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1. Dalton Trans. 2024 Oct 18. doi: 10.1039/d4dt02538e. Online ahead of print. Direct O(2) mediated oxidation of a Ni(II)N(3)O structural model complex for the active site of nickel acireductone dioxygenase (Ni-ARD): characterization, biomimetic reactivity, and enzymatic implications. Kirsch KE(1), Little ME(2), Cundari TR(3), El-Shaer E(2), Barone G(2), Lynch VM(4), Toledo SA(1). Author information: (1)Department of Chemistry, American University, 4400 Massachusetts Ave NW, Washington, DC, 20016, USA. stoledo@american.edu. (2)Department of Chemistry, St Edward's University, 3001 South Congress Ave, Austin, Texas 78704, USA. (3)Department of Chemistry, University of North Texas, 1155 Union Cir, Denton, Texas 76203, USA. (4)Department of Chemistry, The University of Texas at Austin, 120 Inner Campus Dr Stop G2500, Austin, Texas 78712, USA. A new biomimetic model complex of the active site of acireductone dioxygenase (ARD) was synthesized and crystallographically characterized ([Ni(ii)(N-(ethyl-N'Me2)(Py)(2-t-ButPhOH))(OTf)]-1). 1 displays carbon-carbon oxidative cleavage activity in the presence of O2 towards the substrate 2-hydroxyacetophenone. This reactivity was monitored via UV-Visible and NMR spectroscopy. We postulate that the reactivity of 1 with O2 leads to the formation of a putative Ni(III)-superoxo transient species resulting from the direct activation of O2via the nickel center during the oxidative reaction. This proposed intermediate and reaction mechanism were studied in detail using DFT calculations. 1 and its substrate bound derivatives display reactivity toward mild outer sphere oxidants, suggesting ease of access to high valent Ni coordination complexes, consistent with our calculations. If confirmed, the direct activation of O2 at a nickel center could have implications for the mechanism of action of ARD and other nickel-based dioxygenases and their respective non-traditional, enzymatic moonlighting functions, as well as contribute to a general understanding of direct oxidation of nickel(II) coordination complexes by O2. DOI: 10.1039/d4dt02538e PMID: 39421893 2. Molecules. 2024 Oct 1;29(19):4670. doi: 10.3390/molecules29194670. N-Oxide Coordination to Mn(III) Chloride. Saju A(1), Crawley MR(1), MacMillan SN(2), Le Magueres P(3), Del Campo M(3), Lacy DC(1). Author information: (1)Department of Chemistry, University at Buffalo, State University of New York, Buffalo, NY 14260, USA. (2)Department of Chemistry and Chemical Biology, Cornell University, Ithaca, NY 14853, USA. (3)Rigaku Americas, The Woodlands, TX 77381, USA. We report on the synthesis and characterization of Mn(III) chloride (MnIIICl3) complexes coordinated with N-oxide ylide ligands, namely trimethyl-N-oxide (Me3NO) and pyridine-N-oxide (PyNO). The compounds are reactive and, while isolable in the solid-state at room temperature, readily decompose into Mn(II). For example, "[MnIIICl3(ONMe3)n]" decomposes into the 2D polymeric network compound complex salt [MnII(µ-Cl)3MnII(µ-ONMe3)]n[MnII(µ-Cl)3]n·(Me3NO·HCl)3n (4). The reaction of MnIIICl3 with PyNO forms varied Mn(III) compounds with PyNO coordination and these react with hexamethylbenzene (HMB) to form the chlorinated organic product 1-cloromethyl-2,3,4,5,6-pentamethylbenzene (8). In contrast to N-oxide coordination to Mn(III), the reaction between [MnIIICl3(OPPh3)2] and 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) resulted in electron transfer-forming d5 manganate of the [TEMPO] cation instead of TEMPO-Mn(III) adducts. The reactivity affected by N-oxide coordination is discussed through comparisons with other L-MnIIICl3 complexes within the context of reduction potential. DOI: 10.3390/molecules29194670 PMCID: PMC11477729 PMID: 39407599 Conflict of interest statement: The authors declare no conflicts of interest. 