing empirical single phase formation rules in high entropy alloys.</p>","PeriodicalId":14,"journal":{"name":"ACS Combinatorial Science","volume":null,"pages":null},"PeriodicalIF":3.784,"publicationDate":"2020-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1021/acscombsci.0c00096","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"803322","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"An Aptamer Linked Immobilized Sorbent Assay (ALISA) to Detect Circulatory IFN-α, an Inflammatory Protein among Tuberculosis Patients","authors":"Vibha Taneja,&nbsp;Manish Goel,&nbsp;Uma Shankar,&nbsp;Amit Kumar,&nbsp;Gopi C. Khilnani,&nbsp;Hanumanthappa K. Prasad,&nbsp;Godavari B. K. S. Prasad,&nbsp;Umesh D. Gupta,&nbsp;Tarun K. Sharma*","doi":"10.1021/acscombsci.0c00108","DOIUrl":"https://doi.org/10.1021/acscombsci.0c00108","url":null,"abstract":"<p >Dysregulation of IFN-α is the basis for pathogenesis of autoimmune as well as infectious diseases. Identifying inflammatory signatures in peripheral blood of patients is an approach for monitoring active infection. Hence, estimation of type I IFNs as an inflammatory biomarker to scrutinize disease status after treatment is useful. Accordingly, an Aptamer Linked Immobilized Sorbent Assay (ALISA) for the detection of IFN-α in serum samples was developed. Sixteen aptamers were screened for their ability to bind IFN-α. Aptamer IFNα-3 exhibited specificity for IFN-α with no cross-reactivity with interferons β and γ and human serum albumin. The disassociation constant (<i>K</i>_d) was determined to be 3.96 ± 0.36 nM, and the limit of detection was ～2 ng. The characterized IFNα-3 aptamer was used in ALISA to screen tuberculosis (TB) patients’ sera. An elevated IFN-α level in sera derived from untreated TB patients (median = 0.31), compared to nontuberculous household contacts (median = 0.13) and healthy volunteers (median = 0.12), and further a decline in IFN-α level among treated patients (median = 0.13) were seen. The ALISA assay facilitates direct estimation of inflammatory protein(s) in circulation unlike mRNA estimation by real time PCR. Designing of aptamers similar to the IFNα-3 aptamer provides a novel approach to assess other inflammatory protein(s) in patients before, during, and after completion of treatment and would denote clinical improvement in successfully treated patients.</p>","PeriodicalId":14,"journal":{"name":"ACS Combinatorial Science","volume":null,"pages":null},"PeriodicalIF":3.784,"publicationDate":"2020-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1021/acscombsci.0c00108","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"1310484","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Total Synthesis of Semaglutide Based on a Soluble Hydrophobic-Support-Assisted Liquid-Phase Synthetic Method","authors":"Xingbang Liu,&nbsp;Na Zhang,&nbsp;Xiaotong Gu,&nbsp;Yinhui Qin,&nbsp;Di Song,&nbsp;Long Zhang,&nbsp;Shutao Ma*","doi":"10.1021/acscombsci.0c00134","DOIUrl":"https://doi.org/10.1021/acscombsci.0c00134","url":null,"abstract":"<p >Considering the high cost of the production of semaglutide, which is currently the most promising antidiabetic drug especially for the treatment of type 2 diabetes mellitus, a new synthetic route of semaglutide production that possesses excellent yield and high purity is of vital importance. Herein, we reported a newly developed synthetic route of semaglutide that is simple and efficient, based on a soluble hydrophobic-support-assisted liquid-phase synthetic method by applying Alloc-chemistry to the synthesis of the main chain peptide and side chain peptide of semaglutide. With careful optimization of the reaction conditions and innovative strategy of post-synthetic treatments, the total yield and purity of the crude semaglutide was improved satisfactorily.</p>","PeriodicalId":14,"journal":{"name":"ACS Combinatorial Science","volume":null,"pages":null},"PeriodicalIF":3.784,"publicationDate":"2020-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1021/acscombsci.0c00134","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"1304460","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sorting Technology for Circulating Tumor Cells Based on Microfluidics","authors":"Dayu Hu,&nbsp;He Liu,&nbsp;Ye Tian,&nbsp;Zhi Li,&nbsp;Xiaoyu Cui*","doi":"10.1021/acscombsci.0c00157","DOIUrl":"https://doi.org/10.1021/acscombsci.0c00157","url":null,"abstract":"<p >Circulating tumor cells (CTCs) carry reliable clinical information for the diagnosis and treatment of cancer that is a malignant disease with a high mortality rate. However, the amount of CTCs in the blood is quite low. To obtain credible clinical information, an efficient method of extracting CTCs is necessary. Microfluidic technology has proven its effectiveness on CTCs separation in recent years. Here, we present a comprehensive review of CTC sorting methods based on microfluidics. Specifically, we introduce four different microfluidic sorting methods of CTCs and compare their advantages and disadvantages. Finally, we summarize the analysis of CTCs based on microfluidics and present a prospective view of future research.