Biological activity of doubly modified salinomycin analogs – Evaluation in vitro and ex vivo
(2018) In European Journal of Medicinal Chemistry 156. p.510-523- Abstract
The polyether ionophore salinomycin has recently captured much interest due to its potent activity against multi-drug resistant cancer cells and cancer stem cells. Previous studies have shown that either acylation of the C20 position or esterification/amidation of the C1 carboxylate moiety is beneficial in terms of biological properties. In this paper, we present the first analogs combining such modifications. Evaluation of the anti-proliferative activity against a series of cancer cell lines showed that acylation of the C20 hydroxyl group improves the activity of salinomycin C1 amides but not of the corresponding C1 esters. Importantly, the activity of several of the doubly modified analogs surpasses that of commonly used cytostatic... (More)
The polyether ionophore salinomycin has recently captured much interest due to its potent activity against multi-drug resistant cancer cells and cancer stem cells. Previous studies have shown that either acylation of the C20 position or esterification/amidation of the C1 carboxylate moiety is beneficial in terms of biological properties. In this paper, we present the first analogs combining such modifications. Evaluation of the anti-proliferative activity against a series of cancer cell lines showed that acylation of the C20 hydroxyl group improves the activity of salinomycin C1 amides but not of the corresponding C1 esters. Importantly, the activity of several of the doubly modified analogs surpasses that of commonly used cytostatic drugs cisplatin and doxorubicin in the LoVo/DX multi-drug resistant cell line. All analogs were tested against primary acute lymphoblastic leukemia cells in standard cell viability assays; three were more potent than salinomycin. Further studies revealed that selected analogs induced characteristics of apoptotic cell death and increased expression of p53. Additionally, using an ex vivo model of breast tumor, tumor cell viability significantly decreased after treatment with salinomycin or its double-modified derivative (3a) in a time-dependent manner. The present findings indicate that double-modified salinomycin derivatives constitute promising lead compounds for targeting various types of cancer.
(Less)
- author
- Antoszczak, Michał ; Urbaniak, Alicja ; Delgado, Magdalena ; Maj, Ewa ; Borgström, Björn LU ; Wietrzyk, Joanna ; Huczyński, Adam ; Yuan, Youzhong ; Chambers, Timothy C. and Strand, Daniel LU
- organization
- publishing date
- 2018-08-05
- type
- Contribution to journal
- publication status
- published
- subject
- keywords
- Acute lymphoblastic leukemia, Anti-proliferative activity, Breast cancer, Ionophore antibiotics, Regio-selectivity, Salinomycin
- in
- European Journal of Medicinal Chemistry
- volume
- 156
- pages
- 14 pages
- publisher
- Elsevier Masson SAS
- external identifiers
-
- pmid:30025346
- scopus:85049861611
- ISSN
- 0223-5234
- DOI
- 10.1016/j.ejmech.2018.07.021
- language
- English
- LU publication?
- yes
- id
- b01ee6eb-2c3c-4430-b08f-29ebea5d27dd
- date added to LUP
- 2018-07-24 10:27:15
- date last changed
- 2024-04-01 08:26:01
@article{b01ee6eb-2c3c-4430-b08f-29ebea5d27dd,
abstract = {{<p>The polyether ionophore salinomycin has recently captured much interest due to its potent activity against multi-drug resistant cancer cells and cancer stem cells. Previous studies have shown that either acylation of the C20 position or esterification/amidation of the C1 carboxylate moiety is beneficial in terms of biological properties. In this paper, we present the first analogs combining such modifications. Evaluation of the anti-proliferative activity against a series of cancer cell lines showed that acylation of the C20 hydroxyl group improves the activity of salinomycin C1 amides but not of the corresponding C1 esters. Importantly, the activity of several of the doubly modified analogs surpasses that of commonly used cytostatic drugs cisplatin and doxorubicin in the LoVo/DX multi-drug resistant cell line. All analogs were tested against primary acute lymphoblastic leukemia cells in standard cell viability assays; three were more potent than salinomycin. Further studies revealed that selected analogs induced characteristics of apoptotic cell death and increased expression of p53. Additionally, using an ex vivo model of breast tumor, tumor cell viability significantly decreased after treatment with salinomycin or its double-modified derivative (3a) in a time-dependent manner. The present findings indicate that double-modified salinomycin derivatives constitute promising lead compounds for targeting various types of cancer.</p>}},
author = {{Antoszczak, Michał and Urbaniak, Alicja and Delgado, Magdalena and Maj, Ewa and Borgström, Björn and Wietrzyk, Joanna and Huczyński, Adam and Yuan, Youzhong and Chambers, Timothy C. and Strand, Daniel}},
issn = {{0223-5234}},
keywords = {{Acute lymphoblastic leukemia; Anti-proliferative activity; Breast cancer; Ionophore antibiotics; Regio-selectivity; Salinomycin}},
language = {{eng}},
month = {{08}},
pages = {{510--523}},
publisher = {{Elsevier Masson SAS}},
series = {{European Journal of Medicinal Chemistry}},
title = {{Biological activity of doubly modified salinomycin analogs – Evaluation in vitro and ex vivo}},
url = {{http://dx.doi.org/10.1016/j.ejmech.2018.07.021}},
doi = {{10.1016/j.ejmech.2018.07.021}},
volume = {{156}},
year = {{2018}},
}