2-Amino-7-hydroxy-4,6-dimethyl-8-nitro-3-oxo-3H-phenoxazine-1,9-dicarboxylic acid bis-[((5R,8S,9R,12S,17aS)-5,12-diisopropyl-9,13,16-trimethyl-4,7,11,14,17-pentaoxo-hexadecahydro-10-oxa-3a,6,13,16-tetraaza-cyclopentacyclohexadecen-8-yl)-amide] | 95045-11-7

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 肽模拟物
• 英文名称: 2-Amino-7-hydroxy-4,6-dimethyl-8-nitro-3-oxo-3H-phenoxazine-1,9-dicarboxylic acid bis-[((5R,8S,9R,12S,17aS)-5,12-diisopropyl-9,13,16-trimethyl-4,7,11,14,17-pentaoxo-hexadecahydro-10-oxa-3a,6,13,16-tetraaza-cyclopentacyclohexadecen-8-yl)-amide]
• CAS: 95045-11-7
• 化学式: C₆₂H₈₅N₁₃O₁₉
• 分子量: 1316.43
• InChiKey: YDSLSQNDXMJICA-ZYDBJOAXSA-N

反应信息

• 作为反应物：
  描述：

  2-Amino-7-hydroxy-4,6-dimethyl-8-nitro-3-oxo-3H-phenoxazine-1,9-dicarboxylic acid bis-[((5R,8S,9R,12S,17aS)-5,12-diisopropyl-9,13,16-trimethyl-4,7,11,14,17-pentaoxo-hexadecahydro-10-oxa-3a,6,13,16-tetraaza-cyclopentacyclohexadecen-8-yl)-amide] 在 platinum(IV) oxide 氢气 、 氧气 作用下， 生成 7-hydroxy-8-aminoactinomycin D
  参考文献：
  名称：

  放线菌素D的“反向”和“对称”类似物：代谢激活以及体外和体内肿瘤生长抑制活性。

  摘要：

  报道了两类新的放线菌素D类似物，即放线菌素D的四环“反向”类似物和三环“对称”类似物。这些类似物与DNA结合，结合不会通过嵌入机制发生。类似物在纳摩尔浓度下可抑制P388肿瘤细胞中DNA和RNA的合成以及CCRF-CEM细胞的体外生长。与先前报道的放线菌素D恶唑基类似物在结构上相关的四环“反向”类似物在大鼠肝微粒体和肿瘤细胞匀浆的存在下被代谢。新陈代谢是随着恶唑环的丢失而发生的。因此，“反向”类似物产生主要的代谢产物，即“对称”类似物。放线菌素的恶唑基类似物产生7-羟基放线菌素D。此外，微粒体将这些类似物激活为自由基状态，从而催化超氧化物的产生，如刺激肾上腺素的氧化反应以及电子顺磁共振研究所示。“对称”和“反向”类似物在这些系统中也显示出很高的活性。在小鼠体内使用P388 / S，P388 / ADR白血病和B16黑色素瘤的体内研究中，与放线菌素D相比，类似物显示出更高的活性和更高的治疗指数值。

  DOI：

  10.1021/jm50001a015

文献信息

• New actinomycin D analogs as superior chemotherapeutic agents against primary and advanced colon tumors and colon xenografts in nude mice
  作者：Sisir K. Sengupta、Yuri Kogan、Christine Kelly、Josephine Szabo

  DOI：10.1021/jm00399a014

  日期：1988.4

  "Reverse" analogues (RAD's) of actinomycin D (AMD) and their antitumor activity against mouse and human colon tumor cells are reported. RAD's are tetracyclic, and they have an oxazole ring fused on the tricyclic phenoxazine chromophore of AMD. The oxazole ring in RAD is substituted at the C-2 carbon with either a CH3 (in RAD I), a C6H5 (in RAD II), or a CH2CONH(CH2)4NH2 (in RAD III) group. In tumor cells and rat hepatic microsomes, RAD's are metabolized to a tricyclic "symmetrical" analogue of AMD (SAD) with the loss of the oxazole ring and its substituents. RAD and SAD are very active in priming superoxides in the presence of microsomal enzymes as well as in inhibiting the synthesis of DNA and the growth of human colon tumor HT-29 cells in vitro. RAD III and SAD efficiently cleave closed circular plasmid pBR322 DNA like the antitumor agent bleomycin. In addition to their strong inhibitory activity against P388 and B16 tumors in vitro and in vivo, RAD III and SAD demonstrate high levels of activity against primary C26 and advanced C38 colon tumors in mice and against a xenograft of human colon adenocarcinoma CX-1 in athymic mice. In all these biological activities, the analogues demonstrate superiority to AMD in several experimental tumors. Also, the analogues, in contrast to AMD, show reduced toxicity in tumor-free mice, which is possibly due to the metabolic deactivation of SAD in host organs.

  报道了放线菌素D（AMD）的反式类似物（RAD）及其对小鼠和人结肠肿瘤细胞的抗肿瘤活性。 RAD是四环化合物，它们在AMD的三环吩嗪酮发色团上融合了一个噁唑环。 RAD中的噁唑环在C-2碳上被取代，分别带有CH3（在RAD I中）、C6H5（在RAD II中）或 CONH（CH2）4NH2（在RAD III中）基团。在肿瘤细胞和大鼠肝微粒体中，RAD被代谢为一个三环的对称放线菌素D类似物（SAD），并失去了噁唑环及其取代基。 RAD和SAD在微粒体酶存在下对超氧阴离子有很强的活化作用，同时也抑制了人类结肠肿瘤HT-29细胞的DNA合成和体外生长。 RAD III和SAD能够有效地切割闭合环状质粒pBR322 DNA，类似于抗肿瘤药物丝裂霉素。除了对P388和B16肿瘤在体外和体内的强抑制作用外，RAD III和SAD还对小鼠的原发性C26和晚期C38结肠肿瘤以及裸鼠中的人结肠腺癌异种移植物CX-1显示出高水平的活性。在所有这些生物学活性中，这些类比物在多种实验性肿瘤中显示出优于AMD的效果。此外，这些类比物与AMD不同，对无肿瘤的小鼠毒性降低，这可能是由于SAD在宿主器官中的代谢失活所致。