Dorado Roxana Gonzalez, Oceguera Nava Esveidy Isabel, Chen Guanglin, Zhang Qiang, Wang Guangdi, Chen Qiao-Hong
Department of Chemistry & Biochemistry, California State University, Fresno, CA 93740, USA.
Department of Chemistry and RCMI Cancer Research Center, Xavier University of Louisiana, New Orleans, LA 70125, USA.
Molecules. 2024 Dec 20;29(24):6023. doi: 10.3390/molecules29246023.
Prostate cancer remains a significant global health concern, prompting ongoing exploration of novel therapeutic agents. Licochalcone A, a natural product in the chalcone family isolated from licorice root, is characterized by its enone structure and demonstrates antiproliferative activity in the micromolar range across various cell lines, including prostate cancer. Building on our prior success in enhancing curcumin's antiproliferative potency by replacing the substituted phenol with a 1-alkyl-1H-imizadol-2-yl moiety, we applied a similar approach to design a new class of licochalcone A-inspired chalcones. The synthesis of these target chalcones involved key [3,3]-sigmatropic rearrangement of aryl prenyl ethers and Claisen-Schmidt condensations, yielding three derivative series. These compounds were evaluated for antiproliferative activity in both androgen receptor (AR)-positive and AR-null prostate cancer cell models using WST-1 cell proliferation assay. Systematic evaluation of licochalcone A across four prostate cancer cell lines indicated a modest advantage over enzalutamide, an FDA-approved AR antagonist, in suppressing 22Rv1 cell proliferation. Interestingly, three ester derivatives by replacing the phenol next to the carbonyl with an alkoxide demonstrated similar antiproliferative potency to licochalcone A in both AR-positive and AR-negative prostate cancer cell lines. This suggests that the phenol moiety on licochalcone A may be a promising site for chemical manipulations to enhance anti-prostate cancer activity. Among the synthesized chalcones, nine derivatives showed improved selectivity for AR-positive LNCaP and 22RV1 cells relative to AR-negative PC-3 and DU145 cells, surpassing licochalcone A in selectivity. Additionally, the antiproliferative potency was highly dependent on the R group attached to the imidazole. Most of the derivatives showed antiproliferative potency against androgen receptor-positive LNCaP and 22Rv1 cells, comparable to that of enzalutamide and licochalcone A. These findings suggest that optimization of licochalcone A-inspired chalcones as potential anti-prostate cancer agents warrants further investigation.
前列腺癌仍然是一个重大的全球健康问题，促使人们不断探索新型治疗药物。甘草查尔酮A是从甘草根中分离出的查尔酮家族中的一种天然产物，其特征在于其烯酮结构，并在包括前列腺癌在内的各种细胞系中，在微摩尔范围内表现出抗增殖活性。基于我们之前通过用1-烷基-1H-咪唑-2-基部分取代取代苯酚来提高姜黄素抗增殖效力的成功经验，我们采用了类似的方法来设计一类新的受甘草查尔酮A启发的查尔酮。这些目标查尔酮的合成涉及芳基异戊烯基醚的关键[3,3]-σ迁移重排和克莱森-施密特缩合反应，产生了三个衍生物系列。使用WST-1细胞增殖测定法在雄激素受体（AR）阳性和AR阴性前列腺癌细胞模型中评估了这些化合物的抗增殖活性。对甘草查尔酮A在四种前列腺癌细胞系中的系统评估表明，在抑制22Rv1细胞增殖方面比FDA批准的AR拮抗剂恩杂鲁胺有一定优势。有趣的是，通过用醇盐取代羰基旁边的苯酚得到三个酯衍生物，在AR阳性和AR阴性前列腺癌细胞系中均表现出与甘草查尔酮A相似的抗增殖效力。这表明甘草查尔酮A上的苯酚部分可能是进行化学操作以增强抗前列腺癌活性的一个有前景的位点。在合成的查尔酮中，九个衍生物相对于AR阴性的PC-3和DU145细胞，对AR阳性的LNCaP和22RV1细胞表现出更高的选择性，在选择性方面超过了甘草查尔酮A。此外，抗增殖效力高度依赖于连接在咪唑上的R基团。大多数衍生物对雄激素受体阳性LNCaP和22Rv1细胞的抗增殖效力与恩杂鲁胺和甘草查尔酮A相当。这些发现表明，优化受甘草查尔酮A启发的查尔酮作为潜在抗前列腺癌药物值得进一步研究。
