G protein-coupled receptors (GPCRs) constitute the largest protein superfamily in the human genome. GPCRs play key roles in mediating a wide variety of physiological events including proliferation and cancer metastasis. Given the major roles that GPCRs play in mediating cancer growth, they present promising targets for small molecule therapeutics. One of the principal goals of our lab is to identify complex natural products (NPs) suitable for ring distortion, or the dramatic altering of the inherently complex architectures of NPs, to rapidly generate an array of compounds with diverse molecular skeletal systems. The overarching goal of our ring distortion approach is to re-program the biological activity of select natural products and identify new compounds of importance to the treatment of disease, such as cancer. Described herein are the results from biological screens of diverse small molecules derived from the indole alkaloid yohimbine against a panel of GPCRs involved in various diseases. Several analogues displayed highly differential antagonistic activities across the GPCRs tested. We highlight the re-programmed profile of one analogue, Y7g, which exhibited selective antagonistic activities against AVPR2 (IC₅₀ = 459 nM) and OXTR (IC₅₀ = 1.16 µM). The activity profile of Y7g could correlate its HIF-dependent anti-cancer activity to its GPCR antagonism since these receptors are known to be upregulated in hypoxic cellular environments. Our findings demonstrate that the ring distortion of yohimbine can lead to the identification of new compounds capable of interacting with distinct cancer-relevant targets.

G蛋白偶联受体（GPCR）构成了人类基因组中最大的蛋白质超家族。GPCR在介导多种生理事件（包括增殖和癌症转移）中起关键作用。鉴于GPCR在介导癌症生长中所起的主要作用，它们为小分子治疗药物提供了有希望的靶标。我们实验室的主要目标之一是确定适用于环畸变的复杂天然产物（NP），或NP固有复杂结构的急剧变化，以快速生成一系列具有多种分子骨架系统的化合物。我们的环畸变方法的总体目标是重新编程选定天然产物的生物学活性，并确定对疾病如癌症重要的新化合物。本文描述的是从吲哚生物碱育亨宾衍生的多种小分子对涉及多种疾病的一组GPCR进行的生物筛选结果。在测试的GPCR中，几种类似物表现出高度差异的拮抗活性。我们重点介绍了一种类似物的重新编程配置文件，Y7g表现出对AVPR2（IC ₅₀  = 459 nM）和OXTR（IC ₅₀  = 1.16 µM）的选择性拮抗活性。Y7g的活性谱可以将其HIF依赖性抗癌活性与其GPCR拮抗作用相关联，因为已知这些受体在低氧细胞环境中被上调。我们的发现表明育亨宾的环畸变可以导致鉴定出能够与不同的癌症相关靶标相互作用的新化合物。