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Keywords: Carboranes; Homogeneous Catalysis; Ligand Design; Phosphines; Strong Donors; Transition Metal Complexes EN Carboranes Homogeneous Catalysis Ligand Design Phosphines Strong Donors Transition Metal Complexes 1 1 1 03/23/23 20230327 NES 230327 B Carboranes b . Frontispiece: On the Edge of the Known: Extremely Electron-Rich (Di)Carboranyl Phosphines Carboranes, Homogeneous Catalysis, Ligand Design, Phosphines, Strong Donors, Transition Metal Complexes. [Extracted from the article]

Computational protein design is becoming increasingly helpful in the development of new protein therapeutics with enhanced efficacy, specificity, and minimal side effects, for precise modulation of biological pathways. In vascular biology, the interaction between vascular endothelial growth factor A (VEGFA) and its receptors (VEGFR1-R3) is a pivotal process underlying blood vessel growth. Dysregulation of this pathway contributes to diseases such as cancer and diabetic retinopathy. Existing VEGFA inhibitors are effective but have limitations, driving interest in peptide-based therapeutics. Peptide inhibitors offer advantages, including reduced toxicity, improved formulation flexibility, and enhanced stability. This study leverages computational tools, particularly ProteinMPNN and Rosetta, to design optimized peptide-based VEGFA inhibitors. Building on the existing peptide templates mini-Z-1 and Z-1-2, new sequences were computationally predicted and experimentally validated. A novel peptide with improved affinity (KD = 6.2 µM) compared to mini-Z-1 (KD = 9.3 µM) was found, requiring only one round of design and testing. The integration of ProteinMPNN and Rosetta enabled a rapid and cost-effective pipeline for designing potent VEGFA inhibitors, underscoring the potential of computational peptide design in developing next-generation therapeutics targeting angiogenesis-dependent diseases.

Triple-negative breast cancer (TNBC) poses challenges in therapy due to the absence of target expression such as estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). Frequently, the treatment of TNBC involves the combination of several therapeutics. However, an enhanced therapeutic effect can be also achieved within a single molecule. The efficacy of raloxifene can be improved by designing a raloxifene-based hybrid drug bearing a 2,2'-bipyridine moiety (2). Integration of platinum(II), palladium(II), and nickel(II) complexes into this structure dramatically changed the cytotoxicity. The platinum(II) dichloride complex 3 did not demonstrate any activity, while palladium(II) and nickel(II) dichloride complexes 4 and 5 exhibited various cytotoxic behavior towards different types of hormone-receptor positive (HR+) cancer and TNBC cell lines. The replacement of the two chlorido ligands in 3-5 with a dicarbollide (carborate) ion [C 2 B 9 H 11 ] 2- resulted in reduced activity of compounds 6, 7, and 8. However, the palladacarborane complex 7 demonstrated higher selectivity towards TNBC. Furthermore, the mechanism of action was shifted from cytotoxic to explicitly cytostatic with detectable proliferation arrest and accelerated aging, characterized by senescence-associated phenotype of TNBC cells. This study provides valuable insights into the development of hybrid therapeutics against TNBC., (© 2024 The Authors. ChemMedChem published by Wiley-VCH GmbH.)

The development of cannabinoid receptor type 2 (CB2R) PET radioligands has been intensively explored due to the pronounced CB2R upregulation under various pathological conditions. Herein, we report on the synthesis of a series of CB2R affine fluorinated indole-2-carboxamide ligands. Compound RM365 was selected for PET radiotracer development due to its high CB2R affinity ( K i = 2.1 nM) and selectivity over CB1R (factor > 300). Preliminary in vitro evaluation of [ 18 F]RM365 indicated species differences in the binding to CB2R ( K D of 2.32 nM for the hCB2R vs K D > 10,000 nM for the rCB2R). Metabolism studies in mice revealed a high in vivo stability of [ 18 F]RM365. PET imaging in a rat model of local hCB2R(D80N) overexpression in the brain demonstrates the ability of [ 18 F]RM365 to reach and selectively label the hCB2R(D80N) with a high signal-to-background ratio. Thus, [ 18 F]RM365 is a very promising PET radioligand for the imaging of upregulated hCB2R expression under pathological conditions.

The development of cannabinoid receptor type 2 (CB 2 R) radioligands for positron emission tomography (PET) imaging was intensively explored. To overcome the low metabolic stability and simultaneously increase the binding affinity of known CB 2 R radioligands, a carborane moiety was used as a bioisostere. Here we report the synthesis and characterization of carborane-based 1,8-naphthyridinones and thiazoles as novel CB 2 R ligands. All tested compounds showed low nanomolar CB 2 R affinity, with ( Z )- N -[3-(4-fluorobutyl)-4,5-dimethylthiazole-2(3 H )-ylidene]-(1,7-dicarba- closo -dodecaboranyl)-carboxamide ( LUZ5 ) exhibiting the highest affinity (0.8 nM). Compound [ 18 F]LUZ5- d 8 was obtained with an automated radiosynthesizer in high radiochemical yield and purity. In vivo evaluation revealed the improved metabolic stability of [ 18 F]LUZ5- d 8 compared to that of [ 18 F]JHU94620 . PET experiments in rats revealed high uptake in spleen and low uptake in brain. Thus, the introduction of a carborane moiety is an appropriate tool for modifying literature-known CB 2 R ligands and gaining access to a new class of high-affinity CB 2 R ligands, while the in vivo pharmacology still needs to be addressed.

A facile two-step synthesis of bis(1-methylhydrazinyl)pyrimidine from pyridine-2-carbaldehyde and 2-diphenylphosphanylbenzaldehyde gave access to the new asymmetric ligand 1 . The phosphane selectively guides Pd II into the softer tridentate N , N , P pocket, yielding monometallic complex 2 . A second reaction with a 3d transition metal complex precursor (groups 7 to 12) fills the vacant N , N , N pocket and thus provides a variety of heterobimetallic complexes of the type Pd II /M II (M = Mn ( 3 ), Fe ( 4 ), Co ( 5 ), Ni ( 6 ), Cu ( 7 ), Zn ( 8 )). Single-crystal X-ray diffraction studies were performed for all complexes. The assembly of μ 2 -chlorido-bridged dimers was observed for complexes 5 - 7 in the solid state, while DOSY NMR experiments have shown that 5 - 7 are unbridged monomers in solution. As an exception, Fe II prefers to form the homoleptic meridional complex [Fe{PdCl( 1 )} 2 ](OTf) 4 ( 4 ). The electrochemical behavior and the effective magnetic moment in solution were investigated for all complexes by cyclic voltammetry and Evans method, respectively. Experimental UV/vis results were interpreted by performing TD-DFT calculations on 1 , 2 , and 3 .