3-Hydroxy-3-(2-hydroxy-3-isopropyl-6-methyl-phenyl)-3H-benzo[de]isochromen-1-one

• 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: 3-Hydroxy-3-(2-hydroxy-3-isopropyl-6-methyl-phenyl)-3H-benzo[de]isochromen-1-one
• 英文别名: 4-hydroxy-4-(2-hydroxy-6-methyl-3-propan-2-ylphenyl)-3-oxatricyclo[7.3.1.05,13]trideca-1(12),5,7,9(13),10-pentaen-2-one
• 化学式: C₂₂H₂₀O₄
• 分子量: 348.398
• InChiKey: ZTRRJLIOZOJWKS-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.7
• 重原子数：
  26
• 可旋转键数：
  2
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.23
• 拓扑面积：
  66.8
• 氢给体数：
  2
• 氢受体数：
  4

反应信息

• 作为产物：
  描述：

  1,8-萘二甲酸酐 、 百里酚 在 三氯化铝 、 1,1,2,2-四氯乙烷 作用下， 反应 72.0h， 以12%的产率得到3-Hydroxy-3-(2-hydroxy-3-isopropyl-6-methyl-phenyl)-3H-benzo[de]isochromen-1-one
  参考文献：
  名称：

  Phthalein Derivatives as a New Tool for Selectivity in Thymidylate Synthase Inhibition

  摘要：

  A new set of phthalein derivatives stemming from the lead compound, phenolphthalein, were designed to specifically complement structural features of a bacterial form of thymidylate synthase (Lactobacillus casei, LcTS) versus the human TS (hTS) enzyme. The new compounds were screened for their activity and their specificity against TS enzymes from different species, namely, L. casei (LcTS), Pneumocystis carinii (PcTS), Cryptococcus neoformans (CnTS), and human thymidylate synthase (hTS). Apparent inhibition constants (Ki) for all the compounds against LcTS were determined, and inhibition factors (IF,ratio between the initial rates of the enzymatic reaction in the presence and absence of each inhibitor) against each of the four TS species were measured. A strong correlation was found between the two activity parameters, IF and Ki, and therefore the simpler IF was used as a screening factor in order to accelerate biological evaluation. Compounds 5b, 5c, 5ba, and 6bc showed substantial inhibition of LcTS while remaining largely inactive against hTS, illustrating for the first time remarkable species specificity among TSs. Due to sequence homology between the enzymes, several compounds also showed high activity and specificity for CnTS. In particular, 3-hydroxy-3-(3-chloro-4-hydroxyphenyl)-6-nitro-1H,3H-naphtho[1,8-c,d]pyran-1-one, (6bc) showed an IF < 0.04 for CnTS (K-i = 0.45 mu M) while remaining inactive in the hTS assay at the maximum solubility concentration of the compound (200 mu M). In cell culture assays most Of the compounds were found to be noncytotoxic to human cell lines but were cytotoxic against several species of Grampositive bacteria. These results are consistent with the enzymatic assays. Intriguingly, several compounds also had selective activity against Cr. neoformans in cell culture assay. In general, the most active and selective compounds against the Gram-positive bacteria were those designed and found in the enzyme assay to be specific for LcTS versus hTS. The original lead compound was least selective against most of the cell lines tested. To our knowledge these compounds are the first TS inhibitors selective for bacterial TS with respect to hTS.

  DOI：

  10.1021/jm9900016

文献信息

• Phthalein Derivatives as a New Tool for Selectivity in Thymidylate Synthase Inhibition
  作者：Paola M. Costi、Marcella Rinaldi、Donatella Tondi、Piergiorgio Pecorari、Daniela Barlocco、Stefano Ghelli、Robert M. Stroud、Daniel V. Santi、Thomas J. Stout、Chiara Musiu、Elena M. Marangiu、Alessandra Pani、Donatella Congiu、Giulia A. Loi、Paolo La Colla

  DOI：10.1021/jm9900016

  日期：1999.6.1

  A new set of phthalein derivatives stemming from the lead compound, phenolphthalein, were designed to specifically complement structural features of a bacterial form of thymidylate synthase (Lactobacillus casei, LcTS) versus the human TS (hTS) enzyme. The new compounds were screened for their activity and their specificity against TS enzymes from different species, namely, L. casei (LcTS), Pneumocystis carinii (PcTS), Cryptococcus neoformans (CnTS), and human thymidylate synthase (hTS). Apparent inhibition constants (Ki) for all the compounds against LcTS were determined, and inhibition factors (IF,ratio between the initial rates of the enzymatic reaction in the presence and absence of each inhibitor) against each of the four TS species were measured. A strong correlation was found between the two activity parameters, IF and Ki, and therefore the simpler IF was used as a screening factor in order to accelerate biological evaluation. Compounds 5b, 5c, 5ba, and 6bc showed substantial inhibition of LcTS while remaining largely inactive against hTS, illustrating for the first time remarkable species specificity among TSs. Due to sequence homology between the enzymes, several compounds also showed high activity and specificity for CnTS. In particular, 3-hydroxy-3-(3-chloro-4-hydroxyphenyl)-6-nitro-1H,3H-naphtho[1,8-c,d]pyran-1-one, (6bc) showed an IF < 0.04 for CnTS (K-i = 0.45 mu M) while remaining inactive in the hTS assay at the maximum solubility concentration of the compound (200 mu M). In cell culture assays most Of the compounds were found to be noncytotoxic to human cell lines but were cytotoxic against several species of Grampositive bacteria. These results are consistent with the enzymatic assays. Intriguingly, several compounds also had selective activity against Cr. neoformans in cell culture assay. In general, the most active and selective compounds against the Gram-positive bacteria were those designed and found in the enzyme assay to be specific for LcTS versus hTS. The original lead compound was least selective against most of the cell lines tested. To our knowledge these compounds are the first TS inhibitors selective for bacterial TS with respect to hTS.