(+/-)-cis-1,2-dihydroxy-6-methoxy-3,3,14-trimethyl-1,2,3,14-tetrahydro-7H-benzo[b]pyrano[3,2-h]acridin-7-one

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 喹啉及其衍生物
• 英文名称: (+/-)-cis-1,2-dihydroxy-6-methoxy-3,3,14-trimethyl-1,2,3,14-tetrahydro-7H-benzo[b]pyrano[3,2-h]acridin-7-one
• 英文别名: (5S,6S)-5,6-dihydroxy-11-methoxy-2,7,7-trimethyl-8-oxa-2-azapentacyclo[12.8.0.03,12.04,9.016,21]docosa-1(22),3,9,11,14,16,18,20-octaen-13-one
• 化学式: C₂₄H₂₃NO₅
• 分子量: 405.45
• InChiKey: ZRRQKGZERAWFAN-GOTSBHOMSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.2
• 重原子数：
  30
• 可旋转键数：
  1
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.29
• 拓扑面积：
  79.2
• 氢给体数：
  2
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  (+/-)-cis-1,2-dihydroxy-6-methoxy-3,3,14-trimethyl-1,2,3,14-tetrahydro-7H-benzo[b]pyrano[3,2-h]acridin-7-one 在 sodium periodate 作用下， 以 水 、 丙酮 为溶剂， 反应 96.0h， 以94%的产率得到1-methoxy-5-methyl-3-(2-oxo-1,1-dimethylethoxy)-12-oxo-5,12-dihydrobenzo[b]acridine-4-carbaldehyde
  参考文献：
  名称：

  丙烯醛和苯并[b]阿卡洛霉素系列中的构效关系：吡喃环的作用。

  摘要：

  为了研究丙烯醛系列中的构效关系，简化了顺式1,2-二乙酰氧基-1,2-二氢丙烯醛类似物和顺式1,2-二乙酰氧基-1,2-二氢苯并[b]阿克隆胺的类似物（S23906 （-1，在临床试验中）制备了没有稠合的吡喃环，但在位置4具有乙酰氧基甲基离去基团的化合物。与母体化合物相比，这些新的类似物仅显示出有限的抗增殖活性。有角度地稠合的二甲基吡喃环的存在似乎是观察该系列中显着的细胞毒活性必不可少的结构要求。

  DOI：

  10.1016/j.ejmech.2008.01.033
• 作为产物：
  描述：

  1,3-Dihydroxy-5,12-dihydro-benzo[b]acridin-12-one 在 四氧化锇 、 sodium hydride 、 potassium carbonate 、 N-甲基吗啉氧化物 、 potassium iodide 作用下， 以 四氢呋喃 、 水 、 N,N-二甲基甲酰胺 、 叔丁醇 为溶剂， 反应 74.25h， 生成 (+/-)-cis-1,2-dihydroxy-6-methoxy-3,3,14-trimethyl-1,2,3,14-tetrahydro-7H-benzo[b]pyrano[3,2-h]acridin-7-one
  参考文献：
  名称：

  Synthesis and Cytotoxic and Antitumor Activity of Benzo[b]pyrano[3,2-h]acridin-7-one Analogues of Acronycine

  摘要：

  Benzo[b]acronycine (6-methoxy-3,3,14-trimethyl-3,14-dihydro-7H-benzo[b]pyrano[3,2-h]acridin-7-one, 4), an acronycine analogue with an additional aromatic ring linearly fused on the natural alkaloid basic skeleton, was synthesized in three steps, starting from 3-amino-2-naphthalenecarboxylic acid (5). Eight 1,2-dihydroxy-1,2-dihydrobenzo[b]acronycine esters and diesters (17-24) were obtained by catalytic osmic oxidation, followed by acylation. All these compounds were significantly more cytotoxic than acronycine, when tested against L1210 leukemia cells in vitro. The potency of the cyclic carbonate 24 was in the range of the most active drugs currently used in cancer chemotherapy. Two selected diesters (17 and 24) were evaluated in vivo against P388 leukemia and colon 38 adenocarcinoma implanted in mice. Both compounds were markedly active at doses 16-fold lower than the dose of acronycine itself. Against colon 38 adenocarcinoma, compounds 17 and 24 were highly efficient, inhibiting tumor growth by more than 80%. Diacetate 17 was the most active, inhibiting tumor growth by 96% at 6.25 mg/kg, with two of seven mice being tumor-free on day 43.

  DOI：

  10.1021/jm990972l

文献信息

• Benzo[b]pyrano[3,2-h]acridin-7-one cinnamate compounds
  申请人：Koch Michel

  公开号：US20060135545A1

  公开（公告）日：2006-06-22

  A compound selected from those of formula (I): wherein: X and Y represent a group selected from hydrogen, halogen, alkoxy, nitro, cyano, alkyl, alkenyl, polyhaloalkyl and —NR a R b wherein R a and R b are as defined in the description, Z represents oxygen or NR c wherein R c is as defined in the description, Ar represents aryl or heteroaryl, R 1 represents hydrogen or alkyl, R 2 represents a group selected from hydrogen, alkyl, —OR a and —NR a R b wherein R a and R b are as defined in the description, R 3 and R 4 represent hydrogen or alkyl, R 5 represents hydrogen, OR c , NR c R d , W 1 —C(W 2 )—U—V, W 1 —C(W 2 )—W 3 -T 1 or Z-CO—CH═CHAr wherein R c , R d , W 1 , W 2 , W 3 , U, V, T, Z and Ar are as defined in the description, its isomers, and addition salts thereof with a pharmaceutically acceptable acid or base, and medicinal products containing the same which are useful in the treatment of cancer.

