28-propynoylbetulin | 1449483-24-2

• 分子结构分类: 有机化合物 - 脂质和类脂质分子 - 异戊烯醇脂质
• 英文名称: 28-propynoylbetulin
• 英文别名: 28-O-propynoylbetulin；[(1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-9-hydroxy-5a,5b,8,8,11a-pentamethyl-1-prop-1-en-2-yl-1,2,3,4,5,6,7,7a,9,10,11,11b,12,13,13a,13b-hexadecahydrocyclopenta[a]chrysen-3a-yl]methyl prop-2-ynoate
• CAS: 1449483-24-2
• 化学式: C₃₃H₅₀O₃
• 分子量: 494.758
• InChiKey: PAQFZQUCBKFDRM-HXONJNHBSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  9.3
• 重原子数：
  36
• 可旋转键数：
  4
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.85
• 拓扑面积：
  46.5
• 氢给体数：
  1
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  28-propynoylbetulin 在 pyridinium chlorochromate 作用下， 以 二氯甲烷 为溶剂， 反应 2.0h， 以78%的产率得到3-oxo-28-propynoylbetulin
  参考文献：
  名称：

  桦木和桦木酮的新炔属衍生物，合成和细胞毒性活性。

  摘要：

  Betulin 1及其半合成衍生物对各种癌细胞系均具有细胞毒活性。这些化合物是有希望和潜在的抗癌候选物。制备了一系列桦木素衍生物，并测试了其对T47D乳腺癌，CCRF / CEM白血病，HL-60早幼粒细胞白血病，SW707大肠，鼠P388白血病以及BALB3T3正常成纤维细胞系的体外抗增殖活性。顺铂和白蛋白1用作参考化合物。白桦蛋白的某些衍生物显示出比母体化合物1高的细胞毒活性。两种衍生物（5和17）的效力是桦木蛋白1的24倍抗人早幼粒细胞白血病细胞系（HL-60），IC 50值为0.3 µg / mL。

  DOI：

  10.1007/s00044-016-1713-9
• 作为产物：
  描述：

  白桦脂醇 、 丙炔酸 在 4-二甲氨基吡啶 、 N,N'-二环己基碳二亚胺 作用下， 以 二氯甲烷 为溶剂， 以83%的产率得到28-propynoylbetulin
  参考文献：
  名称：

  连接到白桦脂醇衍生物上的 1,4-醌部分作为有效的 DT-黄递酶底物的设计、合成和生物活性

  摘要：

  在这项研究中，桦木脑衍生物通过三唑接头与 1,4-醌片段结合。此外，所使用的酶促测定表明，这些化合物是良好的 DT-黄递酶 (NQO1) 底物，这可以通过相对于链黑素酶的酶促转化率增加来证明。针对一组人类细胞系测试了杂交体的抗癌活性，例如：黑色素瘤、卵巢癌、乳腺癌、结肠癌和肺癌。构效关系表明活性取决于 1,4-醌部分的类型和使用的肿瘤细胞系。还发现对 NQO1 蛋白水平较高的细胞系的抗癌作用正在增加，例如：乳腺癌（T47D、MCF-7）、结肠癌（Caco-2）和肺癌（A549）癌。编码增殖标记（H3组蛋白）的基因的转录活性，确定了所选化合物的细胞周期调节剂（p53 和 p21）和细胞凋亡途径（BCL-2 和 BAX）。进行分子对接研究以检查杂交体与 NQO1 酶之间的相互作用。计算模拟表明，1,4-醌部分的类型会影响化合物在酶活性位点中的位置。值得注意的是，以桦木脑为 NQO1 蛋白底物的

  DOI：

  10.1016/j.bioorg.2020.104478

文献信息

• Betulin-1,4-quinone hybrids: Synthesis, anticancer activity and molecular docking study with NQO1 enzyme
  作者：Monika Kadela-Tomanek、Ewa Bębenek、Elwira Chrobak、Krzysztof Marciniec、Małgorzata Latocha、Dariusz Kuśmierz、Maria Jastrzębska、Stanisław Boryczka

