- Stereo-specific modulation of the extracellular calcium-sensing receptor in colon cancer cells
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Pharmacological allosteric agonists (calcimimetics) of the extracellular calcium-sensing receptor (CaSR) have substantial gastro-intestinal side effects and induce the expression of inflammatory markers in colon cancer cells. Here, we compared the effects of both CaSR-specific (R enantiomers) and-unspecific (S enantiomers) enantiomers of a calcimimetic (NPS 568) and a calcilytic (allosteric CaSR antagonists; NPS 2143) to prove that these effects are indeed mediated via the CaSR, rather than via off-target effects, e.g., on β-adrenoceptors or calcium channels, of these drugs. The unspecific S enantiomer of NPS 2143 and NPS S-2143 was prepared using synthetic chemistry and characterized using crystallography. NPS S-2143 was then tested in HEK-293 cells stably transfected with the human CaSR (HEK-CaSR), where it did not inhibit CaSR-mediated intracellular Ca2+ signals, as expected. HT29 colon cancer cells transfected with the CaSR were treated with both enantiomers of NPS 568 and NPS 2143 alone or in combination, and the expression of CaSR and the pro-inflammatory cytokine interleukin 8 (IL-8) was measured by RT-qPCR and ELISA. Only the CaSR-selective enantiomers of the calcimimetic NPS 568 and NPS 2143 were able to modulate CaSR and IL-8 expression. We proved that pro-inflammatory effects in colon cancer cells are indeed mediated through CaSR activation. The non-CaSR selective enantiomer NPS S-2143 will be a valuable tool for investigations in CaSR-mediated processes.
- Bassetto, Marcella,Iamartino, Luca,Kallay, Enik?,Kariuki, Benson M.,Kupper, Nadja,Manhardt, Teresa,Mansfield, Bethan,Piatek, Karina,Riccardi, Daniela,Schepelmann, Martin,Sladczyk, Marta
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- Design, synthesis, and antibacterial evaluation of novel derivatives of NPS-2143 for the treatment of methicillin-resistant S. aureus (MRSA) infection
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Methicillin-resistant Staphylococcus aureus (MRSA) infections are a significant global health challenge due to the emergence of strains exhibiting resistance to nearly all classes of antibiotics. This necessitates the rapid development of novel antimicrobials to circumvent this critical problem. Screening of compounds based on phenotypes is one of the major strategies for finding new antibiotics at present. Hence, we here performed a phenotypic screening against MRSA and identified NPS-2143 exhibiting activity against MRSA with an MIC value of 16 μg ml?1. In order to discover more potent anti-MRSA agents, a series of derivatives of NPS-2143 were designed and synthesized. The most promising compounds 48 and 49 exhibited favorable antimicrobial activity with an MIC value of 2 μg ml?1.
- Chen, Yao,Ju, Yuan,Li, Chungen,Yang, Tao,Deng, Yong,Luo, Youfu
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p. 545 - 554
(2019/04/10)
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- Synthesis of the calcilytic ligand NPS 2143
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(R)-3 (NPS 2143) is a negative allosteric modulator of the human calcium-sensing receptor (CaSR) and as such represents an important pharmacological tool compound for studying the CaSR. Herein, we disclose for the first time a complete experimental description, detailed characterisation and assessment of enantiomeric purity for (R)-3. An efficient, reproducible and scalable synthesis of (R)-3 that requires a minimum of chromatographic purification steps is presented. (R)-3 was obtained in excellent optical purity (er > 99:1) as demonstrated by chiral HPLC and the pharmacological profile for (R)-3 is in full accordance with that reported in the literature.
- Johansson, Henrik,Cailly, Thomas,Thomsen, Alex Rojas Bie,Braeuner-Osborne, Hans,Pedersen, Daniel Sejer
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supporting information
p. 1383 - 1387
(2013/08/23)
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- Chemoenzymatic synthesis of calcilytic agent NPS-2143 employing a lipase-mediated resolution protocol
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The kinetic resolution of chlorohydrin (±)-6 has been successfully carried out via a lipase-mediated transesterification with vinyl acetate in organic as well as ionic liquid media to yield (R)-alcohol 6 and (S)-acetate 7 in high enantioselectivity. An en
- Kamal, Ahmed,Chouhan, Gagan
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p. 2784 - 2789
(2007/10/03)
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