Cancer Research Institute, Department of Chemistry and Biochemistry, Arizona State University, P.O. Box 871604, Tempe, Arizona 85287-1604, USA.
J Nat Prod. 2012 Jun 22;75(6):1063-9. doi: 10.1021/np300069z. Epub 2012 May 18.
Cephalostatin 1 (1), a remarkably strong cancer cell growth inhibitory trisdecacyclic, bis-steroidal pyrazine isolated from the marine tube worm Cephalodiscus gilchristi, continues to be an important target for practical total syntheses and a model for the discovery of less complex structural modifications with promising antineoplastic activity. In the present study, the cephalostatin E and F rings were greatly simplified by replacement at C-17 with an α-pyrone (in 12), typical of the steroidal bufodienolides, and by a dihydro-γ-pyrone (in 16). The synthesis of pyrazine 12 from 5α-dihydrotestosterone (nine steps, 8% overall yield) provided the first route to a bis-bufadienolide pyrazine. Dihydro-γ-pyrone 16 was synthesized in eight steps from ketone 13. While only insignificant cancer cell growth inhibitory activity was found for pyrones 12 and 16, the results provided further support for the necessity of more closely approximating the natural D-F ring system of cephalostatin 1 in order to obtain potent antineoplastic activity.
头道沙菌素 1（1），一种从海洋管蠕虫 Cephalodiscus gilchristi 中分离出来的具有显著抗癌细胞生长抑制作用的强三癸基、双甾体吡嗪，仍然是实际全合成的重要目标，也是发现具有潜在抗肿瘤活性的结构更简单的修饰物的模型。在本研究中，通过在 C-17 处用α-吡喃酮（在 12 中）代替，典型的甾体 bufodienolides，并通过二氢-γ-吡喃酮（在 16 中）代替，大大简化了头道沙菌素 E 和 F 环。从 5α-二氢睾酮（九步，总收率 8%）合成吡嗪 12 提供了双 bufadienolide 吡嗪的第一条路线。二氢-γ-吡喃酮 16 通过酮 13 经八步合成。虽然吡喃酮 12 和 16 仅显示出微不足道的抗癌细胞生长抑制活性，但结果进一步支持了更接近头道沙菌素 1 的天然 D-F 环系统的必要性，以便获得有效的抗肿瘤活性。