3. Langmuir. 2024 Oct 15;40(41):21407-21426. doi: 10.1021/acs.langmuir.4c02171. Epub 2024 Oct 6. A Study Modeling Bridged Nucleic Acid-Based ASOs and Their Impact on the Structure and Stability of ASO/RNA Duplexes. Dowerah D(1), V N Uppuladinne M(2), Paul S(1)(3), Das D(1), Gour NK(1), Biswakarma N(1), Sarma PJ(1)(4), Sonavane UB(2), Joshi RR(2), Ray SK(5)(6), Deka RC(1)(6). Author information: (1)CMML-Catalysis and Molecular Modelling Lab, Department of Chemical Sciences, Tezpur University, Napaam, Sonitpur, Assam 784028, India. (2)HPC - Medical & Bioinformatics Applications Group, Centre for Development of Advanced Computing (C-DAC), Panchavati, Pashan, Pune 411008, India. (3)Department of Chemistry, Assam University, Silchar, Assam 788011, India. (4)Department of Chemistry, Gargaon College, Simaluguri, Sivasagar, Assam 785686, India. (5)Department of Molecular Biology and Biotechnology, Tezpur University, Napaam, Sonitpur, Assam 784028, India. (6)Center for Multidisciplinary Research, Tezpur University, Napaam, Sonitpur, Assam 784028, India. Antisense medications treat diseases that cannot be treated using traditional pharmacological technologies. Nucleotide monomers of bare and phosphorothioate (PS)-modified LNA, N-MeO-amino-BNA, 2',4'-BNANC[NH], 2',4'-BNANC[NMe], and N-Me-aminooxy-BNA antisense modifications were considered for a detailed DFT-based quantum chemical study to estimate their molecular-level structural and electronic properties. Oligomer hybrid duplex stability is described by performing an elaborate MD simulation study by incorporating the PS-LNA and PS-BNA antisense modifications onto 14-mer ASO/RNA hybrid gapmer type duplexes targeting protein PTEN mRNA nucleic acid sequence (5'-CTTAGCACTGGCCT-3'/3'-GAAUCGUGACCGGA-5'). Replica sets of MD simulations were performed accounting to two data sets, each set simulated for 1 μs simulation time. Bulk properties of oligomers are regulated by the chemical properties of their monomers. As such, the primary goal of this work focused on establishing an organized connection between the monomeric BNA nucleotide's electronic effects observed in DFT studies and the macroscopic behavior of the BNA antisense oligomers, as observed in MD simulations. The results from this study predicted that spatial orientation of MO-isosurfaces of the BNA nucleotides are concentrated in the nucleobase region. These BNA nucleotides may become less accessible for various electronic interactions when coupled as ASOs forming duplexes with target RNAs and when the ASO/RNA duplexes further bind with the RNase H. Understanding such electronic interactions is crucial to design superior antisense modifications with specific electronic properties. Also, for the particular nucleic acid sequence solvation of the duplexes although were higher compared to the natural oligonucleotides, their binding energies being relatively lower may lead to decreased antisense activity compared to existing analogs such as the LNAs and MOEs. Fine tuning these BNAs to obtain superior binding affinity is thus a necessity. DOI: 10.1021/acs.langmuir.4c02171 PMID: 39370641 [Indexed for MEDLINE] 4. J Pept Sci. 2024 Sep 11:e3654. doi: 10.1002/psc.3654. Online ahead of print. Combination of the amide-to-triazole substitution strategy with alternative structural modifications for the metabolic stabilization of tumor-targeting, radiolabeled peptides. Guarrochena X(1)(2)(3), Anderla M(1)(2)(3)(4), Salomon P(1)(4), Feiner IVJ(1)(3)(5), Nock BA(6), Maina T(6), Mindt TL(1)(3)(4). Author