阿克那霉素 S | 64431-69-2

• 分子结构分类: 有机化合物 - 苯丙烷和聚酮 - 蒽环类药物
• 中文名称: 阿克那霉素 S
• 中文别名: 阿克那霉素S
• 英文名称: aclacinomycin S
• 英文别名: 2-deoxy-fucosyl-rhodosaminyl-aklavinone；7-[2-deoxy-α-L-fucopyranosyl-(1→4)-3-dimethylamino-2,3-dideoxy-α-L-fucopyranoside]-aklavinone；(1R,2R,4S)-2-ethyl-2,7-dihydroxy-1-(methoxycarbonyl)-6,11-dioxo-4-{[2,3,6-trideoxy-4-O-(2,6-dideoxy-alpha-L-lyxo-hexopyranosyl)-3-(dimethylazaniumyl)-alpha-L-lyxo-hexopyranosyl]oxy}-1,2,3,4,6,11-hexahydrotetracen-5-olate；(1R,2R,4S)-4-[(2R,4S,5S,6S)-5-[(2S,4S,5S,6S)-4,5-dihydroxy-6-methyloxan-2-yl]oxy-4-(dimethylazaniumyl)-6-methyloxan-2-yl]oxy-2-ethyl-2,7-dihydroxy-1-methoxycarbonyl-6,11-dioxo-3,4-dihydro-1H-tetracen-5-olate
• CAS: 64431-69-2
• 化学式: C₃₆H₄₅NO₁₃
• 分子量: 699.752
• InChiKey: DNZPQXXGAMXDHH-FCNQEGBTSA-N

物化性质

• 沸点：
  817.3±65.0 °C(Predicted)
• 密度：
  1.45±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.9
• 重原子数：
  50
• 可旋转键数：
  8
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.58
• 拓扑面积：
  202
• 氢给体数：
  5
• 氢受体数：
  14

反应信息

• 作为反应物：
  描述：

  阿克那霉素 S 、 dTDP-2-deoxy-beta-L-fucose(2-) 生成 2-deoxy-L-fucosyl-2-deoxy-L-fucosyl-rhodosaminyl-aklavinone 、 TMP 、 氢(+1)阳离子
  参考文献：
  名称：

  AknK Is an l-2-Deoxyfucosyltransferase in the Biosynthesis of the Anthracycline Aclacinomycin A

  摘要：

  The antitumor drug aclacinomycin A is a representative member of the anthracycline subgroup that contains a C-7-O-trisaccharide chain composed Of L-2-deoxysugars. The sugar portion of the molecule, which greatly affects its biological activity, is assembled by dedicated glycosyltransferases; however, these enzymes have not been well-studied. Here we report the heterologous expression and purification of one of these enzymes, AknK, as well as the preparation of dTDP-L-2-deoxysugar donors, dTDP-L-2-deoxyfucose and dTDP-L-daunosamine, and the monoglycosyl aglycone, rhodosaminyl aklavinone. Our experiments show that AknK catalyzes the addition of the second sugar to the chain, using TDP-L-2-deoxyfucose and rhodosaminyl aklavinone, to create the L-2-deoxyfucosyl-L-rhodosaminyl aklavinone. AknK also accepts an alternate dTDP-L-sugar, dTDP-L-daunosamine, and other monoglycosylated anthracyclines, including daunomycin, adriamycin, and idarubicin, to build alternate disaccharides on variant anthracycline backbones. Remarkably, AknK also catalyzes a tandem addition of a second L-2-deoxyfucosyl moiety, albeit with reduced activity, to the natural disaccharide chain to produce L-deoxyfucosyl-L-deoxyfucosyl-L-rhodosaminyl aklavinone, a variant of the natural aclacinomycin A. These results demonstrate that AknK may be a useful enzyme for the chemoenzymatic synthesis of anthracycline variants.

  DOI：

  10.1021/bi035945i
• 作为产物：
  描述：

  聚合甲醛 、 7-[2-deoxy-α-L-fucopyranosyl-(1→4)-3-amino-2,3-dideoxy-α-L-fucopyranoside]-aklavinone 在 乙醇 、 三乙酰氧基硼氢化钠 作用下， 以 水 为溶剂， 反应 2.5h， 以34%的产率得到阿克那霉素 S
  参考文献：
  名称：

  Doxorubicin and Aclarubicin: Shuffling Anthracycline Glycans for Improved Anticancer Agents

  摘要：

  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.

  DOI：

  10.1021/acs.jmedchem.0c01191

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，
• 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.
• AknK Is an <scp>l</scp>-2-Deoxyfucosyltransferase in the Biosynthesis of the Anthracycline Aclacinomycin A
  作者：Wei Lu、Catherine Leimkuhler、Markus Oberthür、Daniel Kahne、Christopher T. Walsh

  DOI：10.1021/bi035945i

  日期：2004.4.1

  The antitumor drug aclacinomycin A is a representative member of the anthracycline subgroup that contains a C-7-O-trisaccharide chain composed Of L-2-deoxysugars. The sugar portion of the molecule, which greatly affects its biological activity, is assembled by dedicated glycosyltransferases; however, these enzymes have not been well-studied. Here we report the heterologous expression and purification of one of these enzymes, AknK, as well as the preparation of dTDP-L-2-deoxysugar donors, dTDP-L-2-deoxyfucose and dTDP-L-daunosamine, and the monoglycosyl aglycone, rhodosaminyl aklavinone. Our experiments show that AknK catalyzes the addition of the second sugar to the chain, using TDP-L-2-deoxyfucose and rhodosaminyl aklavinone, to create the L-2-deoxyfucosyl-L-rhodosaminyl aklavinone. AknK also accepts an alternate dTDP-L-sugar, dTDP-L-daunosamine, and other monoglycosylated anthracyclines, including daunomycin, adriamycin, and idarubicin, to build alternate disaccharides on variant anthracycline backbones. Remarkably, AknK also catalyzes a tandem addition of a second L-2-deoxyfucosyl moiety, albeit with reduced activity, to the natural disaccharide chain to produce L-deoxyfucosyl-L-deoxyfucosyl-L-rhodosaminyl aklavinone, a variant of the natural aclacinomycin A. These results demonstrate that AknK may be a useful enzyme for the chemoenzymatic synthesis of anthracycline variants.