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1.
ACS Org Inorg Au ; 2(3): 214-221, 2022 Jun 01.
Article in English | MEDLINE | ID: mdl-35673680

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 CD24low/CD44high cells, a well-established model of breast CSCs, and its isogenic epithelial cell line (HMLER CD24high/CD44low) 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.

2.
J Antibiot (Tokyo) ; 75(8): 445-453, 2022 08.
Article in English | MEDLINE | ID: mdl-35760901

ABSTRACT

Natural polyether ionophore salinomycin (Sal) has been widely used in veterinary medicine as an antibiotic effective in the treatment of coccidian protozoa and Gram-positive bacteria. Moreover, chemical modification of the Sal structure has been found to be a promising strategy to generate semisynthetic analogs with biological activity profiles improved relative to those of the native compound. In this context, we synthesized and thoroughly evaluated the antibacterial potential of a library of C1/C20 singly and doubly modified derivatives of C20-epi-salinomycin, that is, analogs of Sal with inversed stereochemistry at the C20 position. Among the synthesized analog structures, the most promising antibacterial active agents were those obtained via regioselective O-acylation of C20-epi-hydroxyl, particularly esters 7, 9, and 11. Such C20 singly modified compounds showed excellent inhibitory activity against planktonic staphylococci, both standard and clinical strains, and revealed potential in preventing the formation of bacterial biofilms. In combination with their non-genotoxic properties, these Sal derivatives represent attractive candidates for further antimicrobial drug development.


Subject(s)
Pyrans , Staphylococcus , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/therapeutic use , Cell Line, Tumor , Pyrans/chemistry , Pyrans/pharmacology
3.
Bioorg Med Chem Lett ; 52: 128382, 2021 11 15.
Article in English | MEDLINE | ID: mdl-34592435

ABSTRACT

A series of 22 amine analogs of thiocolchicine were synthesized using the reductive amination reaction. The antiproliferative activities of these compounds were tested against four tumor cell lines as well as one normal cell line. The tested analogs exhibited IC50 values in the nanomolar range accompanied by high selectivity indexes, and most importantly, they were able to break the drug resistance of the human colon adenocarcinoma resistant cell line (LoVo/DX). Also, a correlation between the antiproliferative activity and physicochemical properties of the novel compounds has been found.


Subject(s)
Amines/pharmacology , Antineoplastic Agents/pharmacology , Colchicine/analogs & derivatives , 3T3 Cells , Amines/chemical synthesis , Amines/chemistry , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Cell Line, Tumor , Cell Proliferation/drug effects , Colchicine/chemical synthesis , Colchicine/chemistry , Colchicine/pharmacology , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Humans , Mice , Mice, Inbred BALB C , Molecular Structure , Structure-Activity Relationship
4.
Eur J Pharmacol ; 908: 174347, 2021 Oct 05.
Article in English | MEDLINE | ID: mdl-34265289

ABSTRACT

In developed countries, cancer is the second leading cause of death, with colon and prostate cancer belonging to the group of most often diagnosed types of neoplastic diseases. The search for new treatment strategies against these types of cancer is thus of top current interest. In this context, salinomycin (SAL), a naturally occurring polyether ionophore, has been identified recently as a very promising anticancer drug candidate towards several tumour cells. In the present work, a broad library of 24 derivatives of C20-epi-salinomycin (2), including C1 singly, C20 singly and C1/C20 doubly modified analogue structures, was screened to identify compounds with improved activity against colon and prostate cancer cells. Our study demonstrated that the growth inhibitory potency of the parent compound on both primary and metastatic colon cancer cells was similar to that of the semisynthetic products derived from SAL, and simultaneously the SAL analogues showed more potent toxic action on metastatic prostate cancer cells than that of the chemically unmodified ionophore. In contrast to the widely used oncological drug doxorubicin, some of the SAL derivatives demonstrated promising anticancer activity with no toxic effects on non-tumour cells, and with more favourable cytotoxicity than that of a reference agent 5-fluorouracil. Mechanistically, the SAL analogues induced late apoptosis in colon cancer cells and necrosis in prostate cancer cells, as well as reduced secretion of interleukin 6 (IL-6) in these cells.


Subject(s)
Pyrans , Antineoplastic Agents , Apoptosis/drug effects , Humans , Ionophores/pharmacology
5.
J Org Chem ; 86(16): 11029-11039, 2021 08 20.
Article in English | MEDLINE | ID: mdl-33350834

ABSTRACT

Colchicine is an active pharmaceutical ingredient widely used for treating gout, pericarditis, and familial Mediterranean fever with high antimitotic activity. The photoisomerization of colchicine deactivates its anti-inflammatory and antimitotic properties. However, despite numerous reports on colchicine derivatives, their photostability has not been investigated in detail. This report reveals the effects of UV-induced rearrangement on the structure and reports the biological activity of new N-substituted colchicine derivatives.


