比生群 | 78186-34-2

• 物质功能分类: 原料药 - 抗肿瘤药 - 其它抗肿瘤药
• 分子结构分类: 有机化合物 - 苯类化合物 - 蒽
• 中文名称: 比生群
• 中文别名: 9,10-蒽二甲醛双(4,5-二氢-1H-咪唑-2-基)腙；必桑那；必桑郡
• 英文名称: bisantrene
• 英文别名: Bisantreno；N-[[10-[(4,5-dihydro-1H-imidazol-2-ylhydrazinylidene)methyl]anthracen-9-yl]methylideneamino]-4,5-dihydro-1H-imidazol-2-amine
• CAS: 78186-34-2
• 化学式: C₂₂H₂₂N₈
• 分子量: 398.47
• InChiKey: NJSMWLQOCQIOPE-UHFFFAOYSA-N

物化性质

• 沸点：
  646.3±65.0 °C(Predicted)
• 密度：
  1.41±0.1 g/cm3(Predicted)
• 溶解度：
  去离子水中的溶解度：8mg/mL

计算性质

• 辛醇/水分配系数(LogP)：
  1.9
• 重原子数：
  30
• 可旋转键数：
  6
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.18
• 拓扑面积：
  97.6
• 氢给体数：
  4
• 氢受体数：
  4

安全信息

• 危险品标志：
  Xn,N
• 安全说明：
  S60,S61
• 危险类别码：
  R22,R50/53
• WGK Germany：
  3
• 海关编码：
  2933290090
• 危险标志：
  GHS07,GHS09
• 危险性描述：
  H302,H400
• 危险性防范说明：
  P273

制备方法与用途

生物活性

Bisantrene 是一种高效的抗肿瘤药物，靶向作用于真核生物的II型拓扑异构酶 (II topoisomerases)。Topoisomerase II

Bisantrene 显示出与 DNA 形成复合物的出色能力。它表现出最强的结合力（甚至忽略静电接触），其次是 9-取代化合物，最后是 1-IHA。尽管 Bisantrene 在 K_i 值上减少了六倍，但仍保持了约 10⁶M^-1 的亲和常数。Bisantrene 促进 DNase I 在寡嘌呤-寡嘧啶区段切割 DNA；相比之下，在交替嘌呤-嘧啶序列上的切割活性略有降低。Bisantrene 是治疗转移性乳腺癌的有效新药。它是一种抑制 [³H]尿苷掺入 RNA 和 [³H]胸苷掺入 DNA 的抑制剂。

化学性质

二盐酸比生群 (Bisantrene Dihydrochloride)：C₂₂H₂₂N₈·2HCl。[71439-68-4]。从乙醇中获得橙色结晶性固体，其半水合物熔点为 288～289℃（分解）。UV 最大吸收 (水)：260, 415 nm （ε72700, 16300）

用途

蒽环类细胞生长抑制剂，用于抗肿瘤。对恶性淋巴瘤、黑色素瘤、急性白血病、卵巢癌和肾癌有效。

生产方法

9,10-蒽二醛与 2-肼基-2-咪唑啉二盐酸盐反应，得到二盐酸比生群。

类别

有毒物品

毒性分级

高毒

急性毒性

未名-小鼠 LD₅₀：245毫克/公斤

可燃性危险特性

可燃；燃烧产生有毒氮氧化物烟雾

储运特性

库房通风、低温干燥；与食品原料分开存放

灭火剂

干粉、泡沫、沙土、二氧化碳、雾状水

反应信息

• 作为反应物：
  描述：

  比生群 在 N,O-双三甲硅基乙酰胺 、 碘代三甲硅烷 、 水 、 三苯基膦 作用下， 以 二氯甲烷 为溶剂， 反应 3.5h， 生成 <2-<<<10-<<(4,5-dihydro-1H-imidazol-2-yl)hydrazono>methyl>-9-anthracenyl>methylene>hydrazino>-4,5-dihydro-1H-imidazol-1-yl>phosphonic acid
  参考文献：
  名称：

  N-Phosphoryl derivatives of bisantrene. Antitumor prodrugs with enhanced solubility and reduced potential for toxicity

