Department of Comprehensive Dentistry, University of Texas Health Science Center at San Antonio School of Dentistry, San Antonio, Texas 78229, USA.
Center for Innovative Drug Discovery, Department of Chemistry, University of Texas at San Antonio, San Antonio, TX 78249, USA.
Bioorg Med Chem. 2019 Jan 1;27(1):208-215. doi: 10.1016/j.bmc.2018.11.040. Epub 2018 Nov 29.
We previously demonstrated that capsazepine (CPZ), a synthetic transient receptor potential Vanilloid subtype 1 (TRPV1) antagonist, has significant anti-cancer effects in vivo. The purpose of this study was to develop more potent analogs based upon CPZ pharmacophore and structure-activity relationships (SAR) across analogs. We generated 30 novel compounds and screened for their anti-proliferative effects in cultured HeLa cervical cancer cells. Cell viability assays identified multiple compounds with IC < 15 μM and one compound, 29 with an IC < 5 μM; six fold more potent than CPZ. We validated the anti-proliferative efficacy of two lead compounds, 17 and 29, in vivo using HeLa-derived xenografts in athymic nude mice. Both analogs significantly reduced tumor volumes by day 8 compared to control treated animals (p < 0.001) with no observable adverse effects. Calcium imaging determined that compound 17 activates TRPV1 whereas 29 neither activates nor inhibits TRPV1; indicating a unique mechanism-of-action that does not involve TRPV1 signaling. Cell viability assays using a panel of additional tumor types including oral squamous cell carcinoma, non-small cell lung cancer (NSCLC), breast cancer, and prostate cancer cell lines (HSC-3, H460, MDA-231, and PC-3 respectively) demonstrated that both lead compounds were efficacious against every cancer type tested. Compounds 29 displayed IC of 1-2.5 μM in HSC-3and PC-3cells. Thus, we propose that these novel CPZ analogs may serve as efficacious therapeutic agents against multiple tumor types that warrant further development for clinical application.
我们之前证明，辣椒素（CPZ）是一种合成的瞬时受体电位香草酸亚型 1（TRPV1）拮抗剂，在体内具有显著的抗癌作用。本研究的目的是基于 CPZ 的药效团和构效关系（SAR）开发更有效的类似物。我们生成了 30 种新型化合物，并在培养的宫颈癌 HeLa 细胞中筛选其抗增殖作用。细胞活力测定法确定了多种 IC < 15 µM 的化合物，其中一种化合物 29 的 IC < 5 µM；比 CPZ 强六倍。我们使用 HeLa 衍生的异种移植在裸鼠中验证了两种先导化合物 17 和 29 的体内抗增殖功效。与对照处理的动物相比，两种类似物在第 8 天均显着降低了肿瘤体积（p < 0.001），没有观察到不良反应。钙成像确定化合物 17 激活 TRPV1，而 29 既不激活也不抑制 TRPV1；表明一种不涉及 TRPV1 信号的独特作用机制。使用包括口腔鳞状细胞癌、非小细胞肺癌（NSCLC）、乳腺癌和前列腺癌细胞系（HSC-3、H460、MDA-231 和 PC-3 分别）在内的其他肿瘤类型的细胞活力测定法表明，两种先导化合物对所有测试的癌症类型均有效。化合物 29 在 HSC-3 和 PC-3 细胞中显示出 1-2.5 µM 的 IC。因此，我们提出这些新型 CPZ 类似物可能是针对多种肿瘤类型的有效治疗剂，值得进一步开发用于临床应用。