Subject(s)
Antineoplastic Agents, Phytogenic , Familial Mediterranean Fever , Anti-Inflammatory Agents , Colchicine , Familial Mediterranean Fever/drug therapy , Humans
6.
Eur J Med Chem ; 209: 112900, 2021 Jan 01.
Article in English | MEDLINE | ID: mdl-33071053

ABSTRACT

Polyether ionophores, with >120 molecules belonging to this group, represent a class of naturally-occurring compounds that exhibit a broad range of pharmacological properties, including promising activity towards a variety of parasites. In this context, salinomycin (SAL) seems to be interesting, as this ionophore has been found to be active against parasites that are responsible for a number of human and animal diseases. On the other hand, less explored is the investigation into the anti-parasitic activity of SAL derivatives. Recently, we identified C1 amides and esters of SAL and its analogue, C20-oxosalinomycin, as promising structures for trypanocidal drug candidates. In search for novel compounds effective against African trypanosomes, the synthetic access to a completely new series of C20-epi-salinomycin (compound 2) analogues is described in this paper. This series includes products obtained via derivatisation of either the C1 carboxyl or the C20 hydroxyl of 2, but also C1/C20 double modified derivatives. The anti-trypanosomal activity as well as the cytotoxic activity of these analogues were evaluated with bloodstream forms of T. brucei and human myeloid HL-60 cells, respectively. It was found that the C20 single modified derivatives 8, 12, and 18 (C20 decanoate, C20 ethyl carbonate, and C20 allophanate of 2, respectively) were the most active compounds in selectively targeting bloodstream-form trypanosomes, with 50% growth inhibition (GI50) values of 0.027-0.043 µM and selectivity indices of 165-353. These results indicate that modification at the C20 position of C20-epi-salinomycin 2 can provide semi-synthetic products with enhanced trypanocidal activity that could be of great value for the development of new drugs to treat African trypanosomiasis.


Subject(s)
Pyrans/chemistry , Pyrans/pharmacology , Trypanocidal Agents/chemistry , Trypanocidal Agents/pharmacology , Trypanosoma brucei brucei/drug effects , Animals , Cell Line , Drug Design , Humans , Pyrans/chemical synthesis , Trypanocidal Agents/chemical synthesis , Trypanosomiasis, African/drug therapy
7.
Molecules ; 25(5)2020 Mar 05.
Article in English | MEDLINE | ID: mdl-32151042

ABSTRACT

Colchicine, a pseudoalkaloid isolated from Colchicum autumnale, has been identified as a potent anticancer agent because of its strong antimitotic activity. It was shown that colchicine modifications by regioselective demethylation affected its biological properties. For demethylated colchicine analogs, 10-demethylcolchicine (colchiceine, 1) and 1-demethylthiocolchicine (3), a series of 12 colchicine derivatives including 5 novel esters (2b-c and 4b-d) and 4 carbonates (2e-f and 4e-f) were synthesized. The antiproliferative activity assay, together with in silico evaluation of physicochemical properties, confirmed attractive biological profiles for all obtained compounds. The substitutions of H-donor and H-acceptor sites at C1 in thiocolchicine position provide an efficient control of the hydration affinity and solubility, as demonstrated for anhydrate 3, hemihydrate 4e and monohydrate 4a.


Subject(s)
Antimitotic Agents/chemistry , Antimitotic Agents/pharmacology , Chemistry Techniques, Synthetic , Colchicine/analogs & derivatives , Antimitotic Agents/chemical synthesis , Chemical Phenomena , Colchicine/chemical synthesis , Colchicine/chemistry , Colchicine/pharmacology , Demethylation , Dose-Response Relationship, Drug , Molecular Conformation , Molecular Structure , Spectrum Analysis , Structure-Activity Relationship
8.
ChemMedChem ; 15(2): 236-246, 2020 01 17.
Article in English | MEDLINE | ID: mdl-31702860

