The presence of multidrug resistance (MDR) in malignant tumors is one of the primary causes of treatment failure in cancer chemotherapy. The overexpression of the ATP binding cassette (ABC) transporter, P-glycoprotein (P-gp), which significantly increases the efflux of certain anticancer drugs from tumor cells, produces MDR. Therefore, inhibition of P-gp may represent a viable therapeutic strategy to overcome cancer MDR. Over the past 4 decades, many compounds with P-gp inhibitory efficacy (referred to as first- and second-generation P-gp inhibitors) have been identified or synthesized. However, these compounds were not successful in clinical trials due to a lack of efficacy and/or untoward toxicity. Subsequently, third- and fourth-generation P-gp inhibitors were developed but dedicated clinical trials did not indicate a significant therapeutic effect. In recent years, an extraordinary array of highly potent, selective, and low-toxicity P-gp inhibitors have been reported. Herein, we provide a comprehensive review of the synthetic and natural products that have specific inhibitory activity on P-gp drug efflux as well as promising chemosensitizing efficacy in MDR cancer cells. The present review focuses primarily on the structural features, design strategies, and structure-activity relationships (SAR) of these compounds.

恶性肿瘤中多药耐药（MDR）的存在是癌症化学疗法治疗失败的主要原因之一。ATP结合盒（ABC）转运蛋白P-糖蛋白（P-gp）的过表达会显着增加某些抗癌药物从肿瘤细胞的流出，从而产生MDR。因此，抑制P-gp可能代表克服癌症MDR的可行治疗策略。在过去的40年中，已经鉴定或合成了许多具有P-gp抑制作用的化合物（称为第一代和第二代P-gp抑制剂）。然而，由于缺乏功效和/或不良的毒性，这些化合物在临床试验中并不成功。后来，已经开发了第三和第四代P-gp抑制剂，但是专门的临床试验并未显示出显着的治疗效果。近年来，已经报道了许多非凡的高效，选择性和低毒性的P-gp抑制剂。在这里，我们提供了对P-gp药物外排具有特定抑制活性以及对MDR癌细胞有希望的化学增敏功效的合成和天然产物的全面综述。本综述主要侧重于这些化合物的结构特征，设计策略和结构-活性关系（SAR）。我们提供了对P-gp药物外排具有特定抑制活性以及对MDR癌细胞有希望的化学增敏功效的合成和天然产品的全面综述。本综述主要侧重于这些化合物的结构特征，设计策略和结构-活性关系（SAR）。我们提供了对P-gp药物外排具有特定抑制活性以及对MDR癌细胞有希望的化学增敏功效的合成和天然产品的全面综述。本综述主要侧重于这些化合物的结构特征，设计策略和结构-活性关系（SAR）。