Synthesis and Anticancer Activity of Tertiary Amides of Salinomycin and Their C20‐oxo Analogues

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.

Singly and doubly modified analogues of C20-epi-salinomycin: A new group of antiparasitic agents against Trypanosoma brucei

“…Furthermore, some of the analogues displayed superior trypanocidal activity, which was much higher than that observed for the parent compound SAL, with GI50 and MIC values comparable to those of suramin, a commonly used medication in the therapy of sleeping sickness [9,18]. In addition to their potent anti-parasitic activity, SAL amides and esters obtained via derivatisation of the C1 carboxyl group have shown activity against drug-sensitive and drug-resistant cancer cells of various origin, which clearly demonstrates the promising therapeutic potential of this class of compounds, especially as they exhibited high selectivity of action (low toxicity on non-tumour cells) [19][20][21][22].…”

“…All commercially available reagents and solvents were purchased from two independent sources (Merck (Germany) or Trimen Chemicals S.A. (Poland)) and used in the experiments without further purification. Detailed description of general procedures, used equipment (NMR spectrometer, FT-IR spectrophotometer, mass spectrometer), measurement parameters and software can be found either in the Supplementary material or in the reference literature [18][19].…”

Salinomycin as a potent anticancer stem cell agent: State of the art and future directions

“…Of all the dimers they generated, the salinomycin‐monensin (MON) dimer (SAX3) and a salinomycin dimer (SAL‐dimer2) give similar IC 50 values to that of salinomycin but increase ~three‐ to fourfolds for their SIs after tested in MCF‐7 breast cancer cells and MCF‐10A normal breast cells 177 . They recently further derived a series of tertiary amides of salinomycin and their C20‐oxo analogues, a C1 tertiary amide (SAR2) salinomycin showed an improved SI index when tested against a triple negative breast cancer cell line (MDA‐MB‐231); the C20 ketone derivative (SAR7) displayed cytotoxic effects in an ex vivo model of breast cancer comparable to salinomycin, although did not stand out from in vitro cell‐based assays 173 . In parallel, Rodriguez group also generated this derivative and observed a lower IC 50 against EMT in CSC‐high breast cancer cells in vitro and a higher selectivity over CSC‐low counterpart cells in comparison to salinomycin, though the toxicity to normal cells was not tested 186 …”

“…177 They recently further derived a series of tertiary amides of salinomycin and their C20-oxo analogues, a C1 tertiary amide (SAR2) salinomycin showed an improved SI index when tested against a triple negative breast cancer cell line (MDA-MB-231); the C20 ketone derivative (SAR7) displayed cytotoxic effects in an ex vivo model of breast cancer comparable to salinomycin, although did not stand out from in vitro cell-based assays. 173 In parallel, Rodriguez group also generated this derivative and observed a lower IC 50 against EMT in CSC-high breast cancer cells in vitro and a higher selectivity over CSC-low counterpart cells in comparison to salinomycin, though the toxicity to normal cells was not tested. 186 At the same time, Wu group synthesized salinomycin diastereoisomers at C17 and C21 and their benzoylated derivatives, after tested their antiproliferative effects on colon cancer and breast cancer cell lines as well as rat cerebral cortex neuron cells in vitro, the 17,21-di-epi-20-O-Bz-salinomycin sodium salt (SAR15) showed a nearly twofold improvement and a notably better therapeutic intex.…”

“…Huczyński group made great efforts on the modification of salinomycin's structure to obtain salinomycin derivatives (SARs) and the synthesis of salinomycin conjugates with other drug or compound (SAXs) to enhance its activities, including antimicrobial, antiprotozoal, antiparasitic and antiproliferative activities. 26 , 77 , 146 , 147 , 148 , 149 , 150 , 151 , 152 , 153 , 155 , 156 , 157 , 158 , 170 , 171 , 172 , 173 , 174 , 175 , 176 , 177 , 178 , 179 , 180 , 181 , 182 , 183 , 184 , 185 For instance, by semi‐synthesis they generated series of amide derivatives and ester derivatives at C1 position; by “click” chemistry they synthesized salinomycin conjugates with the anticancer drug floxuridine (FdU or 5‐FU) (SAX1) or with the anti‐HIV drug 3'‐azido‐3'‐deoxythymidine (AZT) (SAX2). Recent reviews published by Antoszczak comprehensively summarized the recent work on salinomycin derivatives.…”