Dextrorotatory Chromomycins from the Marine Streptomyces sp. Associated to Palythoa caribaeorum

A Streptomyces sp. (BRA-384) was selected among nine strains of bacteria isolated from the zoanthids Palythoa caribaeorum due to the high cytotoxic activity presented by its EtOAc extract (inhibitory concentration mean (IC50) of 2 ng mL-1) against colon cancer cell line. From the EtOAc extract of BRA-384 three new chemical entities (A6, A7 and A8) and one dextrorotatory chromomycin (A5), a promising class of anticancer compounds, were identified. The cytotoxicity of chromomycins A5 to A8 was tested against five tumor cell lines (HCT 116 (human colon adenocarcinoma), MCF-7 (human breast carcinoma), PC-3M (human metastatic prostate cancer), 501-mel (human metastatic melanoma) and MM200 (metastatic melanoma)). All chromomycins were highly potent showing IC50 values from 0.2 to 133 nM. Chromomycin A5 was consistently the most potent over all tested cells (IC50 values from 0.2 in MM200 to 7.9 nM in PC-3M), inclusive when compared to the standard chemotherapeutic agent doxorubicin, that presented IC50 values ranging from 147 to 568 nM against MM200 and MCF-7, respectively.

本研究从分离自加勒比海沙群海葵（Palythoa caribaeorum）的9株细菌中，筛选得到一株链霉菌属（Streptomyces sp.）菌株BRA-384，因其乙酸乙酯（EtOAc）提取物对结肠癌细胞系展现出极高的细胞毒活性，其半数抑制浓度均值（IC50）为2 ng·mL⁻¹。从该菌株BRA-384的乙酸乙酯提取物中，鉴定出3个全新化学实体（编号为A6、A7与A8）以及1个右旋色霉素（chromomycin）类化合物（A5），色霉素类属于极具潜力的抗癌化合物类别。随后，针对5种肿瘤细胞系检测了色霉素A5至A8的细胞毒性，受试细胞系包括HCT 116（人结肠腺癌细胞）、MCF-7（人乳腺癌细胞）、PC-3M（人转移性前列腺癌细胞）、501-mel（人转移性黑色素瘤细胞）以及MM200（转移性黑色素瘤细胞）。所有色霉素类化合物均展现出极强的抗肿瘤活性，其IC50值介于0.2至133 nM之间。其中，色霉素A5在所有受试细胞系中均表现出最强的细胞毒活性，IC50值范围为MM200细胞中的0.2 nM至PC-3M细胞中的7.9 nM；相较于临床标准化疗药物多柔比星（doxorubicin）这一优势尤为显著，多柔比星对MM200与MCF-7细胞的IC50值分别为147 nM与568 nM。