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1. A Cationic Pt(II) Dinitrogen Adduct: Synthesis and Characterization of a CCC-aNHC Pincer Pt Complex with Abnormal N -Heterocyclic Carbene Donor Arms

   https://doi.org/10.1021/acs.organomet.3c00411  

   Fosu, Evans; Le, Nghia; Abdulraheem, Taofiq; Donnadieu, Bruno; Patrick, Amanda L.; Webster, Charles Edwin; Hollis, T. Keith (February 2024, Organometallics)

   In contrast to the reported CCC-NHC pincer ligands that contain normal N-heterocyclic carbenes (NHC), herein we report an imidazole-based abnormal NHC (aNHC) pincer ligand, CCC-aNHC. The CCC-aNHC pincer Pt complex with two aNHC donors was synthesized via the in situ metalation and transmetalation methodology. The 1,3-phenylene(bis-2-phenyl-3-butyl imidazolium) diiodide salt was reacted with Zr(NMe2)4 to generate a CCC-aNHC pincer zirconium complex in situ. It was transmetalated to Pt using [Pt(COD)Cl2]. Electrospray ionization of the Pt pincer complex [(BuCa‑iCa‑iCBu)-PtI] in acetonitrile generated an intense peak at m/z = 696.2375, which was assigned to the dinitrogen adduct [M−I+N2]+ of the cationic CCC-aNHC pincer Pt(II) complex [(BuCa‑iCa‑iCBu)Pt− N2]+, representing a rare example of the platinum dinitrogen organometallic complex. The super electron-donating ability of the pincer ligands with abnormal NHC enabled the cationic CCC-aNHC pincer Pt(II) complex to selectively bind N2 over MeCN in a first-order analysis. A collision-induced dissociation (CID) study was conducted on the N2 and MeCN adducts, suggesting that more energy was required to dissociate N2 than MeCN. A computational study suggested that the N2 adduct was kinetically stable in the gas phase whereas the MeCN adduct was thermodynamically preferred. The computational results reconciled the mass spectral data experiment with an attempt to isolate the N2 adduct. DFT computation suggested that N2 dissociation is more challenging due to higher energy transition states, and there is a competitive pathway of N2 tumbling within the coordination sphere of the Pt. This tumbling path is not available from the MeCN ligand due to ligand structural differences. 

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2. Indole N ‐Linked Hydroperoxyl Adduct of Protein‐Derived Cofactor Modulating Catalase‐Peroxidase Functions

   https://doi.org/10.1002/anie.202407018  

   Li, Jiasong; Duan, Ran; Traore, Ephrahime_S; Nguyen, Romie_C; Davis, Ian; Griffth, Wendell_P; Goodwin, Douglas_C; Jarzecki, Andrzej_A; Liu, Aimin (November 2024, Angewandte Chemie International Edition)

   Abstract Bifunctional catalase‐peroxidase (KatG) features a posttranslational methionine‐tyrosine‐tryptophan (MYW) crosslinked cofactor crucial for its catalase function, enabling pathogens to neutralize hydrogen peroxide during infection. We discovered the presence of indole nitrogen‐linked hydroperoxyl adduct (MYW‐OOH) inMycobacterium tuberculosisKatG in the solution state under ambient conditions, suggesting its natural occurrence. By isolating predominantly MYW‐OOH‐containing KatG protein, we investigated the chemical stability and functional impact of MYW‐OOH. We discovered that MYW‐OOH inhibits catalase activity, presenting a unique temporary lock. Exposure to peroxide or increased temperature removes the hydroperoxyl adduct from the protein cofactor, converting MYW‐OOH to MYW and restoring the detoxifying ability of the enzyme against hydrogen peroxide. Thus, theN‐linked hydroperoxyl group is releasable. KatG with MYW‐OOH represents a catalase dormant, but primed, state of the enzyme. These findings provide insight into chemical strategies targeting the bifunctional enzyme KatG in pathogens, highlighting the role ofN‐linked hydroperoxyl modifications in enzymatic function. 