</p>","PeriodicalId":14,"journal":{"name":"ACS Combinatorial Science","volume":null,"pages":null},"PeriodicalIF":3.784,"publicationDate":"2020-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1021/acscombsci.0c00157","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"1304521","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"(Hetero-)(arylidene)arylhydrazides as Multitarget-Directed Monoamine Oxidase Inhibitors","authors":"Ashique Palakkathondi,&nbsp;Jong Min Oh,&nbsp;Sanal Dev,&nbsp;T. M. Rangarajan,&nbsp;Swafvan Kaipakasseri,&nbsp;Fathima Sahla Kavully,&nbsp;Nicola Gambacorta,&nbsp;Orazio Nicolotti,&nbsp;Hoon Kim*,&nbsp;Bijo Mathew*","doi":"10.1021/acscombsci.0c00136","DOIUrl":"https://doi.org/10.1021/acscombsci.0c00136","url":null,"abstract":"<p >Fourteen (hetero-)(arylidene)arylhydrazide derivatives (<b>ABH1</b>–<b>ABH14</b>) were synthesized, and their inhibitory activities against monoamine oxidases (MAOs) and acetylcholinesterase (AChE) were evaluated. Compound <b>ABH5</b> most potently inhibited MAO-B with an IC₅₀ value of 0.025 ± 0.0019 μM; <b>ABH2</b> and <b>ABH3</b> exhibited high IC₅₀ values as well. Most of the compounds weakly inhibited MAO-A, except <b>ABH5</b> (IC₅₀ = 3.31 ± 0.41 μM). Among the active compounds, <b>ABH2</b> showed the highest selectivity index (SI) of 174 for MAO-B, followed by <b>ABH5</b> (SI = 132). <b>ABH3</b> and <b>ABH5</b> effectively inhibited AChE with IC₅₀ values of 15.7 ± 6.52 and 16.5 ± 7.29 μM, respectively, whereas the other compounds were weak inhibitors of AChE. <b>ABH5</b> was shown to be a reversible competitive inhibitor for MAO-A and MAO-B with <i>K</i>_i values of 0.96 ± 0.19 and 0.024 ± 0.0077 μM, respectively, suggesting that this molecule can be considered as an interesting candidate for further development as a multitarget inhibitor relating to neurodegenerative disorders.</p>","PeriodicalId":14,"journal":{"name":"ACS Combinatorial Science","volume":null,"pages":null},"PeriodicalIF":3.784,"publicationDate":"2020-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1021/acscombsci.0c00136","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"1301689","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Detection of Thiol Functionality and Disulfide Bond Formation by Polyoxometalate","authors":"Hiroyuki Konno*,&nbsp;Haruto Yasumiishi,&nbsp;Reika Aoki,&nbsp;Ikumi Nitanai,&nbsp;Shigekazu Yano","doi":"10.1021/acscombsci.0c00176","DOIUrl":"https://doi.org/10.1021/acscombsci.0c00176","url":null,"abstract":"<p >The detection of thiol functionality and intramolecular disulfide bond formation of peptides using the α-Keggin type polyoxometalate molybdenum–oxygen cluster (H₃PMo₁₂O₄₀·<i>n</i>H₂O) is described. Our method entails the addition of this polyoxometalate to solutions of thiol, whereupon the color of the solution changes from colorless to deep blue. Reduction of the polyoxometalate from Mo(VI) to Mo(V) occurs with concomitant oxidation of the thiol functionality, to form disulfide bonds. To exemplify the utility this phenomenon, we accomplished the oxidation of glutathione, reduced linear oxytocin, bactenecin, and α-conotoxin SI; all of which proceeded smoothly and in good conversion in 24 h to less and were accomplished by a change in the color of the reaction solutions.