Tricyclic Diterpenoids Selectively Suppress Androgen Receptor-Positive Prostate Cancer Cells.
Tricyclic Diterpenoids Selectively Suppress Androgen Receptor-Positive Prostate Cancer Cells.
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DOI：
10.3390/molecules28124743
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发表时间：
2023-06-13
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影响因子：
--
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雄激素受体（AR）是致死性去势抵抗性前列腺癌（CRPC）的可行治疗靶点，因为CRPC的持续进展主要由AR转录活性的重新激活驱动。目前FDA批准的与配体结合结构域（LBD）结合的AR拮抗剂在具有AR基因扩增、LBD突变和LBD截短的AR剪接变体进化的CRPC中变得无效。受三环芳香族二萜QW 07最近被确定为潜在的N-末端AR拮抗剂这一事实的鼓舞，本研究旨在探索三环芳香族二萜的构效关系及其抑制AR阳性细胞增殖的潜力。选择脱氢枞胺、枞酸、脱氢枞酸及其衍生物，因为它们具有与QW 07相似的核心结构。制备了20种二萜类化合物，用于使用AR无效细胞模型（PC-3和DU 145）作为比较，评价它们对AR阳性前列腺癌细胞模型（LNCaP和22 Rv 1）的抗增殖效力。我们的数据表明，6种三环二萜类化合物对LNCaP和22 Rv 1 AR阳性细胞的效力高于enzalutamide（FDA批准的AR拮抗剂），4种二萜类化合物对22 Rv 1 AR阳性细胞的效力高于enzalutamide。最佳衍生物对AR阳性22 Rv 1细胞的效力（IC 50 = 0.27 µM）和选择性高于QW 07。
Androgen receptor (AR) is a viable therapeutic target for lethal castration-resistant prostate cancer (CRPC), because the continued progression of CRPC is mainly driven by the reactivation of AR transcriptional activity. The current FDA-approved AR antagonists binding to ligand binding domain (LBD) become ineffective in CRPC with AR gene amplification, LBD mutation, and the evolution of LBD-truncated AR splice variants. Encouraged by the fact that tricyclic aromatic diterpenoid QW07 has recently been established as a potential N-terminal AR antagonist, this study aims to explore the structure–activity relationship of tricyclic diterpenoids and their potential to suppress AR-positive cell proliferation. Dehydroabietylamine, abietic acid, dehydroabietic acid, and their derivatives were selected, since they have a similar core structure as QW07. Twenty diterpenoids were prepared for the evaluation of their antiproliferative potency on AR-positive prostate cancer cell models (LNCaP and 22Rv1) using AR-null cell models (PC-3 and DU145) as comparisons. Our data indicated that six tricyclic diterpenoids possess greater potency than enzalutamide (FDA-approved AR antagonist) towards LNCaP and 22Rv1 AR-positive cells, and four diterpenoids are more potent than enzalutamide against 22Rv1 AR-positive cells. The optimal derivative possesses greater potency (IC50 = 0.27 µM) and selectivity than QW07 towards AR-positive 22Rv1 cells.
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影响因子：
11.2
作者：
Lin, Feng-Min;Tsai, Chin-Hsien;Hsiao, Pei-Wen
通讯作者：
Hsiao, Pei-Wen
具有体内抗肿瘤活性的新型二萜类似物的合成
影响因子：
6.7
作者：
Wang, Ying-Ying;He, Yuan;Qiu, Wen-Wei
通讯作者：
Qiu, Wen-Wei
DOI：
10.1038/ncpuro1296
发表时间：
2009-02
期刊：
NATURE CLINICAL PRACTICE UROLOGY
影响因子：
--
作者：
Harris, William P.;Mostaghel, Elahe A.;Nelson, Peter S.;Montgomery, Bruce
通讯作者：
Montgomery, Bruce
影响因子：
7.2
作者：
Kar, Susanta;Palit, Shreyasi;Das, Pijush K.
通讯作者：
Das, Pijush K.
影响因子：
6.7
作者：
Gonzalez, Miguel A.;Perez-Guaita, David;Betancur-Galvis, Liliana
通讯作者：
Betancur-Galvis, Liliana