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Raloxifene, a selective oestrogen receptor modulator (SERM), has demonstrated efficacy in the prevention and therapy of oestrogen receptor-positive (ER+) breast cancer, with some degree of effectiveness against triple-negative forms. This suggests the presence of oestrogen receptor-independent pathways in raloxifene-mediated anticancer activity. To enhance the potential of raloxifene against the most aggressive breast cancer cells, hybrid molecules combining the drug with a metal chelator moiety have been developed. In this study, we synthetically modified the structure of raloxifene by incorporating a 2,2′-bipyridine (2,2′-bipy) moiety, resulting in [6-methoxy-2-(4-hydroxyphenyl)benzo[b]thiophen-3-yl]-[4-(2,2′-bipyridin-4′-yl-methoxy)phenyl]methanone (bipyraloxifene). We investigated the cytotoxic activity of both raloxifene and bipyraloxifene against ER+ breast adenocarcinomas, glioblastomas, and a triple-negative breast cancer (TNBC) cell line, elucidating their mode of action against TNBC. Bipyraloxifene maintained a mechanism based on caspase-mediated apoptosis but exhibited significantly higher activity and selectivity compared to the original drug, particularly evident in triple-negative stem-like MDA-MB-231 cells.

The development of cannabinoid receptor type 2 (CB2R) radioligands for positron emission tomography (PET) imaging was intensively explored. To overcome the low metabolic stability and simultaneously increase the binding affinity of known CB2R 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 CB2R ligands. All tested compounds showed low nanomolar CB2R affinity, with (Z)-N-[3-(4-fluorobutyl)-4,5-dimethylthiazole-2(3H)-ylidene]-(1,7-dicarba-closo-dodecaboranyl)-carboxamide (LUZ5) exhibiting the highest affinity (0.8 nM). Compound [18F]LUZ5-d8was obtained with an automated radiosynthesizer in high radiochemical yield and purity. In vivoevaluation revealed the improved metabolic stability of [18F]LUZ5-d8compared to that of [18F]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 CB2R ligands and gaining access to a new class of high-affinity CB2R ligands, while the in vivopharmacology still needs to be addressed.

For decades, tamoxifen-based hormone therapy has effectively addressed oestrogen receptor positive (ER+) luminal A breast cancer. Nonetheless, the emergence of tamoxifen resistance required innovative approaches, leading to hybrid metallodrugs with several therapeutic effects besides the inhibition of oestrogen receptor α (ERα). Drawing inspiration from tamoxifen metabolite structures (4-hydroxytamoxifen and 4,4′-dihyroxytamoxifen), a phenyl ring was replaced by a bidentate 2,2′-bipyridine donor moiety to give 4-[1,1-bis(4-methoxyphenyl)but-1-en-2-yl]-2,2′-bipyridine (L), enabling coordination of bioactive transition metal compounds such as copper(ii) dichloride, yielding [CuCl(μ-Cl)(L-κ2N,N′)]2(1). Notably, copper(ii) complex 1exhibited remarkable activity within the low micromolar concentration range against ER+ human glioblastoma U251, as well as breast carcinomas MDA-MB-361 and MCF-7, surpassing the efficacy of previously reported palladium(ii) and platinum(ii) dichloride analogs against these cell lines. The pronounced efficacy of complex 1against triple-negative MDA-MB-231 cells highlights its potential multitherapeutic approach, evident through induction of apoptosis and antioxidant activity. This study evaluates the potential of copper–tamoxifen hybrid complex 1as a potent therapeutic candidate, highlighting its diverse mechanism of action against challenging breast cancer subtypes.

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 (Ki= 2.1 nM) and selectivity over CB1R (factor > 300). Preliminary in vitroevaluation of [18F]RM365 indicated species differences in the binding to CB2R (KDof 2.32 nM for the hCB2R vs KD> 10,000 nM for the rCB2R). Metabolism studies in mice revealed a high in vivo stability of [18F]RM365. PET imaging in a rat model of local hCB2R(D80N) overexpression in the brain demonstrates the ability of [18F]RM365 to reach and selectively label the hCB2R(D80N) with a high signal-to-background ratio. Thus, [18F]RM365 is a very promising PET radioligand for the imaging of upregulated hCB2R expression under pathological conditions.

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 PdIIinto the softer tridentate N,N,Ppocket, yielding monometallic complex 2. A second reaction with a 3d transition metal complex precursor (groups 7 to 12) fills the vacant N,N,Npocket and thus provides a variety of heterobimetallic complexes of the type PdII/MII(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 μ2-chlorido-bridged dimers was observed for complexes 5–7in the solid state, while DOSY NMR experiments have shown that 5–7are unbridged monomers in solution. As an exception, FeIIprefers 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.