information: (1)Institute of Inorganic Chemistry, Faculty of Chemistry, University of Vienna, Vienna, Austria. (2)Vienna Doctoral School in Chemistry, University of Vienna, Vienna, Austria. (3)Department of Biomedical Imaging and Image Guided Therapy, Division of Nuclear Medicine, Medical University of Vienna, Vienna, Austria. (4)Joint Applied Medicinal Radiochemistry Facility, University of Vienna and Medical University of Vienna, Vienna, Austria. (5)Ludwig Boltzmann Institute Applied Diagnostics, Vienna, Austria. (6)Molecular Radiopharmacy, INRaSTES, NCSR "Demokritos", Athens, Greece. Radiolabeled peptides play a key role in nuclear medicine to selectively deliver radionuclides to malignancies for diagnosis (imaging) and therapy. Yet, their efficiency is often compromised by low metabolic stability. The use of 1,4-disubstituted 1,2,3-triazoles (1,4-Tzs) as stable amide bond bioisosteres can increase the half-life of peptides in vivo while maintaining their biological properties. Previously, the amide-to-triazole substitution strategy was used for the stabilization of the pansomatostatin radioligand [111In]In-AT2S, resulting in the mono-triazolo-peptidomimetic [111In]In-XG1, a radiotracer with moderately enhanced stability in vivo and retained ability to bind multiple somatostatin receptor (SSTR) subtypes. However, inclusion of additional 1,4-Tz led to a loss of affinity towards SST2R, the receptor overexpressed by most SSTR-positive cancers. To enhance further the stability of [111In]In-XG1, alternative modifications at the enzymatically labile position Thr10-Phe11 were employed. Three novel 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA)-peptide conjugates were synthesized with a 1,4-Tz (Asn5-Ψ[Tz]-Phe6) and either a β-amino acid (β-Phe11), reduced amide bond (Thr10-Ψ[NH]-Phe11), or N-methylated amino acid (N-Me-Phe11). Two of the new peptidomimetics were more stable in blood plasma in vitro than [111In]In-XG1. Yet none of them retained high affinity towards SST2R. We demonstrate for the first time the combination of the amide-to-triazole substitution strategy with alternative stabilization methods to improve the metabolic stability of tumor-targeting peptides. © 2024 The Author(s). Journal of Peptide Science published by European Peptide Society and John Wiley & Sons Ltd. DOI: 10.1002/psc.3654 PMID: 39262129 5. RSC Adv. 2024 Aug 28;14(37):27372-27384. doi: 10.1039/d4ra05347h. eCollection 2024 Aug 22. Integrated synthesis of 3,4-carbazoquinone alkaloids N-Me-carbazoquinocin A, B and D-F. Bommanaboina B(1), Roy D(1), Baire B(1). Author information: (1)Department of Chemistry, Indian Institute of Technology Madras Chennai-600036 Tamil Nadu India beeru@iitm.ac.in. Carbazole alkaloids carbazoquinocin A-F possessing a 1-alkyl-2-methyl-3,4-ortho-carabazoquinone framework were isolated from the microorganism Streptomyces violaceus 2448-SVT2 in 1995. Furthermore, they were found to exhibit strong inhibitory activity against lipid peroxidation. Herein, we report the integrated synthesis of N-Me-analogues of 5 members of the carbazoquinocin family of natural products, namely, N-Me-carbazoquinocin A, B and D-F. We employed an acid-catalyzed, intramolecular benzannulation of indole-appended Z-enoate propargylic alcohols, which was developed earlier in our laboratory, for the construction of the required carbazole framework. All five natural products were obtained in an overall yield of 50-60%, starting from a commercially available indole. This journal is © The Royal Society of Chemistry. DOI: 10.1039/d4ra05347h PMCID: PMC11350554 PMID: 39205936 Conflict of interest statement: The authors declare no competing financial interest.