Development of Novel Chalcone Analogs as Potential Multi-Targeted Therapies for Castration-Resistant Prostate Cancer

O. Hussein, F. Alali, Ala‐Eddin Al Mustafa, Ashraf Khalil
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Abstract

Prostate cancer (PCa) is the second most frequently diagnosed malignancy, as well as a leading cause of cancer-related mortality in men globally. Despite the initial response to hormonal targeted therapy, the majority of patients ultimately progress to a lethal form of the disease, castration-resistant prostate cancer (CRPC). Therefore, the objective of this study was to discover and develop novel treatment modalities for CRPC. Chalcones are among the highly attractive scaffolds being investigated for their antitumor activities. A library of 26 chalcone analogs were designed, synthesized and evaluated as potential therapies for CRPC. The design was guided by in-silico ADMET prediction in which analogs with favorable drug-likeness properties were prioritized. The new compounds were synthesized, purified and characterized by extensive structural elucidation studies. The compounds in vitro cytotoxicity was evaluated against two androgen receptor (AR)-negative prostate cancer cell lines (PC3 and DU145). Among the tested compounds, pyridine containing analogs (13, 15 and 16) showed potent antiproliferative activities with IC50 values ranging between 4.32-6.47 µM against PC3 and DU145 cell lines. Detailed biological studies of the lead molecule 16 revealed that it can significantly induce apoptosis through upregulation of Bax and downregulation of Bcl-2. In addition, compound 16 potently inhibited colony formation and reduced cell migration of AR-negative PCa cell lines (PC3 and DU145). The molecular pathway analysis showed that the anticancer activity of compound 16 is associated with blocking of ERK1/2 and Akt activities. Furthermore, compound 16 inhibited angiogenesis in the chick chorioallantoic membrane (CAM) model as compared to control. Structure-activity relationship study revealed that the cytotoxicity could dramatically improve via changing the methoxylation pattern by more than 2-folds (IC50 << 2.5 μM). These results indicate that pyridine-based chalcones could serve as promising lead molecules for the treatment of CRPC; thus, further in vitro and in vivo studies are warranted.
新型查尔酮类似物作为去势抵抗性前列腺癌潜在多靶点治疗的进展
前列腺癌(PCa)是第二常见的恶性肿瘤,也是全球男性癌症相关死亡的主要原因。尽管最初对激素靶向治疗有反应,但大多数患者最终进展为一种致命的疾病,去势抵抗性前列腺癌(CRPC)。因此,本研究的目的是发现和发展CRPC的新治疗方式。查尔酮因其抗肿瘤活性而成为备受关注的支架材料之一。设计、合成了26个查尔酮类似物,并对其作为CRPC的潜在治疗药物进行了评价。该设计以计算机ADMET预测为指导,其中具有良好药物相似特性的类似物被优先考虑。这些新化合物经过合成、纯化并进行了广泛的结构解析研究。对两种雄激素受体(AR)阴性的前列腺癌细胞株PC3和DU145进行了体外细胞毒性评价。在这些化合物中,含有吡啶的类似物(13、15和16)对PC3和DU145细胞株具有较强的抗增殖活性,IC50值在4.32 ~ 6.47µM之间。对铅分子的详细生物学研究表明,其可通过上调Bax和下调Bcl-2显著诱导细胞凋亡。此外,化合物16还能有效抑制ar阴性PCa细胞株(PC3和DU145)的集落形成和细胞迁移。分子通路分析表明,化合物16的抗癌活性与阻断ERK1/2和Akt活性有关。此外,与对照组相比,化合物16抑制了鸡绒毛膜尿囊膜(CAM)模型的血管生成。构效关系研究表明,通过改变甲氧基化模式,细胞毒性可显著提高2倍以上(IC50 << 2.5 μM)。上述结果表明,吡啶类查尔酮可作为治疗CRPC的铅分子;因此,进一步的体外和体内研究是必要的。
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