5-甲氧基-2,2-二甲基色烯-6-羧酸 | 62499-04-1

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并吡喃
• 中文名称: 5-甲氧基-2,2-二甲基色烯-6-羧酸
• 英文名称: 5-methoxy-2,2-dimethyl-2H-chromene-6-carboxylic acid
• 英文别名: 5-Methoxy-2,2-dimethyl-2H-chromene-6-carboxylic Acid；5-methoxy-2,2-dimethylchromene-6-carboxylic acid
• CAS: 62499-04-1
• 化学式: C₁₃H₁₄O₄
• 分子量: 234.252
• InChiKey: WCOAPPFQEKMTCI-UHFFFAOYSA-N

物化性质

• 沸点：
  386.0±42.0 °C(Predicted)
• 密度：
  1?+-.0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.3
• 重原子数：
  17
• 可旋转键数：
  2
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.31
• 拓扑面积：
  55.8
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  5-甲氧基-2,2-二甲基色烯-6-羧酸 在 叠氮磷酸二苯酯 、 四丁基氟化铵 、 氢气 、 sodium hydride 、 1-羟基苯并三唑 、 1,8-二氮杂双环[5.4.0]十一碳-7-烯 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 三乙胺 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 甲醇 、 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 34.5h， 生成 N-(2-aminoethyl)-N-(5,6-dimethoxypyridin-2-yl)-5-methoxy-2,2-dimethyl-2H-chromene-6-carboxamide
  参考文献：
  名称：

  Investigation of B,C-ring truncated deguelin derivatives as heat shock protein 90 (HSP90) inhibitors for use as anti-breast cancer agents

  摘要：

  On the basis of deguelin, a series of the B, C-ring truncated surrogates with N-substituted amide linkers were investigated as HSP90 inhibitors. The structure activity relationship of the template was studied by incorporating various substitutions on the nitrogen of the amide linker and examining their HIF-1 alpha inhibition. Among them, compound 57 showed potent HIF-1 alpha inhibition and cytotoxicity in triple-negative breast cancer lines in a dose-dependent manner. Compound 57 downregulated expression and phosphorylation of major client proteins of HSP90 including AKT, ERK and STAT3, indicating that its antitumor activity was derived from the inhibition of HSP90 function. The molecular modeling of 57 demonstrated that 57 bound well to the C-terminal ATP-binding pocket in the open conformation of the hHSP90 homodimer with hydrogen bonding and pi-cation interactions. Overall, compound 57 is a potential antitumor agent for triple-negative breast cancer as a HSP90 Cterminal inhibitor.

  DOI：

  10.1016/j.bmc.2019.02.040
• 作为产物：
  描述：

  5-methoxy-2,2-dimethyl-2H-chromene-6-carbaldehyde 在 silver nitrate 、 sodium hydroxide 作用下， 以 水 为溶剂， 生成 5-甲氧基-2,2-二甲基色烯-6-羧酸
  参考文献：
  名称：

  Novel Hypoxia-Inducible Factor 1α (HIF-1α) Inhibitors for Angiogenesis-Related Ocular Diseases: Discovery of a Novel Scaffold via Ring-Truncation Strategy

  摘要：

  Ocular diseases featuring pathologic neovascularization are the leading cause of blindness, and anti-VEGF agents have been conventionally used to treat these diseases. Recently, regulating factors upstream of VEGF, such as HIF-1 alpha, have emerged as a desirable therapeutic approach because the use of anti-VEGF agents is currently being reconsidered due to the VEGF action as a trophic factor. Here, we report a novel scaffold discovered through the complete structure-activity relationship of ring-truncated deguelin analogs in HIF-1 alpha inhibition. Interestingly, analog 6i possessing a 2-fluorobenzene moiety instead of a dimethoxybenzene moiety exhibited excellent HIF-1 alpha inhibitory activity, with an IC50 value of 100 nM. In particular, the further ring-truncated analog 34f, which showed enhanced HIF-la inhibitory activity compared to analog 2 previously reported by us, inhibited in vitro angiogenesis and effectively suppressed hypoxia-mediated retinal neovascularization. Importantly, the heteroatom-substituted benzene ring as a key structural feature of analog 34f was identified as a novel scaffold for HIF-1 alpha inhibitors that can be used in lieu of a chromene ring.

  DOI：

  10.1021/acs.jmedchem.8b00971

文献信息

• Discovery of deguelin derivatives in combination with fluconazole against drug-resistant Candida albicans
  作者：Biaoqi Liu、Youwei Wu、Dingmei Qin、Hairong Wang、Hongjie Chen、Yi Zhang、Weilie Xiao、Xiaoli Li、Ruirui Wang、Ruihan Zhang

  DOI：10.1007/s00044-023-03118-7

  日期：2023.10

  promising therapeutic strategy. In this study, a series of deguelin (Deg) derivative were prepared and identified with in vitro antifungal activity against drug-resistant C. albicans combined with fluconazole (FLC). The combination of Deg derivative 17c and FLC exhibited the best activity, with a fractional inhibitory combination index (FICI) of 0.02. The sensitization effect of 17c + FLC was further

