aklavin | 60504-57-6

• 分子结构分类: 有机化合物 - 苯丙烷和聚酮 - 蒽环类药物
• 英文名称: aklavin
• 英文别名: (1R,2R,4S)-2-ethyl-2,7-dihydroxy-1-(methoxycarbonyl)-6,11-dioxo-4-{[2,3,6-trideoxy-3-(dimethylazaniumyl)-alpha-L-lyxo-hexopyranosyl]oxy}-1,2,3,4,6,11-hexahydrotetracen-5-olate；(1R,2R,4S)-4-[(2R,4S,5S,6S)-4-(dimethylazaniumyl)-5-hydroxy-6-methyloxan-2-yl]oxy-2-ethyl-2,7-dihydroxy-1-methoxycarbonyl-6,11-dioxo-3,4-dihydro-1H-tetracen-5-olate
• CAS: 60504-57-6
• 化学式: C₃₀H₃₅NO₁₀
• 分子量: 569.609
• InChiKey: LJZPVWKMAYDYAS-QKKPTTNWSA-N

物化性质

• 沸点：
  633.08°C (rough estimate)
• 密度：
  1.2894 (rough estimate)

计算性质

• 辛醇/水分配系数(LogP)：
  3.1
• 重原子数：
  41
• 可旋转键数：
  6
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  163
• 氢给体数：
  4
• 氢受体数：
  11

反应信息

• 作为反应物：
  描述：

  aklavin 在 aclacinomycin-10-hydroxylase from streptomyces purpurascens 作用下， 生成 11-deoxy-β-rhodomycin T
  参考文献：
  名称：

  Divergent evolution of an atypical S -adenosyl- l -methionine–dependent monooxygenase involved in anthracycline biosynthesis

  摘要：

  标题：重要性 自然产物由链霉菌生产，在治疗各种医疗状况中被广泛使用。多年来，从这些土壤细菌的培养物中分离出了成千上万具有复杂化学结构的代谢产物。促进化学多样性的进化压力似乎对生成这种丰富的生物活性化合物来源至关重要。这体现在生物合成酶中，类似蛋白质的功能可能有很大不同。在这里，我们已经阐明了一个经典的甲基转移酶如何演变成两种蒽环类抗癌药物的生物合成途径中不寻常的羟化酶的分子基础。对参与抗生素生物合成的酶的详细理解将有助于未来的蛋白质工程努力，以生成改进的生物活性天然产物。

  DOI：

  10.1073/pnas.1501765112
• 作为产物：
  描述：

  7-(tetrahydropyranyl)-10-epi-aklavinone 在 吡啶 、 1,5-二氮杂双环[4.3.0]壬-5-烯 、 sodium methylate 、 sodium cyanoborohydride 、 对甲苯磺酸 、 溶剂黄146 作用下， 以 甲醇 、 二氯甲烷 、 水 、 苯 为溶剂， 反应 3.0h， 生成 aklavin
  参考文献：
  名称：

  Practical total synthesis of (.+-.)-aklavinone and total synthesis of aklavin

  摘要：

  DOI：

  10.1021/ja00404a047

文献信息

• Characterization of Rhodosaminyl Transfer by the AknS/AknT Glycosylation Complex and Its Use in Reconstituting the Biosynthetic Pathway of Aclacinomycin A
  作者：Catherine Leimkuhler、Micha Fridman、Tania Lupoli、Suzanne Walker、Christopher T. Walsh、Daniel Kahne

  DOI：10.1021/ja072909o

  日期：2007.8.1

  The tetracyclic core of anthracycline natural products with antitumor activity such as aclacinomycin A are tailored during biosynthesis by regioselective glycosylation. We report the first synthesis of TDP-L-rhodosamine and demonstrate that the glycosyltransferase AknS transfers L-rhodosamine to the aglycone to initiate construction of the side-chain trisaccharide. The partner protein AknT accelerates

  具有抗肿瘤活性的蒽环类天然产物（如阿克拉霉素 A）的四环核心在生物合成过程中通过区域选择性糖基化进行定制。我们报告了 TDP-L-罗多糖胺的首次合成，并证明糖基转移酶 AknS 将 L-罗多糖胺转移到苷元以启动侧链三糖的构建。伙伴蛋白 AknT 将用于 L-紫多糖胺转移的 AknS 周转率提高了 200 倍。AknT 不影响 Km，而是影响 kcat。使用这些数据，我们建议 AknT 导致 AknS 的构象变化，从而稳定过渡状态并最终增强转移。当随后的糖基转移酶 AknK 及其底物 TDP-L-岩藻糖也加入到苷元中时，
• Antibiotics aclacinomycins A and B
  申请人：Zaidan Hojin Biseibutsu Kagaku Kenkyu Kai

  公开号：US03988315A1

  公开（公告）日：1976-10-26

  New antitumor agents named aclacinomycins A and B, which are anthracycline glycosides and inhibit the growth of various microorganisms e.g., Staphylococcus aureus, Micrococcus flavus, Corynebacterium bovis and inhibit the growth of animal tumors such as leukemia L1210 and P388 and lymphoma 6C3HED in mice and hepatomas in rats are produced by the fermentation of a microorganism belonging to the genus Streptomyces which has been designated Streptomyces galilaeus (MA144-M1 and A.T.C.C. 31133); they are recovered from the broth by conventional methods for recovering antibiotics.

