5-bis<<(tert-butyldiphenylsilyl)oxy>methyl>tetrahydro-2-furanone | 172843-14-0

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 内酯类
• 英文名称: 5-bis<<(tert-butyldiphenylsilyl)oxy>methyl>tetrahydro-2-furanone
• 英文别名: 5,5-bis[(2,2-dimethyl-1,1-diphenyl-1-silapropoxy)methyl]-3,4,5-trihydrofuran-2-one；5,5-bis[(2,2-dimethyl-1,1-diphenyl-1-silapropoxy)methoxy]oxolan-2-one；5,5-bis(((tert-butyldiphenylsilyl)oxy)methyl)dihydrofuran-2(3H)-one；5,5-bis[[tert-butyl(diphenyl)silyl]oxymethyl]oxolan-2-one
• CAS: 172843-14-0
• 化学式: C₃₈H₄₆O₄Si₂
• 分子量: 622.952
• InChiKey: NXSSEMNSSZKBML-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  6.22
• 重原子数：
  44
• 可旋转键数：
  12
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.34
• 拓扑面积：
  44.8
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  5-bis<<(tert-butyldiphenylsilyl)oxy>methyl>tetrahydro-2-furanone 在 10percent Pd/C 吡啶 、 氢氟酸 、 氢气 、 1,8-二氮杂双环[5.4.0]十一碳-7-烯 、 三乙胺 、 lithium diisopropyl amide 作用下， 以 四氢呋喃 、 乙醇 、 正庚烷 、 二氯甲烷 、 乙基苯 为溶剂， -78.0~20.0 ℃ 、275.8 kPa 条件下， 反应 14.5h， 生成 (E)-5,5-bis(hydroxymethyl)-3-[4-methyl-3-(methylethyl)pentyl]oxolan-2-one
  参考文献：
  名称：

  构象受限的二酰基甘油（DAG）类似物。16.识别和对蛋白激酶C的高结合亲和力需要多少结构复杂性？

  摘要：

  具有低纳摩尔结合亲和力的有效蛋白激酶C（PK-C）配体的设计是通过结合使用基于生理酶激活剂二酰基甘油（DAG）的药效基团和受体指导的方法来完成的。以前使用基于DAG和佛波酯酯药效基团的结构等效性的方法，确定了用于构建半刚性“识别域”的固定模板，该模板包含受限制在内酯环（DAG）中的DAG的三个主要药效基团。 -内酯）。在目前的工作中，基于与佛波醇13-O-乙酸酯复合的PK-Cdelta C1b结构域的X射线结构，将药效团引导的方法改进到了更高的水平。一个系统的搜索，涉及用线性或支链酰基和α-亚烷基链的组合修饰DAG-内酯模板，它们起可变的疏水“亲和结构域”的作用，帮助鉴定了优化与一组保守的疏水氨基酸的疏水接触的化合物位于佛波结合的C1域的上半部分。分子的亲水/疏水平衡通过根据基于片段的方法计算出的辛醇/水分配系数（log P）进行估算。支链α-亚烷基或酰基链的存在对于达到PK-C的低纳摩尔

  DOI：

  10.1021/jm9904607
• 作为产物：
  描述：

  在 pyridinium chlorochromate 作用下， 以 二氯甲烷 为溶剂， 反应 36.0h， 生成 5-bis<<(tert-butyldiphenylsilyl)oxy>methyl>tetrahydro-2-furanone
  参考文献：
  名称：

  Conformationally Constrained Analogues of Diacylglycerol. 10. Ultrapotent Protein Kinase C Ligands Based on a Racemic 5-Disubstituted Tetrahydro-2-furanone Template