ABSTRACT

The polyether ionophore salinomycin (SAL) has captured much interest because of its potent activity against cancer cells and cancer stem cells. Our previous studies have indicated that C1/C20 double-modification of SAL is a useful strategy to generate diverse agents with promising biological activity profiles. Thus, herein we describe the synthesis of a new class of SAL analogues that combine key modifications at the C1 and C20 positions. The activity of the obtained SAL derivatives was evaluated using primary acute lymphoblastic leukemia, human breast adenocarcinoma and normal mammary epithelial cells. One single- [N,N-dipropyl amide of salinomycin (5 a)] and two novel double-modified analogues [N,N-dipropyl amide of C20-oxosalinomycin (5 b) and piperazine amide of C20-oxosalinomycin (13 b)] were found to be more potent toward the MDA-MB-231 cell line than SAL or its C20-oxo analogue 2. When select analogues were tested against the NCI-60 human tumor cell line panel, 4 a [N,N-diethyl amide of salinomycin] showed particular activity toward the ovarian cancer cell line SK-OV-3. Additionally, both SAL and 2 were found to be potent ex vivo against human ER/PR+ , Her2- invasive mammary carcinoma, with 2 showing minimal toxicity toward normal epithelial cells. The present findings highlight the therapeutic potential of SAL derivatives for select targeting of different cancer types.


Subject(s)
Amides/pharmacology , Antineoplastic Agents/pharmacology , Pyrans/chemistry , Pyrans/pharmacology , Amides/chemical synthesis , Amides/chemistry , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Cell Proliferation/drug effects , Cell Survival/drug effects , Cells, Cultured , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Humans , Molecular Conformation , Pyrans/chemical synthesis , Structure-Activity Relationship
9.
Eur J Med Chem ; 116: 216-221, 2016 Jun 30.
Article in English | MEDLINE | ID: mdl-27061985

ABSTRACT

New rifamycins (1-12) combined with different l-amino acids, containing methyl, ethyl, tert-butyl and benzyl groups at the ester part, via amine linkage, were synthesized and their structures in solution were determined by spectroscopic FT-IR and 1D and 2D NMR methods as well as visualized by DFT calculations. Two types of rifamycin structures were detected in solution: a zwitterionic one with the transferred proton from O(8)H phenol to secondary N(38) atom and a pseudocyclic structure stabilized via formation of intramolecular H-bond within the protonated basic C(3)-substituent. The presence of these rifamycins' structures influenced physico-chemical (logP, solubility) parameters and antibacterial properties. The bulkiness at the ester substituent of new rifamycins containing aromatic l-amino acids was found to be an important factor, besides the solubility, to achieve relatively high antibacterial activity against reference S. epidermidis and reference S. aureus and MRSA strains (MICs 0.016-0.063 µg/mL), comparable to that of rifampicin. SAR for the novel derivatives was discussed in view of the calculated structures of rifamycin-RNAP complexes.


Subject(s)
Amino Acids/chemistry , DNA-Directed RNA Polymerases/antagonists & inhibitors , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Esters/chemistry , Rifamycins/chemistry , Rifamycins/pharmacology , DNA-Directed RNA Polymerases/chemistry , DNA-Directed RNA Polymerases/metabolism , Enzyme Inhibitors/metabolism , Hydrogen Bonding , Methicillin-Resistant Staphylococcus aureus/drug effects , Methicillin-Resistant Staphylococcus aureus/enzymology , Microbial Sensitivity Tests , Molecular Conformation , Molecular Docking Simulation , Rifamycins/metabolism , Staphylococcus epidermidis/drug effects , Staphylococcus epidermidis/enzymology , Structure-Activity Relationship
10.
Bioorg Med Chem Lett ; 25(18): 3903-9, 2015 Sep 15.
Article in English | MEDLINE | ID: mdl-26254943

ABSTRACT

Spectroscopic studies of ether rifamycins (1-9) have shown that all these compounds tend to be zwitterions with different localizations of intramolecularly transferred proton, which influences their solubility and logP values. According to ESI MS studies, rifamycins 3 and 4 form complexes with Li(+) or Na(+), while the other ones (7-9) coordinate small organic molecules, which can be further replaced by Na(+) cation. Biological assays revealed that the use of 7-9 in the form of complexes with small organic molecules improves their antibacterial potency as a result of changed: logP, solubility and binding mode with bacterial RNA polymerases.


Subject(s)
Anti-Bacterial Agents/pharmacology , Ethers/chemistry , Macrocyclic Compounds/chemistry , Nitrogen/chemistry , Organometallic Compounds/pharmacology , Staphylococcus aureus/drug effects , Staphylococcus epidermidis/drug effects , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/chemistry , Dose-Response Relationship, Drug , Ethers/pharmacology , Lithium/chemistry , Lithium/pharmacology , Macrocyclic Compounds/pharmacology , Microbial Sensitivity Tests , Molecular Conformation , Organometallic Compounds/chemical synthesis , Organometallic Compounds/chemistry , Rifamycins/chemistry , Rifamycins/pharmacology , Sodium/chemistry , Sodium/pharmacology , Structure-Activity Relationship
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