Abstract：
Pancreatic cancer (PC) shows a high fatality rate that can only be faced with a combination of surgery and chemotherapy or palliative treatment in the case of advanced patients. Besides, PC tumors are enriched with subpopulations of cancer stem cells (CSCs) that are resistant to the existing chemotherapeutic agents, which raises an important need for the identification of new drugs. To fill this gap, we have tested the anti-tumoral activity of microbial extracts, which chemical diversity offers a broad spectrum of potential new bioactive compounds. Extracts derived from the fungus Onychocola sp. CF-107644 were assayed via high throughput screening followed by bioassay-guided fractionation and resulted in the identification and isolation of six benzophenone derivatives with antitumoral activity: onychocolones A-F (#1-6). The structures of the compounds were established by spectroscopic methods, including ESI-TOF MS, 1D and 2D NMR analyses and X-ray diffraction. Compounds #1-4 significantly inhibited the growth of the pancreas tumoral cell lines, with low-micromolar Median Effective Doses (ED50s). Compound #1 (onychocolone A) was prioritized for further profiling due to its pro-apoptotic effect, which was further validated on 3D spheroids and pancreatic CSCs. Protein expression assays showed that the effect was mechanistically linked to the inhibition of MEK onco-signaling pathway. The efficacy of onychocolone A was also demonstrated in vivo by the reduction of tumor growth in a pancreatic xenograft mouse model generated by CSCs. Altogether, the data support that onychocolone A is a promising new small molecule for hit-to-lead development of a new treatment for PC.
摘要：
胰腺癌（PC）显示出很高的致死率，在晚期患者的情况下，只能通过手术和化疗或姑息治疗的组合来面对。此外,PC肿瘤富含对现有化学治疗剂具有抗性的癌症干细胞（CSC）亚群，这引起了对新药鉴定的重要需求。为了填补这个空白，我们已经测试了微生物提取物的抗肿瘤活性，这种化学多样性提供了广泛的潜在新生物活性化合物。来自真菌Onychocolasp.的提取物。CF-107644通过高通量筛选进行测定，然后进行生物测定指导的分级分离，并鉴定和分离了六种具有抗肿瘤活性的二苯甲酮衍生物：甲骨癌A-F（＃1-6）。用光谱法建立了化合物的结构,包括ESI-TOFMS,1D和2DNMR分析和X射线衍射。化合物#1-4显著抑制胰腺肿瘤细胞系的生长,低微摩尔中位数有效剂量（ED50s）。由于其促凋亡作用，化合物#1（甲骨颈酮A）被优先用于进一步分析，在3D球体和胰腺CSC上进一步验证。蛋白质表达测定表明，该作用在机械上与MEK癌基因信号通路的抑制有关。还通过减少由CSC产生的胰腺异种移植小鼠模型中的肿瘤生长,在体内证明了甲乔酮A的功效。总之,数据支持甲乔酮A是一种有前途的新型小分子，可用于开发PC的新疗法。