  摘要：

  5,5-Bis(hydroxymethyl)tetrahydro-2-furanone and its isomer 4,4-bis(hydroxymethyl)tetrahydro-2-furanone were investigated as possible templates for the construction of conformationally constrained analogues of the biologically important second messenger, diacylglycerol (DAG). The former lactone contains embedded within its structure an exact glycerol moiety, while in the latter the ring oxygen has been transposed to the other side of the carbonyl group. Al target compounds were synthesized as racemates from 1,3-dihydroxy-2-propanone. The 5,5-bis(hydroxymethyl)tetrahydro-2-furanone proved to be the better template for the construction of DAG surrogates that were demonstrated to have high binding affinities for the biological target, protein kinase C (PK-C). The simplest target compounds derived from this template (3e and 3f) have one of the hydroxyl moieties functionalized either as a myristate or as an oleate ester. The simplest target compound (9e) derived from the ineffective 4,4-bis(hydroxymethyl)tetrahydro-2-furanone template was investigated only with a myristoyl acyl chain. Reducing the long acyl chain to an acetyl moiety and attaching a compensating lipophilic chain to the lactone ring as an alpha-alkylidene moiety produced compounds 10e and 10f(Z-isomers) and 11e and 11f(E-isomers), which were constructed on the more effective 5,5-bis(hydroxymethyl)tetrahydro-2-furanone template. Targets 14c (Z-isomer) and 15c (E-isomer) were derived, in turn, from 4,4-bis(hydroxymethyl)tetrahydro-2-furan. The affinities of these ligands for PK-C were assessed in terms of their ability to displace bound [H-3-20]phorbol 12,13-dibutyrate (PDBU) from the single isozyme PK-C alpha. The biological data support the hypothesis that the increase in binding affinity for PK-C shown by some of these constrained DAG mimetics appears to be entropic in nature. Two of the designed ligands (10e and 10f) showed the highest affinities (34 and 24 nM, respectively) reported so far for a DAG analogue. Assuming that the interaction between these racemic compounds and PK-C is stereospecific, the potency of the active enantiomer is anticipated to double.

  DOI：

  10.1021/jm950276v

文献信息

• Synthesis, biological, and biophysical studies of DAG-indololactones designed as selective activators of RasGRP
  作者：Lia C. Garcia、Lucia Gandolfi Donadío、Ella Mann、Sofiya Kolusheva、Noemi Kedei、Nancy E. Lewin、Colin S. Hill、Jessica S. Kelsey、Jing Yang、Timothy E. Esch、Marina Santos、Megan L. Peach、James A. Kelley、Peter M. Blumberg、Raz Jelinek、Victor E. Marquez、Maria J. Comin

  DOI：10.1016/j.bmc.2014.04.024

  日期：2014.6

  The development of selective agents capable of discriminating between protein kinase C (PKC) isoforms and other diacylglycerol (DAG)-responsive C1 domain-containing proteins represents an important challenge. Recent studies have highlighted the role that Ras guanine nucleotide-releasing protein (RasGRP) isoforms play both in immune responses as well as in the development of prostate cancer and melanoma

  开发能够区分蛋白激酶 C (PKC) 亚型和其他二酰基甘油 (DAG) 响应性 C1 结构域蛋白的选择剂是一项重要挑战。最近的研究强调了 Ras 鸟嘌呤核苷酸释放蛋白 (RasGRP) 同种型在免疫反应以及前列腺癌和黑色素瘤发展中的作用，表明选择性配体的发现可能具有潜在的治疗价值。迄今为止，N-甲基取代的吲哚内酯1是相对于 PKC 对 RasGRP 具有最高报告效力和选择性的激动剂。在这里，我们介绍了与1的区域异构体家族（化合物2 – 5) 在吲哚环和内酯部分之间的连接位置不同。研究这些结构变化是为了探索活性复合物（C1 结构域-配体）与细胞膜的相互作用，这被认为是激活含有 DAG 响应 C1 结构域的信号蛋白的选择性的重要因素。与 PKCα 相比，所有化合物都是 RasGRP 的有效选择性激活剂，选择性范围为 6 至 65 倍。然而，母体化合物1明显比任何其他异构体更具选择性。在完整的细胞中，观察到
• [EN] PROTEIN KINASE C AGONISTS<br/>[FR] AGONISTES DE PROTÉINE KINASE C
  申请人：GILEAD SCIENCES INC

  公开号：WO2020176505A1

  公开（公告）日：2020-09-03

  The present disclosure relates generally to certain diacylglycerol lactone compounds, pharmaceutical compositions comprising said compounds, and methods of making and using said compounds and pharmaceutical compositions. The compounds and compositions disclosed herein may be used for the treatment or prevention of diseases, disorders, or infections modifiable by protein kinase C (PKC) agonists, such as HIV.

