Pancreatic Ductal Adenocarcinoma (PDAC), representing over 90 % of pancreatic cancer diagnoses, is an aggressive disease with survivability among the worst of all cancers due to its difficulty in detection and its high metastatic properties. Current therapies for PDAC show limited success at extending life expectancies, primarily due to cancer resistance and lack of patient-specific targeted therapies. This work highlights the design and evaluation of estrone-derived analogs with both heterocyclic side-chain functionality and 11-oxygenated functionality for use in pancreatic cancer. First-round heterocyclic analogs show preliminary promise in AsPC-1 and Panc-1 cell lines, with IC values as low as 10.16 ± 0.83 µM. Their success, coupled with design choices from other studies, led to the synthesis of novel 11-hydroxyl and 11-keto estrone analogs that show potent toxicity against various pancreatic cancer models. The three most cytotoxic analogs, KA1, KA2, and KA9 demonstrated low micromolar activities in both MTT and CellTiter assays in three pancreatic cancer cell lines: AsPC-1, Panc-1, and BxPC-3, as well as in a co-culture of Panc-1 and pancreatic stellate cells. IC values for KA9 (4.17 ± 0.90, 5.28 ± 1.87, and 5.70 ± 0.65 µM respectively) shows consistency in all cell lines tested. KA9 is also able to cause an increase in caspases 3 and 7 activity, key markers for apoptosis, at non-cytotoxic concentrations. Additional work was performed by generating 3D pancreatic cancer spheroids to better modulate the pancreatic tumor microenvironment, and KA9 continued to show the best IC values (21.0 and 24.3 µM) in both cell types tested. KA9 was also able to prevent the growth of spheroids whereas the standard chemotherapy, Gemcitabine, could not, suggesting that it may be a potent analog for future development of treatments. Molecular dynamic simulations were also performed to confirm biological findings and uncovered that KA9′s preferential binding location is in the active site pocket of key proteins involved in cytotoxicity.

中文翻译：

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胰腺癌单层和 3D 球体中 11-含氧和杂环雌酮类似物的合成和生物活性

胰腺导管腺癌 (PDAC) 占胰腺癌诊断的 90% 以上，是一种侵袭性疾病，由于其难以检测和高转移特性，其生存率是所有癌症中最差的。目前的 PDAC 疗法在延长预期寿命方面效果有限，这主要是由于癌症耐药性和缺乏针对患者的靶向疗法。这项工作重点介绍了用于胰腺癌的具有杂环侧链功能和 11-氧化功能的雌酮衍生类似物的设计和评估。第一轮杂环类似物在 AsPC-1 和 Panc-1 细胞系中显示出初步前景，IC 值低至 10.16 ± 0.83 µM。他们的成功，加上其他研究的设计选择，导致合成了新型 11-羟基和 11-酮雌酮类似物，这些类似物对各种胰腺癌模型表现出强大的毒性。三种最具细胞毒性的类似物 KA1、KA2 和 KA9 在三种胰腺癌细胞系（AsPC-1、Panc-1 和 BxPC-3）以及共培养物中的 MTT 和 CellTiter 测定中均表现出低微摩尔活性Panc-1 和胰腺星状细胞。 KA9 的 IC 值（分别为 4.17 ± 0.90、5.28 ± 1.87 和 5.70 ± 0.65 µM）显示所有测试细胞系的一致性。在非细胞毒性浓度下，KA9 还能够导致 caspase 3 和 7 活性增加，这是细胞凋亡的关键标志物。通过生成 3D 胰腺癌球体以更好地调节胰腺肿瘤微环境进行了额外的工作，KA9 在测试的两种细胞类型中继续显示出最佳 IC 值（21.0 和 24.3 µM）。 KA9 还能够阻止球状体的生长，而标准化疗药物吉西他滨则不能，这表明它可能是未来治疗开发的有效类似物。还进行了分子动力学模拟以证实生物学发现，并发现 KA9 的优先结合位置位于参与细胞毒性的关键蛋白的活性位点袋中。