  DOI：10.1016/j.ejmech.2019.05.063

  日期：2019.9

  4-quinone hybrids were obtain by connecting two active structures with a linker. This strategy allows for obtaining compounds showing a high biological activity and better bioavailability. In this research, synthesis, anticancer activity and molecular docking study of betulin-1,4-quinone hybrids are presented. Newly synthesized compounds were characterized by 1H, 13C NMR, IR and HR-MS. Hybrids were tested in vitro

  Betulin-1,4-醌杂化物是通过将两个活性结构与接头连接而获得的。该策略允许获得显示出高生物活性和更好的生物利用度的化合物。在这项研究中，提出了betulin-1,4-quinone杂种的合成，抗癌活性和分子对接研究。新合成的化合物通过1 H，13 C NMR，IR和HR-MS进行表征。杂种体外测试对抗包括胶质母细胞瘤，黑素瘤，乳腺癌和肺癌在内的一系列人类细胞系。它们显示出高的细胞毒活性，具体取决于1，4-醌部分的类型和所应用的肿瘤细胞系。发现研究的杂种对具有较高NQO1蛋白水平的细胞系的细胞毒性活性正在增加，例如黑色素瘤（C-32），乳腺癌（MCF-7）和肺癌（A-549）。测试了选定的杂种对编码增殖标记（H3组蛋白），细胞周期调节子（p53和p21）和凋亡途径（BCL-2和BAX）的基因的转录活性。获得的结果表明，所测试的化合物在A549和MCF-7细胞系中引起线粒体凋亡途径。分子对接用于检查杂种与人NAD
• Novel Triazole Hybrids of Betulin: Synthesis and Biological Activity Profile
  作者：Ewa Bębenek、Maria Jastrzębska、Monika Kadela-Tomanek、Elwira Chrobak、Beata Orzechowska、Katarzyna Zwolińska、Małgorzata Latocha、Anna Mertas、Zenon Czuba、Stanisław Boryczka

  DOI：10.3390/molecules22111876

  日期：——

  biological activities, including antiviral, anticancer, and antibacterial activity. A series of novel triazoles were prepared by the 1,3-dipolar cycloaddition reaction between the alkyne derivatives of betulin and organic azides. The chemical structures of the obtained compounds were defined by 1H and 13C NMR, IR, and high-resolution mass spectrometry (HR-MS) analysis. The target triazoles were screened

  含有 1,2,3-三唑环的桦木脑衍生物具有广泛的生物活性，包括抗病毒、抗癌和抗菌活性。通过桦木醇炔衍生物与有机叠氮化物之间的1,3-偶极环加成反应制备了一系列新型三唑类化合物。所得化合物的化学结构由 1H 和 13C NMR、IR 和高分辨率质谱 (HR-MS) 分析确定。筛选目标三唑类化合物对 DNA 和 RNA 病毒的抗病毒活性。使用五种人类癌细胞系（T47D、MCF-7、SNB-19、Colo-829 和 C-32）通过 WST-1 测定法测定所得化合物 5a-k 和 6a-h 的细胞毒活性。双三唑 6b 显示出有希望的 IC50 值 (0. 05 μM）对抗人导管癌 T47D（比顺铂的效力高 500 倍）。微量稀释法用于评价所有化合物的抗微生物活性。含有 3'-脱氧胸苷-5'-基部分的三唑 5e 对两种革兰氏阴性菌 vz 表现出抗菌活性。肺炎克雷伯菌和大肠杆菌（最小抑制浓度 (MIC)
• Synthesis, Structure and Cytotoxic Activity of New Acetylenic Derivatives of Betulin
  作者：Stanisław Boryczka、Ewa Bębenek、Joanna Wietrzyk、Katarzyna Kempińska、Maria Jastrzębska、Joachim Kusz、Maria Nowak

