(+)-deoxyisoaustamide

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: (+)-deoxyisoaustamide
• 英文别名: Deoxyisoaustamide；(1S,13Z)-12,12-dimethyl-10,15,21-triazapentacyclo[13.7.0.03,11.04,9.017,21]docosa-3(11),4,6,8,13,17-hexaene-16,22-dione
• 化学式: C₂₁H₂₁N₃O₂
• 分子量: 347.417
• InChiKey: VSXXSJJFEXRTPT-CCCPALQASA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.1
• 重原子数：
  26
• 可旋转键数：
  0
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.33
• 拓扑面积：
  56.4
• 氢给体数：
  1
• 氢受体数：
  2

反应信息

• 作为反应物：
  描述：

  (+)-deoxyisoaustamide 在 manganese(IV) oxide 作用下， 以 二氯甲烷 为溶剂， 以30 %的产率得到deoxy-14,15-dehydroisoaustamide
  参考文献：
  名称：

  New Marine Fungal Deoxy-14,15-Dehydroisoaustamide Resensitizes Prostate Cancer Cells to Enzalutamide

  摘要：

  海洋真菌是具有各种生物活性的新生物活性分子的宝贵来源。在本研究中，我们报告了从与软珊瑚相关的海洋源真菌二孢青霉 KMM 4689 中分离出一种新的吲哚二酮哌嗪生物碱脱氧-14,15-脱氢异乌司他胺 (1)。通过 HR-MS、1D 和 2D NMR 以及 CD 数据确定了这种代谢物的结构，包括其绝对构型。化合物 1 是一种在脯氨酸环上具有两个双键的脱氧异乌斯塔酰胺生物碱。分离出的化合物对人类正常细胞株和癌细胞株无细胞毒性，毒性最高可达 100 µM。同时，化合物 1 能使前列腺癌 22Rv1 细胞对雄激素受体（AR）阻断剂恩杂鲁胺（enzalutamide）重新敏感。这一现象的机制被确定为药物诱导的雄激素受体转录变体 V7（AR-V7）的特异性降解，这也导致了 AR 信号的普遍抑制。我们的数据表明，分离出的生物碱是联合治疗阉割耐药前列腺癌（包括耐药亚型）的理想候选药物。

  DOI：

  10.3390/md21010054
• 作为产物：
  描述：

  3-甲基-2-丁烯醛 在 palladium diacetate 、 sodium tetrahydroborate 、 二甲基硫 、 氧气 、 溶剂黄146 、 甲基磺酰氯 、 三乙胺 、 过氧化苯甲酰 作用下， 以 四氢呋喃 、 甲醇 、 二氯甲烷 、 苯 为溶剂， 65.0 ℃ 、101.33 kPa 条件下， 反应 7.67h， 生成 (+)-deoxyisoaustamide
  参考文献：
  名称：

  A Short Synthetic Route to (+)-Austamide, (+)-Deoxyisoaustamide, and (+)-Hydratoaustamide from a Common Precursor by a Novel Palladium-Mediated Indole → Dihydroindoloazocine Cyclization

  摘要：

  The first synthesis of (+)-austamide (1), (+)-deoxyisoaustamide (2), and (+)-hydratoaustamide (10) by a very direct route is described (Scheme 1). Starting from tryptophan methyl ester (3) intermediate 5 is generated in two steps in >98% overall yield. The key step in the synthesis is a novel cyclization of 5 involving organopalladium intermediates which gives the dihydroazocine 6. From this key intermediate the target structures are accessible in just a few steps as shown in Scheme 1. The remarkable conversion of 5 --> 6 can be rationalized by the mechanistic pathway shown in Scheme 2 that involves a multistep sequence which includes palladation, cyclization, and rearrangement.

  DOI：

  10.1021/ja026663t

文献信息

• A Short Synthetic Route to (+)-Austamide, (+)-Deoxyisoaustamide, and (+)-Hydratoaustamide from a Common Precursor by a Novel Palladium-Mediated Indole → Dihydroindoloazocine Cyclization
  作者：Phil S. Baran、E. J. Corey

  DOI：10.1021/ja026663t

  日期：2002.7.1

  The first synthesis of (+)-austamide (1), (+)-deoxyisoaustamide (2), and (+)-hydratoaustamide (10) by a very direct route is described (Scheme 1). Starting from tryptophan methyl ester (3) intermediate 5 is generated in two steps in >98% overall yield. The key step in the synthesis is a novel cyclization of 5 involving organopalladium intermediates which gives the dihydroazocine 6. From this key intermediate the target structures are accessible in just a few steps as shown in Scheme 1. The remarkable conversion of 5 --> 6 can be rationalized by the mechanistic pathway shown in Scheme 2 that involves a multistep sequence which includes palladation, cyclization, and rearrangement.
• New Marine Fungal Deoxy-14,15-Dehydroisoaustamide Resensitizes Prostate Cancer Cells to Enzalutamide
  作者：Sergey A. Dyshlovoy、Olesya I. Zhuravleva、Jessica Hauschild、Tobias Busenbender、Dmitry N. Pelageev、Anton N. Yurchenko、Yuliya V. Khudyakova、Alexandr S. Antonov、Markus Graefen、Carsten Bokemeyer、Gunhild von Amsberg

  DOI：10.3390/md21010054

  日期：——

  Marine fungi serve as a valuable source for new bioactive molecules bearing various biological activities. In this study, we report on the isolation of a new indole diketopiperazine alkaloid deoxy-14,15-dehydroisoaustamide (1) from the marine-derived fungus Penicillium dimorphosporum KMM 4689 associated with a soft coral. The structure of this metabolite, including its absolute configuration, was determined by HR-MS, 1D and 2D NMR as well as CD data. Compound 1 is a very first deoxyisoaustamide alkaloid possessing two double bonds in the proline ring. The isolated compound was noncytotoxic to a panel of human normal and cancer cell lines up to 100 µM. At the same time, compound 1 resensitized prostate cancer 22Rv1 cells to androgen receptor (AR) blocker enzalutamide. The mechanism of this phenomenon was identified as specific drug-induced degradation of androgen receptor transcription variant V7 (AR-V7), which also resulted in general suppression of AR signaling. Our data suggest that the isolated alkaloid is a promising candidate for combinational therapy of castration resistant prostate cancer, including drug-resistant subtypes.

  海洋真菌是具有各种生物活性的新生物活性分子的宝贵来源。在本研究中，我们报告了从与软珊瑚相关的海洋源真菌二孢青霉 KMM 4689 中分离出一种新的吲哚二酮哌嗪生物碱脱氧-14,15-脱氢异乌司他胺 (1)。通过 HR-MS、1D 和 2D NMR 以及 CD 数据确定了这种代谢物的结构，包括其绝对构型。化合物 1 是一种在脯氨酸环上具有两个双键的脱氧异乌斯塔酰胺生物碱。分离出的化合物对人类正常细胞株和癌细胞株无细胞毒性，毒性最高可达 100 µM。同时，化合物 1 能使前列腺癌 22Rv1 细胞对雄激素受体（AR）阻断剂恩杂鲁胺（enzalutamide）重新敏感。这一现象的机制被确定为药物诱导的雄激素受体转录变体 V7（AR-V7）的特异性降解，这也导致了 AR 信号的普遍抑制。我们的数据表明，分离出的生物碱是联合治疗阉割耐药前列腺癌（包括耐药亚型）的理想候选药物。