12 research outputs found
Bipyraloxifene – a modified raloxifene vector against triple-negative breast cancer
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
Supplementary materials for: Metallodrugs against Breast Cancer: Combining the Tamoxifen Vector with Platinum(II) and Palladium(II) Complexes
The luminal A-subtype of breast cancer, where the oestrogen receptor α (ERα) is overexpressed, is the most frequent one. The prodrug tamoxifen (1) is the clinically used agent, inhibiting the ERα activity via the formation of several active metabolites, such as 4-hydroxytamoxifen (2) or 4,4′-dihydroxytamoxifen (3). In this study, we present the tamoxifen derivative 4-[1,1-bis(4-methoxyphenyl)but-1-en-2-yl]-2,2′-bipyridine (4), which was combined with platinum or palladium dichloride, the former a well-known scaffold in anticancer treatment, to give [PtCl2(4-κ2N,N′)] (5) or [PdCl2(4-κ2N,N′] (6). To prevent fast exchange of weakly coordinating chlorido ligands in aqueous solution, a bulky, highly stable and hydrophobic nido-carborate(−2) ([C2B9H11]2−) was incorporated. The resulting complexes [3-(4-κ2N,N′)-3,1,2-PtC2B9H11] (7) and [3-(4-κ2N,N′)-3,1,2-PdC2B9H11] (8) exhibit a dramatic change in electronic and biological properties compared to 5 and 6. Thus, 8 is highly selective for triple-negative MDA-MB-231 cells (IC50 = 3.7 μM, MTT test), while 7 is completely inactive against this cell line. The observed cytotoxicity of compounds 4–6 and 8 against this triple-negative cell line suggests off-target mechanisms rather than only ERα inhibition, for which these compounds were originally designed. Spectroscopic properties and electronic structures of the metal complexes were investigated for possible explanations of the biological activities.Related to published version: [https://cherry.chem.bg.ac.rs/handle/123456789/5892]Supplementary material for: [https://doi.org/10.3390/pharmaceutics15020682
Metallodrugs against Breast Cancer: Combining the Tamoxifen Vector with Platinum(II) and Palladium(II) Complexes
The luminal A-subtype of breast cancer, where the oestrogen receptor α (ERα) is overexpressed, is the most frequent one. The prodrug tamoxifen (1) is the clinically used agent, inhibiting the ERα activity via the formation of several active metabolites, such as 4-hydroxytamoxifen (2) or 4,4′-dihydroxytamoxifen (3). In this study, we present the tamoxifen derivative 4-[1,1-bis(4-methoxyphenyl)but-1-en-2-yl]-2,2′-bipyridine (4), which was combined with platinum or palladium dichloride, the former a well-known scaffold in anticancer treatment, to give [PtCl2(4-κ2N,N′)] (5) or [PdCl2(4-κ2N,N′] (6). To prevent fast exchange of weakly coordinating chlorido ligands in aqueous solution, a bulky, highly stable and hydrophobic nido-carborate(−2) ([C2B9H11]2−) was incorporated. The resulting complexes [3-(4-κ2N,N′)-3,1,2-PtC2B9H11] (7) and [3-(4-κ2N,N′)-3,1,2-PdC2B9H11] (8) exhibit a dramatic change in electronic and biological properties compared to 5 and 6. Thus, 8 is highly selective for triple-negative MDA-MB-231 cells (IC50 = 3.7 μM, MTT test), while 7 is completely inactive against this cell line. The observed cytotoxicity of compounds 4–6 and 8 against this triple-negative cell line suggests off-target mechanisms rather than only ERα inhibition, for which these compounds were originally designed. Spectroscopic properties and electronic structures of the metal complexes were investigated for possible explanations of the biological activities
Correction: Kazimir et al. Metallodrugs against Breast Cancer: Combining the Tamoxifen Vector with Platinum(II) and Palladium(II) Complexes. <i>Pharmaceutics</i> 2023, <i>15</i>, 682
In the original publication [...
Development of the High-Affinity Carborane-Based Cannabinoid Receptor Type 2 PET Ligand [<sup>18</sup>F]LUZ5‑<i>d</i><sub>8</sub>
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-d8 was obtained with an automated radiosynthesizer
in high radiochemical yield and purity. In vivo evaluation
revealed the improved metabolic stability of [18F]LUZ5-d8 compared 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 vivo pharmacology
still needs to be addressed
Development of the High-Affinity Carborane-Based Cannabinoid Receptor Type 2 PET Ligand [<sup>18</sup>F]LUZ5‑<i>d</i><sub>8</sub>
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-d8 was obtained with an automated radiosynthesizer
in high radiochemical yield and purity. In vivo evaluation
revealed the improved metabolic stability of [18F]LUZ5-d8 compared 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 vivo pharmacology
still needs to be addressed
Development of the High-Affinity Carborane-Based Cannabinoid Receptor Type 2 PET Ligand [<sup>18</sup>F]LUZ5‑<i>d</i><sub>8</sub>
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-d8 was obtained with an automated radiosynthesizer
in high radiochemical yield and purity. In vivo evaluation
revealed the improved metabolic stability of [18F]LUZ5-d8 compared 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 vivo pharmacology
still needs to be addressed
Development of the High-Affinity Carborane-Based Cannabinoid Receptor Type 2 PET Ligand [<sup>18</sup>F]LUZ5‑<i>d</i><sub>8</sub>
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-d8 was obtained with an automated radiosynthesizer
in high radiochemical yield and purity. In vivo evaluation
revealed the improved metabolic stability of [18F]LUZ5-d8 compared 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 vivo pharmacology
still needs to be addressed
Development of the High-Affinity Carborane-Based Cannabinoid Receptor Type 2 PET Ligand [<sup>18</sup>F]LUZ5‑<i>d</i><sub>8</sub>
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-d8 was obtained with an automated radiosynthesizer
in high radiochemical yield and purity. In vivo evaluation
revealed the improved metabolic stability of [18F]LUZ5-d8 compared 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 vivo pharmacology
still needs to be addressed
Development of the High-Affinity Carborane-Based Cannabinoid Receptor Type 2 PET Ligand [<sup>18</sup>F]LUZ5‑<i>d</i><sub>8</sub>
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-d8 was obtained with an automated radiosynthesizer
in high radiochemical yield and purity. In vivo evaluation
revealed the improved metabolic stability of [18F]LUZ5-d8 compared 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 vivo pharmacology
still needs to be addressed