  白色念珠菌作为最常见的条件致病菌，给临床治疗带来了很大的困难。与此同时，随着唑类药物在临床实践中的广泛应用，耐药性也随之出现。在这种情况下，采用联合治疗就成为一种有前景的治疗策略。本研究制备了一系列德桂林（Deg）衍生物，并鉴定其与氟康唑（FLC）联用对耐药白色念珠菌具有体外抗真菌活性。Deg衍生物17c和FLC的组合表现出最好的活性，其抑制组合指数(FICI)为0.02。 通过时间杀菌曲线分析进一步验证了17c +FLC的致敏效果。此外，17c + FLC 还对耐药白色念珠菌 的菌丝转化和生物膜形成具有抑制作用，并显着降低与 RAS1/cAMP/PKA 细胞转导途径相关的关键基因的表达。
• Discovery of indazole inhibitors for heat shock protein 90 as anti-cancer agents
  作者：Minh Thanh La、Van-Hai Hoang、Raghaba Sahu、Cong-Truong Nguyen、Gibeom Nam、Hyun-Ju Park、Minsu Park、Yoon-Jae Kim、Ji Young Kim、Jihyae Ann、Jae Hong Seo、Jeewoo Lee

  DOI：10.1016/j.ejmech.2024.116620

  日期：2024.10

  A series of indazole analogs, derived from the B,C-ring-truncated scaffold of deguelin, were designed to function as C-terminal inhibitors of heat shock protein 90 (HSP90) and investigated as novel antitumor agents against HER2-positive breast cancer. Among the synthesized compounds, compound 12d exhibited substantial inhibitory effects in trastuzumab-sensitive (BT474) and trastuzumab-resistant (JIMT-1)

  一系列吲唑类似物来源于 deguelin 的 B，C 环截短支架，被设计为热休克蛋白 90 （HSP90） 的 C 末端抑制剂，并作为针对 HER2 阳性乳腺癌的新型抗肿瘤药物进行研究。在合成的化合物中，化合物 12d 对曲妥珠单抗敏感 （BT474） 和曲妥珠单抗耐药 （JIMT-1） 乳腺癌细胞表现出显著的抑制作用，IC50 值分别为 6.86 和 4.42 μM。值得注意的是，化合物 12d 在正常细胞中没有表现出细胞毒性。化合物 12d 在两种细胞类型中均显著下调主要 HSP90 客户蛋白的表达，将其细胞毒性归因于 HSP90 客户蛋白的不稳定和失活。使用 HSP90 同源二聚体同源模型的分子对接研究表明，抑制剂 12d 非常适合 C 端结构域，具有比 ATP 更高的静电互补评分。
• Discovery of novel anti-breast cancer agents derived from deguelin as inhibitors of heat shock protein 90 (HSP90)
  作者：Cong-Truong Nguyen、Jihyae Ann、Raghaba Sahu、Woong Sub Byun、Sangkook Lee、Gibeom Nam、Hyun-Ju Park、Soeun Park、Yoon-Jae Kim、Ji Young Kim、Jae Hong Seo、Jeewoo Lee

  DOI：10.1016/j.bmcl.2020.127374

  日期：2020.9

  A series of O-substituted analogues of the B,C-ring truncated scaffold of deguelin were designed as C-terminal inhibitors of heat shock protein 90 (HSP90) and investigated as novel antiproliferative agents against HER2-positive breast cancer. Among the synthesized compounds, compound 80 exhibited significant inhibition in both trastuzumab-sensitive and trastuzumab-resistant breast cancer cells, whereas compound 80 did not show any cytotoxicity in normal cells. Compound 80 markedly downregulated the expression of the major client proteins of HSP90 in both cell types, indicating that the cytotoxicity of 80 in breast cancer cells is attributed to the destabilization and inactivation of HSP90 client proteins and that HSP90 inhibition represents a promising strategy to overcome trastuzumab resistance. A molecular docking study of 80 with the homology model of a HSP90 homodimer showed that 80 fit nicely in the C-terminal domain with a higher electrostatic complementary score than that of ATP.
• Burrows et al., Proceedings of the Chemical Society, London, 1959, p. 150
  作者：Burrows et al.

  DOI：——

  日期：——
• [EN] NOVEL BENZOPYRAN DERIVATIVE OR PHARMACEUTICALLY ACCEPTABLE SALT THEREOF AND PHARMACEUTICAL COMPOSITION COMPRISING SAME AS EFFECTIVE INGREDIENT<br/>[FR] NOUVEAU DÉRIVÉ DE BENZOPYRANE OU SEL PHARMACEUTIQUEMENT ACCEPTABLE DE CELUI-CI ET COMPOSITION PHARMACEUTIQUE LE COMPRENANT EN TANT QUE PRINCIPE ACTIF<br/>[KO] 신규한 벤조파이란 유도체 또는 이의 약학적으로 허용가능한 염 및 이를 유효성분으로 함유하는 약학적 조성물
  申请人：UNIV KOREA RES & BUS FOUND

  公开号：WO2020040582A1

  公开（公告）日：2020-02-27

  본 발명은 신규한 벤조파이란 유도체 또는 이의 약학적으로 허용가능한 염 및 이를 유효성분으로 함유하는 약학적 조성물에 관한 것으로, 본 발명의 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용가능한 염, 또는 그 용매화물은 HSP90과 HSF-1의 complex 구조에 영향을 미치지 않으므로 HSF-1의 활성화나 HSP gene들의 발현을 유도하지 않아 효과적으로 암세포의 사멸을 촉진하므로, 항암제의 유효성분으로 사용될 수 있다.