</p>","PeriodicalId":14,"journal":{"name":"ACS Combinatorial Science","volume":null,"pages":null},"PeriodicalIF":3.784,"publicationDate":"2020-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1021/acscombsci.0c00176","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"860248","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cautionary Guidelines for Machine Learning Studies with Combinatorial Datasets","authors":"Andrew F. Zahrt,&nbsp;Jeremy J. Henle,&nbsp;Scott E. Denmark*","doi":"10.1021/acscombsci.0c00118","DOIUrl":"https://doi.org/10.1021/acscombsci.0c00118","url":null,"abstract":"<p >Regression modeling is becoming increasingly prevalent in organic chemistry as a tool for reaction outcome prediction and mechanistic interrogation. Frequently, to acquire the requisite amount of data for such studies, researchers employ combinatorial datasets to maximize the number of data points while limiting the number of discrete chemical entities required. An often-overlooked problem in modeling studies using combinatorial datasets is the tendency to fit on patterns in the datasets (i.e., the presence or absence of a reactant or catalyst) rather than to identify meaningful trends between descriptors and the response variable. Consequently, the generality and interpretability of such models suffer. This report illustrates these well-known pitfalls in a case study, demonstrates the necessary control experiments to identify when this property will be problematic, and suggests how to perform further validation to assess general applicability and interpretability of models trained using combinatorial datasets.</p>","PeriodicalId":14,"journal":{"name":"ACS Combinatorial Science","volume":null,"pages":null},"PeriodicalIF":3.784,"publicationDate":"2020-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1021/acscombsci.0c00118","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"1289082","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Multicomponent Petasis Reaction for the Synthesis of Functionalized 2-Aminothiophenes and Thienodiazepines","authors":"Jimin Hwang,&nbsp;Lydia Borgelt,&nbsp;Peng Wu*","doi":"10.1021/acscombsci.0c00173","DOIUrl":"https://doi.org/10.1021/acscombsci.0c00173","url":null,"abstract":"<p >Multicomponent Petasis reaction has been widely applied for the synthesis of functionalized amine building blocks and biologically active compounds. Employing primary aromatic amines that are not typical reactive substrates contributes to expand the application scope of the Petasis reaction. In this study, we demonstrated the synthesis of functionalized 2-aminothiophenes using Gewald-reaction-derived 2-aminothiophenes as the amine substrates, whose low reactivity in the Petasis reaction was overcome using hexafluoro-2-propanol as the solvent in a mild condition. The obtained Petasis products are amenable for further transformations owing to the presence of multiple functional handles. A following intramolecular cyclization of selected Petasis products afforded substituted tricyclic heterocycles that incorporate a pharmaceutically interesting thienodiazepine moiety.</p>","PeriodicalId":14,"journal":{"name":"ACS Combinatorial Science","volume":null,"pages":null},"PeriodicalIF":3.784,"publicationDate":"2020-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1021/acscombsci.0c00173","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"961873","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"TRAF2 and NCK-Interacting Kinase Inhibitors for Colorectal Cancer: In Vitro and Theoretical Validations","authors":"Sherlin Rosita Arokiaraj,&nbsp;Nargis Begum Tajuddin*,&nbsp;Karthikeyan Muthusamy,&nbsp;John Marshal Jayaraj,&nbsp;Manikandan Alagumuthu*","doi":"10.1021/acscombsci.0c00027","DOIUrl":"https://doi.org/10.1021/acscombsci.0c00027","url":null,"abstract":"<p >TRAF2 and NCK-interacting kinase (TNIK) is a critical factor in colorectal cancer (CRC) proliferation mediated by <i>Wnt</i> signaling. We attempted to identify efficient TNIK inhibitors using computational high-throughput virtual screening (HTVS) from various drug banks and databases. By performing/on performing e-pharmacophore screening and molecular docking methods, from ～700?000 molecules, compounds LC_222150, LC_112060, and LC_64796 were identified as potential leads, through molecular dynamics (MD) simulations and density functional theory (DFT). These top 3 structures were commercially procured, and their inhibitory activity was assessed in vitro. Significant TNIK inhibition was observed, with an average IC₅₀ of 18.33 ± 0.75 nM. In terms of anticancer activity, the observed average relative % activity (RPA) of 90.28 ± 1.04 for these compounds compared well with doxorubicin (86.75 ± 1.45) as a standard. Compounds LC_222150, LC_112060, and LC_64796, therefore, warrant further evaluation in vivo to assess their CRC therapeutic effects.</p>","PeriodicalId":14,"journal":{"name":"ACS Combinatorial Science","volume":null,"pages":null},"PeriodicalIF":3.784,"publicationDate":"2020-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1021/acscombsci.0c00027","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"1427411","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}