Thermal treatment of indenyl-functionalized imidazolium salts and N-heterocyclic carbenes with Ru3(CO)12 gave different products. The normal mononuclear metal complexes (2a, 2b) were obtained via direct reaction of indenyl-functionalized imidazolium salts (1a, 1b) with Ru3(CO)12. Unexpected intramolecular C-H activated products (3a, 3b, 4a, 4b) were obtained via thermal treatment of corresponding indenyl-functionalized N-heterocyclic carbenes. All complexes were determined by 1H NMR, 13C NMR, IR spectra and elemental analysis. The molecular structures of 2b, 3a, 3b and 4b were determined by X-ray diffraction.
Targeting tumors using miniature antibodies is a novel and attractive therapeutic approach, as these biomolecules exhibit low immunogenicity, rapid clearance, and high targeting specificity. However, most of the small-sized antibodies in existence do not exhibit marked anti-tumor effects, which limit their use in targeted cancer immunotherapy. To overcome this difficulty in targeting multiple biomarkers by combination therapies, we designed a new bifunctional antibody, named MaAbNA (multivalent antibody comprised of nanobody and affibody moieties), capable of targeting EGFR1 and HER2, which are widely overexpressed in a variety of tumor types. The small-sized (29 kDa) MaAbNA, which was expressed in E.coli, consists of one anti-EGFR1 nanobody and two anti-HER2 affibodies, and possesses high affinity (KD) for EGFR1 (~4.1 nM) and HER2 (~4.7 nM). In order to enhance its anti-tumor activity, MaAbNA was conjugated with adriamycin (ADM) using a PEG2000 linker, forming a new complex anticancer drug, MaAbNA-PEG2000-ADM. MaAbNA exhibited high inhibitory effects on tumor cells over-expressing both EGFR1 and HER2, but displayed minimal cytotoxicity in cells expressing low levels of EGFR1 and HER2. Moreover, MaAbNA-PEG2000-ADM displayed increased tumoricidal effects than ADM or MaAbNA alone, as well exhibited greater antitumor efficacy than EGFR1 (Cetuximab) and HER2 (Herceptin) antibody drugs. The ability of MaAbNA to regulate expression of downstream oncogenes c-jun, c-fos, c-myc, as well as AEG-1 for therapeutic potential was evaluated by qPCR and western-blot analyses. The antitumor efficacy of MaAbNA and its derivative MaAbNA-PEG2000-ADM were validated in vivo, highlighting the potential for use of MaAbNA as a highly tumor-specific dual molecular imaging probe and targeted cancer therapeutic.
Development of alternative linear peptides for targeting αvβ3 integrin has attracted much attention, as the traditional peptide ligand, cyclic RGD, is limited by inferior water-solubility and complex synthesis. Using pharmacophore-based virtual screening and high-throughput molecular docking, we identified two novel linear small peptides RWr and RWrNM with high affinity and specificity to αvβ3 integrin. The competitive binding with cyclic RGD (c(RGDyK)) and cellular uptake related to the integrin expression levels verified their affinity to αvβ3 integrin. The intermolecular interaction measurement and dynamics simulation demonstrated the high binding affinity and stability, especially for RWrNM. In vivo peptide-guided tumor imaging and targeted therapy further confirmed their specificity. Results indicated that the newly identified small linear peptide RWrNM, with high affinity and specificity to αvβ3 integrin, better water-solubility, and simplified synthetic process, could overcome limitations of the current cyclic RGD peptides, paving the way for diverse use in diagnosis and therapy.
Reactions of a series of unsymmetrically substituted N-heterocyclic carbene ligands with Ru3(CO)12 afforded a variety of mononuclear (1, 2), trinuclear (3, 4, 5, and 5′), and tetranuclear (6, 7) ruthenium complexes via intramolecular ruthenium-mediated sp2 and sp3 C–H bond activations. Complexes 6 and 7 include an octahedral cluster skeleton consisting of four ruthenium atoms and two metalated carbon atoms. The formation of this type of ruthenium clusters is proposed to involve the initial C–C double-bond migration and subsequent sp2 C–H bond activations. All new complexes were fully characterized, and the molecular structures of 1, 2, 5, 6, and 7 were determined by X-ray diffraction analysis.
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