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Expeditive Synthesis of Potent C20-epi-Amino Derivatives of Salinomycin against Cancer Stem-Like Cells.

ABSTRACT: As a continuation of our studies toward the development of small molecules to selectively target cancer stem cells (CSCs), a library of 18 novel derivatives of salinomycin (Sal), a naturally occurring polyether ionophore, was synthesized with a good overall yield using a one-pot Mitsunobu-Staudinger procedure. Compared to the parent structure, the newly synthesized products contained the mono- or disubstituted C20-epi-amine groups. The biological activity of these compounds was evaluated against human mammary mesenchymal HMLER CD24^low/CD44^high cells, a well-established model of breast CSCs, and its isogenic epithelial cell line (HMLER CD24^high/CD44^low) lacking CSC properties. Importantly, the vast majority of Sal derivatives were characterized by low nanomolar activities, comparing favorably with previous data in the literature. Furthermore, some of these derivatives exhibited a higher selectivity for the mesenchymal state compared to the reference Sal and ironomycin, representing a promising new series of compounds with anti-CSC activity.

SUBMITTER: Czerwonka D

PROVIDER: S-EPMC9164233 | biostudies-literature | 2022 Jun

REPOSITORIES: biostudies-literature

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Expeditive Synthesis of Potent C20-epi-Amino Derivatives of Salinomycin against Cancer Stem-Like Cells.

Czerwonka Dominika D Müller Sebastian S Cañeque Tatiana T Colombeau Ludovic L Huczyński Adam A Antoszczak Michał M Rodriguez Raphaël R

ACS organic & inorganic Au 20220105 3

As a continuation of our studies toward the development of small molecules to selectively target cancer stem cells (CSCs), a library of 18 novel derivatives of salinomycin (Sal), a naturally occurring polyether ionophore, was synthesized with a good overall yield using a one-pot Mitsunobu-Staudinger procedure. Compared to the parent structure, the newly synthesized products contained the mono- or disubstituted C20-epi-amine groups. The biological activity of these compounds was eva ...[more]

PMID: 35673680

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Project description:Background and purposeAlthough pain is one of the most common symptoms of diseases, it is often mismanaged due to limited access to painkillers and ineffectiveness, unacceptable side effects, or the possibility of abuse. However, an alternative approach to existing analgesics is to indirectly increase endogenous pain relief pathways by neprilysin (an enkephalinase) inhibitors. This enzyme breaks down and inactivates enkephalin, dynorphin, endorphins, and their derivatives.Experimental approachIn this project, a new series of racecadotril-tetrazole-amino acid derivatives 15a-l was synthesized and characterized on the basis of IR, 1H and 13C NMR, mass spectrometry, and elemental analysis. The antinociceptive activity of synthesized compounds was assessed by a hot plate, tail-flick, and formalin assays in mice. Docking was used to identify the possible interactions between neprilysin and synthesized compounds. 15a-l was synthesized and characterized on the basis of IR, 1H and 13C NMR, mass spectrometry, and elemental analysis. The antinociceptive activity of synthesized compounds was assessed by a hot plate, tail-flick, and formalin assays in mice. Docking was used to identify the possible interactions between neprilysin and synthesized compounds.Findings/resultsMost of the synthesized compounds showed moderate to good analgesic effects in hot plat and tail-flick test in comparison to morphine and racecadotril. Compounds 15l and 15j were the most potent compounds. The synergistic analgesic effect of compounds 15l and 15j with morphine and the antagonistic effect of naloxone on the activity of these compounds confirm that the analgesic effect of compounds 15l and 15j could be mediated through the opioidergic system. The negative and high binding energy of docking simulation of the most potent compounds in the catalytic site of neprilysin was also in good agreement with the inhibitory activity of test compounds.Conclusion and implicationsRacecadotril-tetrazole-amino acid derivatives, as potential antinociceptive agents, demonstrated moderate to good antinociceptive activities comparable with morphine and higher than racecadotril.

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Expeditive Synthesis of Potent C20-epi-Amino Derivatives of Salinomycin against Cancer Stem-Like Cells.

Publications

Expeditive Synthesis of Potent C20-<i>epi</i>-Amino Derivatives of Salinomycin against Cancer Stem-Like Cells.

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