  摘要：

  The selective phosphorylation of bisantrene (1) affords bis(phosphonoguanidinic acid) 6, a prodrug with enhanced aqueous solubility (as sodium salt 7) at physiological pH. Unlike 1, in a rat tail vein model, no precipitation was observed when bis(phosphonoguanidinic acid) 6 was injected. While in rats 6 hydrolyzed to monophosphonoguanidinic acid 9 with a half-life of ca. 12 min., complete hydrolysis to bisantrene required several hours. The corresponding monophosphonoguanidinic acid 9 was synthesized from bisantrene and also showed good solubility and antitumor activity. While the antitumor activities of 6 in mice were comparable to bisantrene against B-16 melanoma and P-388 and L-1210 leukemias, it was inactive in vitro vs several tumor cell types. Thus, its activity in vivo resulted from its ability to serve as a prodrug for bisantrene.

  DOI：

  10.1021/jm00067a007

文献信息

• 一种高活性的离子型比生群衍生物及其合成 方法和应用
  申请人：广西师范大学

  公开号：CN108822038B

  公开（公告）日：2021-09-24

  本发明公开了一种高活性的离子型比生群衍生物及其合成方法和应用。所述衍生物的合成方法为：取氯金酸或氯金酸盐和比生群在极性溶剂中，在加热条件下反应，所得反应物冷却，静置析晶，收集晶体，即得目标产物；其中，所述的氯金酸盐为二水合氯金酸钠或氯金酸钾；所述的极性溶剂为选自含1‑3个碳原子的低碳醇中的一种或两种以上的组合，或者是二氯甲烷和/或三氯甲烷与选自含1‑3个碳原子的低碳醇中的一种或两种以上的组合，此时，二氯甲烷和/或三氯甲烷在极性溶剂中所占的比例为≤50v/v％。本发明所述衍生物对某些典型的人肿瘤细胞株具体显著的体外抗肿瘤活性，且对正常肝细胞HL‑7702的毒性低。本发明所述衍生物的结构如下式(I)所示：
• Antitumor agents. II. Bis(guanylhydrazones) of anthracene-9,10-dicarboxaldehydes
  作者：K. C. Murdock、R. G. Child、Yang I Lin、J. D. Warren、P. F. Fabio、Ving J. Lee、P. T. Izzo、S. A. Lang、Robert B. Angier

  DOI：10.1021/jm00347a006

  日期：1982.5

  9,10-Anthracenedicarboxaldehyde bis[(4,5-dihydro-1H-imidazol-2-yl)hydrazone] (bisantrene, VI-1) showed anticancer activity in mice vs. both leukemias and solid tumors. Increases in life span vs. the following neoplasms were: P-388 leukemia, 137%; B-16 melanoma, 122%; Lieberman plasma cell tumor, greater than 85%; colon tumor 26, 150%; Ridgway osteogenic sarcoma, 85%. There were significant numbers of long-term survivors. Both DNA and RNA synthesis were strongly inhibited. The drug was resistant to biodegradation and was bound strongly to tissues; in monkeys the half-life for disappearance from serum was 6 days. Related hydrazones were synthesized, and structure-activity relationships are discussed. Two routes to ring-substituted anthracene-9,10-dicarboxaldehyde intermediates were developed.
• N-Phosphoryl derivatives of bisantrene. Antitumor prodrugs with enhanced solubility and reduced potential for toxicity
  作者：K. C. Murdock、Ving J. Lee、Ronald V. Citarella、Frederick E. Durr、Gabriela Nicolau、Michael Kohlbrenner

  DOI：10.1021/jm00067a007

  日期：1993.7

  The selective phosphorylation of bisantrene (1) affords bis(phosphonoguanidinic acid) 6, a prodrug with enhanced aqueous solubility (as sodium salt 7) at physiological pH. Unlike 1, in a rat tail vein model, no precipitation was observed when bis(phosphonoguanidinic acid) 6 was injected. While in rats 6 hydrolyzed to monophosphonoguanidinic acid 9 with a half-life of ca. 12 min., complete hydrolysis to bisantrene required several hours. The corresponding monophosphonoguanidinic acid 9 was synthesized from bisantrene and also showed good solubility and antitumor activity. While the antitumor activities of 6 in mice were comparable to bisantrene against B-16 melanoma and P-388 and L-1210 leukemias, it was inactive in vitro vs several tumor cell types. Thus, its activity in vivo resulted from its ability to serve as a prodrug for bisantrene.