  新的抗肿瘤药物被命名为aclacinomycins A和B，它们是蒽环素糖苷，并抑制各种微生物的生长，如金黄色葡萄球菌、黄色微球菌、博氏杆菌，以及抑制动物肿瘤，如小鼠的白血病L1210和P388、淋巴瘤6C3HED和大鼠的肝癌。这些药物是通过属于链霉菌属的微生物Streptomyces galilaeus（MA144-M1和A.T.C.C. 31133）的发酵生产而来，可以通过传统的抗生素回收方法从培养基中提取。
• Antitumor antibiotics aclacinomycins A and B [RD-9187A]
  申请人：Zaidan Hojin Biseibutsu Kagaku Kenkyu Kai

  公开号：US04071411A1

  公开（公告）日：1978-01-31

  New antitumor agents named aclacinomycins A and B, which are anthracycline glycosides and inhibit the growth of various microorganisms e.g., Staphylococcus aureus, Micrococcus flavus, Corynebacterium bovis and inhibit the growth of animal tumors such as leukemia L1210 and P388 and lymphoma 6C3HED in mice and hepatomas in rats are produced by the fermentation of a microorganism belonging to the genus Streptomyces which has been designated Streptomyces galilaeus (MA144-M1 and A.T.C.C. 31133); they are recovered from the broth by conventional methods for recovering antibiotics.

  新的抗肿瘤药物命名为aclacinomycins A和B，它们是蒽环类糖苷，可以抑制多种微生物（如金黄色葡萄球菌、黄色微球菌、牛科林氏杆菌）的生长，并且可以抑制小鼠的白血病L1210和P388、淋巴瘤6C3HED以及大鼠的肝癌的生长。这些药物是由属于链霉菌属的微生物Streptomyces galilaeus（MA144-M1和ATCC 31133）通过发酵生产的，可以通过常规的抗生素回收方法从培养基中提取。
• Crystal Structure of Aclacinomycin Methylesterase with Bound Product Analogues
  作者：Anna Jansson、Jarmo Niemi、Pekka Mäntsälä、Gunter Schneider

  DOI：10.1074/jbc.m304008200

  日期：2003.10

  purpurascens in complex with the product analogues 10-decarboxymethylaclacinomycin T and 10-decarboxymethylaclacinomycin A were determined to nominal resolutions of 1.45 and 1.95 A, respectively. RdmC is built up of two domains. The larger alpha/beta domain shows the common alpha/beta hydrolase fold, whereas the smaller domain is alpha-helical. The active site and substrate binding pocket are located at the

  Aclacinomycin甲基酯酶（RdmC）是修饰链霉菌属类蒽环霉素生物合成中akakinone骨架的定制酶之一。来自紫链霉菌的该酶与产物类似物10-脱羧甲基aclacinomycin T和10-脱羧甲基aclacinomycin A复合的晶体结构分别被确定为标称分辨率1.45和1.95A。RdmC由两个域组成。较大的alpha / beta结构域显示常见的alpha / beta水解酶折叠，而较小的结构域为alpha-螺旋。活性位点和底物结合口袋位于两个结构域之间的界面。脱羧甲基ac霉素T和脱羧甲基ac霉素A在疏水口袋中靠近催化三联体（Ser102-His276-Asp248）结合，糖部分位于酶表面。配体的结合主要由疏水相互作用决定，特异性似乎主要由结合口袋的形状而不是特定的氢键控制。与RdmC与产物类似物的复合物结构一致的机制关键特征是Ser102充当亲核试剂，并通过残基Gly32和
• Doxorubicin and Aclarubicin: Shuffling Anthracycline Glycans for Improved Anticancer Agents
  作者：Dennis P. A. Wander、Sabina Y. van der Zanden、Gijsbert A. van der Marel、Herman S. Overkleeft、Jacques Neefjes、Jeroen D. C. Codée

  DOI：10.1021/acs.jmedchem.0c01191

  日期：2020.11.12

  Anthracycline anticancer drugs doxorubicin and aclarubicin have been used in the clinic for several decades to treat various cancers. Although closely related structures, their molecular mode of action diverges, which is reflected in their biological activity profile. For a better understanding of the structure-function relationship of these drugs, we synthesized ten doxorubicin/aclarubicin hybrids varying in three distinct features: aglycon, glycan, and amine substitution pattern. We continued to evaluate their capacity to induce DNA breaks, histone eviction, and relocated topoisomerase II alpha in living cells. Furthermore, we assessed their cytotoxicity in various human tumor cell lines. Our findings underscore that histone eviction alone, rather than DNA breaks, contributes strongly to the overall cytotoxicity of anthracyclines, and structures containing N,N-dimethylamine at the reducing sugar prove that are more cytotoxic than their nonmethylated counterparts. This structural information will support further development of novel anthracycline variants with improved anticancer activity.