多杀菌素B | 131929-61-8

• 分子结构分类: 有机化合物 - 有机氧化合物
• 中文名称: 多杀菌素B
• 英文名称: N-demethyl-spinosyn A
• 英文别名: Spinosyn B；(1S,2R,5S,7R,9R,10S,14R,15S,19S)-19-ethyl-14-methyl-15-[(2R,5S,6R)-6-methyl-5-(methylamino)oxan-2-yl]oxy-7-[(2R,3R,4R,5S,6S)-3,4,5-trimethoxy-6-methyloxan-2-yl]oxy-20-oxatetracyclo[10.10.0.02,10.05,9]docosa-3,11-diene-13,21-dione
• CAS: 131929-61-8
• 化学式: C₄₀H₆₃NO₁₀
• 分子量: 717.941
• InChiKey: VESRDXZDAAOUHS-KXRJSVEISA-N

物化性质

• 沸点：
  800.8±65.0 °C(Predicted)
• 密度：
  1.17±0.1 g/cm3(Predicted)
• 溶解度：
  可溶于氯仿（少许）、甲醇（少许）

计算性质

• 辛醇/水分配系数(LogP)：
  4.5
• 重原子数：
  51
• 可旋转键数：
  9
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.85
• 拓扑面积：
  120
• 氢给体数：
  1
• 氢受体数：
  11

反应信息

• 作为反应物：
  描述：

  多杀菌素B 在 potassium carbonate 作用下， 以 乙腈 为溶剂， 反应 72.0h， 生成 3-[[(2R,3S,6R)-6-[[(1S,2R,5S,7R,9R,10S,14R,15S,19S)-19-ethyl-14-methyl-13,21-dioxo-7-[(2R,3R,4R,5S,6S)-3,4,5-trimethoxy-6-methyloxan-2-yl]oxy-20-oxatetracyclo[10.10.0.02,10.05,9]docosa-3,11-dien-15-yl]oxy]-2-methyloxan-3-yl]-methylamino]propyl-triphenylphosphanium;bromide
  参考文献：
  名称：

  DLC修饰的多杀菌素衍生物的合成及抗OXPHOS，抗肿瘤活性

  摘要：

  合成了一系列DLC（离域亲脂性阳离子）修饰的多杀菌素衍生物，并在体内和体外评估了其抗肿瘤功效。基于癌细胞的抗增殖试验表明，亲脂性越强的衍生物对被测癌细胞系的抑制作用越强。化合物7b和8b表现出强的抗OXPHOS和细胞凋亡诱导能力。在体内观察到了显着的7b（5 mg / kg）和8b（2.5 mg / kg）的抗肿瘤功效肿瘤异种移植实验，然而，在更高剂量下观察到致命毒性。我们的发现表明，DLC修饰是增强多杀菌素衍生物抗OXPHOS和抗肿瘤功效的可行策略。

  DOI：

  10.1016/j.bmcl.2020.127047
• 作为产物：
  描述：

  多杀菌素 在 碘 、 sodium acetate 作用下， 以 甲醇 、 水 为溶剂， 反应 12.0h， 以81%的产率得到多杀菌素B
  参考文献：
  名称：

  DLC修饰的多杀菌素衍生物的合成及抗OXPHOS，抗肿瘤活性

  摘要：

  合成了一系列DLC（离域亲脂性阳离子）修饰的多杀菌素衍生物，并在体内和体外评估了其抗肿瘤功效。基于癌细胞的抗增殖试验表明，亲脂性越强的衍生物对被测癌细胞系的抑制作用越强。化合物7b和8b表现出强的抗OXPHOS和细胞凋亡诱导能力。在体内观察到了显着的7b（5 mg / kg）和8b（2.5 mg / kg）的抗肿瘤功效肿瘤异种移植实验，然而，在更高剂量下观察到致命毒性。我们的发现表明，DLC修饰是增强多杀菌素衍生物抗OXPHOS和抗肿瘤功效的可行策略。

  DOI：

  10.1016/j.bmcl.2020.127047

文献信息

• Synthetic modification of Spinosyn compounds
  申请人：Dow AgroSciences LLC

  公开号：US06001981A1

  公开（公告）日：1999-12-14

  The compounds of the present invention are prepared directly or indirectly by modifying the compounds that are naturally produced from Saccharopolyspora spinosa. The compounds of the invention have been shown to have activity against insects and mites. The compounds are prepared by modifying the rhamnose sugar, modification of the forosamine sugar, or starting with pseuodoaglycone and then replacement with a nonsugar derivative or different sugar, modification of the 5,6,5-tricyclic and 12-membered macrocyclic lactone part of the compounds naturally produced or of the pseudoaglycone of the natural compounds.

  该发明的化合物是通过直接或间接修改从Saccharopolyspora spinosa自然产生的化合物而制备的。该发明的化合物已被证明对昆虫和螨有活性。该化合物是通过修改鼠李糖糖、修改佛罗萨胺糖，或者从伪甘基酮开始，然后用非糖衍生物或不同的糖替换，修改自然产生的化合物的5,6,5-三环和12-成员大环内酯部分，或者修改自然化合物的伪甘基酮而制备的。
• A HIGH-THROUGHPUT (HTP) GENOMIC ENGINEERING PLATFORM FOR IMPROVING SACCHAROPOLYSPORA SPINOSA
  申请人：Zymergen Inc.

