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.

中文翻译：

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盐霉素及其C20-氧羰基类似物的叔酰胺的合成及其抗癌活性

聚醚离子载体盐霉素（SAL）因其对癌细胞和癌干细胞的有效活性而备受关注。我们以前的研究表明，SAL的C1 / C20双重修饰是一种有用的策略，可以产生具有良好生物活性的多种药物。因此，在本文中，我们描述了在S1和C20位置结合关键修饰的新型SAL类似物的合成。使用原发性急性淋巴细胞白血病，人乳腺腺癌和正常的乳腺上皮细胞评估获得的SAL衍生物的活性。一个单[[沙利霉素的N，N-二丙基酰胺（5 a）]和两个新颖的双修饰类似物[N，发现C20-氧代水杨霉素的N-二丙基酰胺（5b）和C20-氧代水杨霉素的哌嗪酰胺（13b）]比SAL或其C20-氧代类似物2对MDA-MB-231细胞系更有效。针对NCI-60人肿瘤细胞系，测试了所选的类似物，4 a [salinomycin的N，N-二乙基酰胺]对卵巢癌细胞系SK-OV-3表现出特定的活性。此外，SAL和2被发现对人ER / PR +，Her2浸润性乳腺癌有较强的离体作用，其中2对正常上皮细胞的毒性最小。目前的发现强调了SAL衍生物对不同癌症类型的选择性靶向的治疗潜力。盐霉素的N-二乙基酰胺]对卵巢癌细胞系SK-OV-3表现出特殊的活性。此外，SAL和2被发现对人ER / PR +，Her2浸润性乳腺癌有较强的离体作用，其中2对正常上皮细胞的毒性最小。目前的发现强调了SAL衍生物对不同癌症类型的选择性靶向的治疗潜力。盐霉素的N-二乙基酰胺]对卵巢癌细胞系SK-OV-3表现出特殊的活性。此外，SAL和2被发现对人ER / PR +，Her2浸润性乳腺癌有较强的离体作用，其中2对正常上皮细胞的毒性最小。目前的发现强调了SAL衍生物对不同癌症类型的选择性靶向的治疗潜力。