National Center for Natural Products Research, School of Pharmacy, Research Institute of Pharmaceutical Sciences, The University of Mississippi, University, MS, USA.
Planta Med. 2012 Oct;78(15):1690-7. doi: 10.1055/s-0032-1315213. Epub 2012 Aug 17.
Two new pentacyclic ingamine alkaloids, namely 22(S)-hydroxyingamine A (2) and dihydroingenamine D (3), together with the known ingamine A (1), have been isolated from marine sponge Petrosid Ng5 Sp5 (family Petrosiidae) obtained from the open repository of the National Cancer Institute, USA. The structures of compounds 1-3 were determined using 1D and 2D NMR, and HRESIMS techniques. The absolute configuration of both the C9 and C22 of 2 was determined as (S) using a modified Mosher esterification method. Compounds 1 and 3 showed strong antiplasmodial activity against chloroquine-sensitive (D6) and -resistant (W2) strains of Plasmodium falciparum with IC₅₀ values of 90 and 78 ng/mL and 72 and 57 ng/mL, respectively, while 2 was found to be less active (IC₅₀ values of 200 and 140 ng/mL, respectively). Compounds 1-3 were found to be devoid of in vitro cytotoxicity against human solid tumor cells of breast (BT-549), ovary (SK-OV-3), and epidermoid (KB) carcinomas and skin melanoma (SK-MEL), as well as against noncancerous monkey kidney fibroblasts (VERO) and pig kidney epithelial (LLC-PK₁₁) cells, up to a maximum concentration of 10 µg/mL. Compounds 1-3 also displayed weak antimicrobial and moderate antileishmanial activities against Leishmania donovani promastigotes. These polycyclic ingamine alkaloids represent the first example of antiplasmodial leads without a β-carboline ring, which is known to be responsible for the cytotoxicity of the well-known manzamine class of marine alkaloids related to 1-3.
从美国国立癌症研究所的开放库中获得的海洋海绵 Petrosid Ng5 Sp5（Petrosiidae 科）中分离得到了两种新的五环吲哚烷生物碱，即 22(S)-羟基吲哚烷 A（2）和二氢吲哚烷 D（3），以及已知的吲哚烷 A（1）。化合物 1-3 的结构通过 1D 和 2D NMR 以及 HRESIMS 技术确定。使用改进的 Mosher 酯化法确定了 2 的 C9 和 C22 的绝对构型均为（S）。化合物 1 和 3 对氯喹敏感（D6）和耐药（W2）株恶性疟原虫表现出强烈的抗疟活性，IC₅₀ 值分别为 90 和 78 ng/mL 和 72 和 57 ng/mL，而 2 的活性较低（IC₅₀ 值分别为 200 和 140 ng/mL）。化合物 1-3 对人类实体瘤细胞（乳腺癌 BT-549、卵巢 SK-OV-3 和表皮癌 KB）和皮肤黑色素瘤 SK-MEL 以及非癌细胞猴肾成纤维细胞（VERO）和猪肾上皮细胞（LLC-PK₁₁）均无体外细胞毒性，最大浓度可达 10 μg/mL。化合物 1-3 对利什曼原虫前鞭毛体也表现出较弱的抗菌和中等的抗利什曼原虫活性。这些多环吲哚烷生物碱代表了首例无β-咔啉环的抗疟先导化合物，β-咔啉环已知是与 1-3 相关的著名海洋生物碱曼扎胺类化合物的细胞毒性的原因。