  公开号：US20200115705A1

  公开（公告）日：2020-04-16

  The present disclosure provides a HTP microbial genomic engineering platform for Saccharopolyspora spp. that is computationally driven and integrates molecular biology, automation, and advanced machine learning protocols. This integrative platform utilizes a suite of HTP molecular tool sets to create HTP genetic design libraries, which are derived from, inter alia, scientific insight and iterative pattern recognition.
• Synthesis and anti-OXPHOS, antitumor activities of DLC modified spinosyn derivatives
  作者：Da-You Ma、Qin Lai、Kun-Jian Peng、Long-Long Wang、Zeng-Xia Li、Li-Jun Liu、Zhi-Yong Luo、Su-You Liu

  DOI：10.1016/j.bmcl.2020.127047

  日期：2020.5

  A series of DLC (delocalized lipophilic cation) modified spinosyn derivatives were synthesized and evaluated for antitumor efficacies both in vitro and in vivo. Cancer cell based antiproliferative assays indicated that the more lipophilic derivatives had stronger inhibitory effects on the tested cancer cell lines. Compound 7b and 8b exhibited strong anti-OXPHOS and apoptosis inducing ability. Notable

  合成了一系列DLC（离域亲脂性阳离子）修饰的多杀菌素衍生物，并在体内和体外评估了其抗肿瘤功效。基于癌细胞的抗增殖试验表明，亲脂性越强的衍生物对被测癌细胞系的抑制作用越强。化合物7b和8b表现出强的抗OXPHOS和细胞凋亡诱导能力。在体内观察到了显着的7b（5 mg / kg）和8b（2.5 mg / kg）的抗肿瘤功效肿瘤异种移植实验，然而，在更高剂量下观察到致命毒性。我们的发现表明，DLC修饰是增强多杀菌素衍生物抗OXPHOS和抗肿瘤功效的可行策略。
• Naturally-occurring spinosyn A and its derivatives function as argininosuccinate synthase activator and tumor inhibitor
  作者：Zizheng Zou、Xiyuan Hu、Tiao Luo、Zhengnan Ming、Xiaodan Chen、Li Xia、Wensong Luo、Jijia Li、Na Xu、Ling Chen、Dongsheng Cao、Min Wen、Fanrong Kong、Kunjian Peng、Yuanzhu Xie、Xuan Li、Dayou Ma、Chuanyu Yang、Ceshi Chen、Wenjun Yi、Ousheng Liu、Suyou Liu、Junli Luo、Zhiyong Luo

  DOI：10.1038/s41467-021-22235-8

  日期：——

  Argininosuccinate synthase (ASS1) is a ubiquitous enzyme in mammals that catalyzes the formation of argininosuccinate from citrulline and aspartate. ASS1 genetic deficiency in patients leads to an autosomal recessive urea cycle disorder citrullinemia, while its somatic silence or down-regulation is very common in various human cancers. Here, we show that ASS1 functions as a tumor suppressor in breast cancer, and the pesticide spinosyn A (SPA) and its derivative LM-2I suppress breast tumor cell proliferation and growth by binding to and activating ASS1. The C13-C14 double bond in SPA and LM-2I while the Cys97 (C97) site in ASS1 are critical for the interaction between ASS1 and SPA or LM-2I. SPA and LM-2I treatment results in significant enhancement of ASS1 enzymatic activity in breast cancer cells, particularly in those cancer cells with low ASS1 expression, leading to reduced pyrimidine synthesis and consequently the inhibition of cancer cell proliferation. Thus, our results establish spinosyn A and its derivative LM-2I as potent ASS1 enzymatic activator and tumor inhibitor, which provides a therapeutic avenue for tumors with low ASS1 expression and for those non-tumor diseases caused by down-regulation of ASS1.

  摘要：精氨酸琥珀酸合成酶（ASS1）是哺乳动物中广泛存在的一种酶，可以催化柠檬酸和天冬氨酸形成精氨酸琥珀酸。患者中的ASS1遗传缺陷会导致常染色体隐性遗传的尿素循环障碍柠檬酸血症，而其体细胞的沉默或下调在各种人类癌症中非常常见。在这里，我们展示了ASS1在乳腺癌中作为肿瘤抑制剂的功能，杀虫剂spinosyn A（SPA）及其衍生物LM-2I通过与激活ASS1结合来抑制乳腺肿瘤细胞的增殖和生长。SPA和LM-2I中的C13-C14双键，而ASS1中的Cys97（C97）位点对ASS1与SPA或LM-2I之间的相互作用至关重要。SPA和LM-2I的治疗导致乳腺癌细胞中ASS1酶活性显著增强，特别是在那些ASS1表达较低的癌细胞中，导致嘧啶合成减少，从而抑制癌细胞的增殖。因此，我们的结果确定了spinosyn A及其衍生物LM-2I作为有效的ASS1酶活化剂和肿瘤抑制剂，为那些ASS1表达较低的肿瘤和由ASS1下调引起的非肿瘤性疾病提供了治疗途径。