  DOI：10.3390/molecules18044526

  日期：——

  A new series of betulin derivatives containing one or two pharmacophores bearing an acetylenic and carbonyl function at the C-3 and/or C-28 positions has been synthesized and characterized by 1H- and 13C-NMR, IR, MS and elemental analyses. The crystal structure of 28-O-propynoylbetulin was determined by X-ray structural analysis. All new compounds, as well as betulin, were tested in vitro for their antiproliferative activity against human SW707 colorectal, CCRF/CEM leukemia, T47D breast cancer, and against murine P388 leukemia and Balb3T3 normal fibroblasts cell lines. Most of the compounds showed better cytotoxicity than betulin and cisplatin used as reference agent. 28-O-Propynoylbetulin was the most potent derivative, being over 500 times more potent than betulin and about 100 times more cytotoxic than cisplatin against the human leukemia (CCRF/CEM) cell line, with an ID50 value of 0.02 μg/mL.

  一种新的含有一个或两个药效团的贝图林衍生物已被合成，这些药效团在C-3和/或C-28位置上具有炔烃和羰基功能。通过高分辨率的1H-NMR、13C-NMR、红外光谱、质谱以及元素分析对其进行了表征。28-O-丙炔酰贝图林的晶体结构通过X射线结构分析确定。所有新的化合物以及贝图林在体外测试了其对人SW707结肠癌、CCRF/CEM白血病、T47D乳腺癌及小鼠P388白血病和Balb3T3正常成纤维细胞株的抗增殖活性。大多数化合物的细胞毒性优于作为参考药物的贝图林和顺铂。28-O-丙炔酰贝图林是最有效的衍生物，其活性比贝图林强超过500倍，对人白血病（CCRF/CEM）细胞株的细胞毒性约为顺铂的100倍，ID50值为0.02 μg/mL。
• Anticancer Activity of the Acetylenic Derivative of Betulin Phosphate Involves Induction of Necrotic-Like Death in Breast Cancer Cells In Vitro
  作者：Arkadiusz Orchel、Ewa Chodurek、Marzena Jaworska-Kik、Piotr Paduszyński、Anna Kaps、Elwira Chrobak、Ewa Bębenek、Stanisław Boryczka、Paulina Borkowska、Janusz Kasperczyk

  DOI：10.3390/molecules26030615

  日期：——

  Betulin (BT) is a natural pentacyclic lupane-type triterpene exhibiting anticancer activity. Betulin derivatives bearing propynoyloxy and phosphate groups were prepared in an effort to improve the availability and efficacy of the drug. In this study, a comparative assessment of the in vitro anticancer activity of betulin and its four derivatives was carried out using two human breast cancer cell lines: SK-BR-3 and MCF-7. In both studied cell lines, 30-diethoxyphosphoryl-28-propynoylbetulin (compound 4) turned out to be the most powerful inhibitor of growth and inducer of cellular death. Detailed examination of that derivative pertained to the mechanisms underlying its anticancer action. Treatment with compound 4 decreased DNA synthesis and up-regulated p21WAF1/Cip1 mRNA and protein levels in both cell lines. On the other hand, that derivative caused a significant increase in cell death, as evidenced by increased lactate dehydrogenase (LDH) release and ethidium homodimer uptake. Shortly after the compound addition, an increased generation of reactive oxygen species and loss of mitochondrial membrane potential were detected. The activation of caspase-3 and fragmentation of genomic DNA suggested an apoptotic type of cell death. However, analysis of cellular morphology did not reveal any nuclear features typical of apoptosis. Despite necrosis-like morphology, dead cells exhibited activation of the cascade of caspases. These observations have led to the conclusion that compound 4 pushed cells to undergo a form of necrotic-like regulated cell demise.