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3. Design, Synthesis, and Mechanistic Studies of ( R )-3-Amino-5,5-difluorocyclohex-1-ene-1-carboxylic Acid as an Inactivator of Human Ornithine Aminotransferase

   https://doi.org/10.1021/acschembio.4c00022  

   Devitt, Allison N; Vargas, Abigail L; Zhu, Wei; Des_Soye, Benjamin James; Butun, Fatma Ayaloglu; Alt, Tyler; Kaley, Nicholas; Ferreira, Glaucio M; Moran, Graham R; Kelleher, Neil L; et al (May 2024, ACS Chemical Biology)

   He, Chuan (Ed.)

   Human ornithine aminotransferase (hOAT), a pyridoxal 5'-phosphate (PLP)-dependent enzyme, has been shown to play an essential role in the metabolic reprogramming and progression of hepatocellular carcinoma (HCC). HCC accounts for approximately 75% of primary liver cancers and is within the top three causes of cancer death worldwide. As a result of treatment limitations, the overall 5-year survival rate for all patients with HCC is under 20%. The prevalence of HCC necessitates continued development of novel and effective treatment methods. In recent years, the therapeutic potential of selective inactivation of hOAT has been demonstrated for the treatment of HCC. Inspired by previous increased selectivity for hOAT by the expansion of the cyclopentene ring scaffold to a cyclohexene, we designed, synthesized, and evaluated a series of novel fluorinated cyclohexene analogues and identified (R)-3-amino-5,5-difluorocyclohex-1-ene-1-carboxylic acid as a time-dependent inhibitor of hOAT. Structural and mechanistic studies have elucidated the mechanism of inactivation of hOAT by 5, resulting in a PLP-inactivator adduct tightly bound to the active site of the enzyme. Intact protein mass spectrometry, 19F NMR spectroscopy, transient state kinetic studies, and X-ray crystallography were used to determine the structure of the final adduct and elucidate the mechanisms of inactivation. Interestingly, despite the highly electrophilic intermediate species conferred by fluorine and structural evidence of solvent accessibility in the hOAT active site, Lys292 and water did not participate in nucleophilic addition during the inactivation mechanism of hOAT by 5. Instead, rapid aromatization to yield the final adduct was favored. 

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4. Synthesis and structure of 1′,4′-diphenyl-1a,1′,4′,4′′,5′′,9b-hexahydro-2′′ H -dispiro[cyclopropa[ l ]phenanthrene-1,2′-[1,4]epoxynaphthalene-3′,3′′-thiophene]

   https://doi.org/10.1107/S2056989025004104  

   Wen, Yuewei; Thamattoor, Dasan M (June 2025, Acta Crystallographica Section E Crystallographic Communications)

   The title compound, C₃₉H₃₀OS, was inadvertently prepared as a Diels–Alder adduct between 1,3-diphenylisobenzofuran and 3-(1a,9b-dihydro-1H-cyclopropa[l]phenanthren-1-ylidene)tetrahydrothiophene. A combination of fused, bridged, and spirocyclic ring systems are all featured within a single molecular structure of this highly crowded polycyclic compound. 

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5. Unorthodox crystalline drug salts via the reaction of amine-containing drugs with CO ₂

   https://doi.org/10.1039/C9CC06429J  

   Soltani, Mohammad; Mash, Brandon L.; Henseler, Julian; Badri, Sharhzad; Zeller, Matthias; Salter, E. Alan; Wierzbicki, Andrzej; Stenson, Alexandra C.; Davis, James H. (November 2019, Chemical Communications)

   Drugs containing amine groups react with CO 2 to form crystalline ammonium carbamates or carbamic acids. In this approach, both the cation and anion of the salt, or the neutral CO 2 adduct, are derived from the parent drug, generating new crystalline versions in a ‘masked’ or prodrug form. It is proposed that this approach may serve as a valuable new tool in engineering the physical properties of drugs for formulation purposes. 

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