Cannabis and its major cannabinoid cannabidiol (CBD) are reported to exhibit anticancer activity against skin tumors. However, the cytotoxic effects of other minor cannabinoids and synthetic CBD derivatives in melanoma are not fully elucidated. Herein, the antiproliferative activity of a panel of phytocannabinoids was screened against murine (B16F10) and human (A375) melanoma cells. CBD was the most cytotoxic natural cannabinoid with respective IC50 of 28.6 and 51.6 μM. Further assessment of the cytotoxicity of synthetic CBD derivatives in B16F10 cells identified two bipiperidinyl group-bearing derivatives (22 and 34) with enhanced cytotoxicity (IC50 = 3.1 and 8.5 μM, respectively). Furthermore, several cell death assays including flow cytometric (for apoptosis and ferroptosis) and lactate dehydrogenase (for pyroptosis) assays were used to characterize the antiproliferative activity of CBD and its bipiperidinyl derivatives. The augmented cytotoxicity of 22 and 34 in B16F10 cells was attributed to their capacity to promote apoptosis (as evidenced by increased apoptotic population). Taken together, this study supports the notion that CBD and its derivatives are promising lead compounds for cannabinoid-based interventions for melanoma management.

中文翻译：

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大麻二酚的联哌啶基衍生物增强其对黑色素瘤细胞的抗增殖作用

据报道，大麻及其主要大麻素大麻二酚 (CBD) 对皮肤肿瘤具有抗癌活性。然而，其他次要大麻素和合成 CBD 衍生物对黑色素瘤的细胞毒性作用尚未完全阐明。在此，针对鼠（B16F10）和人（A375）黑色素瘤细胞筛选了一组植物大麻素的抗增殖活性。 CBD 是细胞毒性最强的天然大麻素，IC50 分别为 28.6 和 51.6 μM。对 B16F10 细胞中合成 CBD 衍生物的细胞毒性的进一步评估发现了两种具有增强细胞毒性的带有联哌啶基的衍生物（22 和 34）（IC50 分别为 3.1 和 8.5 μM）。此外，包括流式细胞仪（用于细胞凋亡和铁死亡）和乳酸脱氢酶（用于焦亡）测定在内的几种细胞死亡测定用于表征 CBD 及其联哌啶基衍生物的抗增殖活性。 22 和 34 在 B16F10 细胞中增强的细胞毒性归因于它们促进细胞凋亡的能力（如凋亡群体增加所证明的）。综上所述，这项研究支持了这样一种观点，即 CBD 及其衍生物是基于大麻素的黑色素瘤治疗干预措施的有前景的先导化合物。