  莽桦醇（BT）是一种天然的五环鲁班型三萜，具有抗癌活性。为了提高药物的可用性和功效，制备了带有丙炔氧基和磷酸酯基团的莽桦醇衍生物。本研究使用两种人类乳腺癌细胞系SK-BR-3和MCF-7对莽桦醇及其四个衍生物的体外抗癌活性进行了比较评估。在两种研究的细胞系中，30-二乙氧磷酰基-28-丙炔酰基莽桦醇（化合物4）被证明是生长抑制和诱导细胞死亡最强大的抑制剂。对该衍生物的详细检查涉及其抗癌作用的机制。用化合物4处理可降低DNA合成并在两种细胞系中上调p21WAF1/Cip1 mRNA和蛋白水平。另一方面，该衍生物导致细胞死亡显著增加，表现为乳酸脱氢酶（LDH）释放和乙溴溴化丙啶摄取增加。化合物添加后不久，检测到活性氧自由基的产生增加和线粒体膜电位的丧失。激活caspase-3和基因组DNA断裂表明细胞凋亡型死亡。然而，细胞形态学分析未显示出任何典型凋亡的核特征。尽管有类似坏死的形态，死细胞表现出一系列caspases的激活。这些观察结果导致结论，化合物4促使细胞经历一种类似坏死的调节性细胞死亡形式。
• Acetylenic Synthetic Betulin Derivatives Inhibit Akt and Erk Kinases Activity, Trigger Apoptosis and Suppress Proliferation of Neuroblastoma and Rhabdomyosarcoma Cell Lines
  作者：Sylwia K. Król、Ewa Bębenek、Magdalena Dmoszyńska-Graniczka、Adrianna Sławińska-Brych、Stanisław Boryczka、Andrzej Stepulak

  DOI：10.3390/ijms222212299

  日期：——

  Neuroblastoma (NB) and rhabdomyosarcoma (RMS), the most common pediatric extracranial solid tumors, still represent an important clinical challenge since no effective treatment is available for metastatic and recurrent disease. Hence, there is an urgent need for the development of new chemotherapeutics to improve the outcome of patients. Betulin (Bet), a triterpenoid from the bark of birches, demonstrated interesting anti-cancer potential. The modification of natural phytochemicals with evidenced anti-tumor activity, including Bet, is one of the methods of receiving new compounds for potential implementation in oncological treatment. Here, we showed that two acetylenic synthetic Bet derivatives (ASBDs), EB5 and EB25/1, reduced the viability and proliferation of SK-N-AS and TE671 cells, as measured by MTT and BrdU tests, respectively. Moreover, ASBDs were also more cytotoxic than temozolomide (TMZ) and cisplatin (cis-diaminedichloroplatinum [II], CDDP) in vitro, and the combination of EB5 with CDDP enhanced anti-cancer effects. We also showed the slowdown of cell cycle progression at S/G2 phases mediated by EB5 using FACS flow cytometry. The decreased viability and proliferation of pediatric cancers cells after treatment with ASBDs was linked to the reduced activity of kinases Akt, Erk1/2 and p38 and the induction of apoptosis, as investigated using Western blotting and FACS. In addition, in silico analyses of the ADMET profile found EB5 to be a promising anti-cancer drug candidate that would benefit from further investigation.

  神经母细胞瘤（NB）和横纹肌肉瘤（RMS）是最常见的儿童体外实体肿瘤，由于对于转移性和复发性疾病没有有效的治疗方法，它们仍然代表着一个重要的临床挑战。因此，迫切需要开发新的化疗药物来改善患者的预后。白桦树皮中的三萜类化合物苯丙醇（Bet）显示出有趣的抗癌潜力。改性天然植物化学物质，包括Bet，是获得新化合物以潜在地用于肿瘤治疗的方法之一。在这里，我们展示了两种乙炔合成的Bet衍生物（ASBDs），EB5和EB25/1，通过MTT和BrdU测试分别减少了SK-N-AS和TE671细胞的存活率和增殖率。此外，在体外，ASBDs也比替莫唑胺（TMZ）和顺铂（二氯氨基铂，CDDP）更具细胞毒性，EB5与CDDP的联合使用增强了抗癌效果。我们还展示了使用FACS流式细胞术介导的EB5对S/G2期细胞周期进程的减速。在使用Western bloTTing和FACS进行研究后，发现ASBDs处理后儿童癌细胞的减少存活率和增殖率与激酶Akt、Erk1/2和p38的活性降低以及细胞凋亡诱导有关。此外，ADMET剖析的体外分析发现EB5是一个有前途的抗癌药物候选物，需要进一步研究。