  本公开涉及某些二酰基甘油内酯化合物，包括该化合物的药物组合物，以及制备和使用该化合物和药物组合物的方法。本文所披露的化合物和组合物可用于治疗或预防可通过蛋白激酶C（PKC）激动剂调节的疾病、疾病或感染，如艾滋病。
• Fluorescence-Quenching Screening of Protein Kinase C Ligands with an Environmentally Sensitive Fluorophore
  作者：Wataru Nomura、Nami Ohashi、Yoshiaki Okuda、Tetsuo Narumi、Teikichi Ikura、Nobutoshi Ito、Hirokazu Tamamura

  DOI：10.1021/bc100567k

  日期：2011.5.18

  corresponded well to the Ki values measured by a radioisotope method. These results indicate that washing, which is a laborious step in binding evaluations, is not required for this environmentally sensitive fluorophore based system. Screening with the system was performed for 2560 preselected library compounds with possible pharmacophores, and some lead compounds were found. This fluorescence-based

  利用溶剂变色荧光团开发了一种新的蛋白激酶C（PKC）配体的荧光猝灭筛选方法。溶剂变色染料对与PKCδ（δC1b）的C1b结构域结合时竞争性配体的存在或缺乏高度敏感，与已知的1,2-二酰基甘油（DAG）内酯药效基团PKC配体结合。向荧光化合物中添加δC1b会导致荧光强度与δC1b的增加成比例地逐渐增加。当竞争性配体添加到δC1b域和荧光化合物的复合物中时，观察到荧光强度逐渐降低。通过这种荧光方法成功地确定了已知配体的相对结合亲和力，并与K i很好地对应。通过放射性同位素方法测量的值。这些结果表明，对于这种对环境敏感的基于荧光团的系统，不需要洗涤，这是结合评估中的一项艰巨的步骤。用该系统筛选了2560种可能带有药效基团的预选文库化合物，发现了一些先导化合物。这种基于荧光的方法可以广泛应用于已知的配体-受体组合。
• Total synthesis of lycoperdic acid and stereoisomers (part 1): Double asymmetric hydrogenation of a racemic enamide
  作者：Kenji Morokuma、Kento Tanaka、Raku Irie、Masato Oikawa

  DOI：10.1016/j.tet.2023.133622

  日期：2023.10

  Design, synthesis, and double asymmetric hydrogenation of a racemic enamide are reported toward stereodivergent synthesis of lycoperdic acid and its isomers. The hydrogenation outcome (yield, ee) was used to identify matched and mismatched products, the information is important to clarify the reaction mechanism. It is also proposed that if the reaction mechanism is known, structure of the products would

  据报道，外消旋烯酰胺的设计、合成和双不对称氢化可用于番茄酸及其异构体的立体发散合成。氢化结果（产率，ee）用于识别匹配和不匹配的产物，该信息对于阐明反应机理非常重要。还提出，如果反应机理已知，则无需通过匹配/不匹配分析进行光谱分析即可鉴定产物的结构。
• Conformationally Constrained Analogues of Diacylglycerol. 26. Exploring the Chemical Space Surrounding the C1 Domain of Protein Kinase C with DAG-Lactones Containing Aryl Groups at the <i>sn</i>-1 and <i>sn</i>-2 Positions
  作者：Ji-Hye Kang、Samira Benzaria、Dina M. Sigano、Nancy E. Lewin、Yongmei Pu、Megan L. Peach、Peter M. Blumberg、Victor E. Marquez

  DOI：10.1021/jm060011o

  日期：2006.6.1

  Diacylglycerol lactones (DAG-lactones) are known to operate as effective agonists of protein kinase C (PKC), surpassing in potency the activity of natural diacylglycerol (DAG). Localization of activated PKC isozymes in the cell is determined in part by the different cellular scaffolds, the lipid composition of the specific membranes, and the targeting information intrinsic to the individual isoforms bound to DAG. This multifaceted control of diversity suggests that, to develop effective DAG-lactones capable of honing in on a specific cellular target, we need to gain a better understanding of the chemical space surrounding its binding site. Seeking to augment the chemical repertoire of DAG-lactone side chains that could steer the translocation of PKC to specific cellular domains, we report herein the effects of incorporating simple or substituted phenyl residues. A combined series of n-alkyl and phenyl substitutions were used to explore the optimal location of the phenyl group on the side chains. The substantial differences in binding affinity between DAG-lactones with identical functionalized phenyl groups at either the sn-1 or sn-2 position are consistent with the proposed binding model in which the DAG-lactone binds to the C1 domain of PKC with the acyl chain oriented toward the interior of the membrane and the alpha-alkylidene or alpha-arylalkylidene chains directed to the surface of the C1 domain adjacent to the lipid interface. We conclude that DAG-lactones containing alpha-phenylalkylidene side chains at the sn-2 position represent excellent scaffolds upon which to explore further chemical diversity.