  从式（I）中选择的一种化合物： 其中： X和Y代表从氢、卤素、烷氧基、硝基、氰基、烷基、烯基、多卤代烷基和-NR a R b 中选择的基团， 其中R a 和R b 如描述中所定义， Z代表氧或NR c 其中R c 如描述中所定义，Ar代表芳基或杂环芳基， R 1 代表氢或烷基， R 2 代表从氢、烷基、-OR a 和-NR a R b 中选择的基团，其中R a 和R b 如描述中所定义， R 3 和R 4 代表氢或烷基， R 5 代表氢、OR c 、NR c R d 、W 1 -C(W 2 )-U-V、W 1 -C(W 2 )-W 3 -T 1 或Z-CO-CH═CHAr其中R c 、R d 、W 1 、W 2 、W 3 、U、V、T、Z和Ar如描述中所定义，其异构体，以及其与药学上可接受的酸或碱形成的加合盐，以及含有这种化合物的用于治疗癌症的药物。
• Synthesis, cytotoxic activity, and DNA binding properties of antitumor cis-1,2-dihydroxy-1,2-dihydrobenzo[b]acronycine cinnamoyl esters
  作者：Quyên Do、Wen Tian、Rodrigue Yougnia、Thomas Gaslonde、Bruno Pfeiffer、Alain Pierré、Stéphane Léonce、Laurence Kraus-Berthier、Marie-Hélène David-Cordonnier、Sabine Depauw、Amélie Lansiaux、Romain Mazinghien、Michel Koch、François Tillequin、Sylvie Michel、Hanh Dufat

  DOI：10.1016/j.bmc.2009.01.062

  日期：2009.3

  Monocinnamoyl esters at position 2 of (±)-cis-1,2-dihydroxy-6-methoxy-3,3,14-trimethyl-1,2,3,14-tetrahydro-7H-benzo[b]pyrano[3,2-h]acridin-7-one and their acetyl derivatives at position 1 were prepared as stabilized analogues of the anticancer alkylating agent S23906-1. Monocinnamoyl esters at position 2 were slower DNA alkylators than the reference 2-monoacetate. Mixed esters bearing an acetyl ester

  （±）-顺式-1,2-二羟基-6-甲氧基-3,3,14-三甲基-1,2,3,14-四氢-7 H-苯并[ b ]吡喃并[3] 2位的单肉桂酸酯，2-小时制备在1位的] acridin-7-one及其乙酰基衍生物作为抗癌烷基化剂S23906-1的稳定类似物。第2位的单肉桂酰基酯比参考的2-单乙酸酯的DNA烷基化剂慢。比S23906-1慢的在1位带有乙酰酯基和2位肉桂酰酯基的混合酯使烷基化DNA慢。观察到细胞毒性和DNA烷基化动力学之间有很强的相关性，较慢的烷基化剂显示出更强的抗增殖活性。事实证明，最具细胞毒性的化合物在体内对植入小鼠的鼠C-38腺癌具有显着的活性，但效力不及S23906-1。
• Synthesis and Cytotoxic and Antitumor Activity of 1,2-Dihydroxy-1,2-dihydrobenzo[b]acronycine Diacid Hemiesters and Carbamates
  作者：Huong Doan Thi Mai、Thomas Gaslonde、Sylvie Michel、Michel Koch、François Tillequin、Bruno Pfeiffer、Pierre Renard、Laurence Kraus-Berthier、Stéphane Léonce、Alain Pierré

  DOI：10.1248/cpb.52.293

  日期：——

  A series of cis-1,2-dihydroxy-1,2-dihydrobenzo[b]acronycine diacid hemiesters and dicarbamates were prepared by acylation of cis-1,2-dihydroxy-6-methoxy-3,3,14-trimethyl-1,2,3,14-tetrahydro-7H-benzo[b]pyrano[3,2-h]acridin-7-one. The cytotoxicity of the dicarbamates depended on the steric hindrance of the esterifying groups at positions 1 and 2. Diacid hemiesters displayed significant in vitro cytotoxic activities and induced cell cycle perturbations similar to those obtained with cis-1,2-diacetoxy-1,2-dihydrobenzo[b]acronycine (S23906-1) currently under preclinical development. cis-1-Acetoxy-2-hemiglutaryloxy-1,2-dihydrobenzo[b]acronycine was the most promizing compound of the series, inducing complete inhibition of tumor growth when tested against C38 colon adenocarcinoma implanted in mice.

  通过顺式-1,2-二羟基-6-甲氧基-3,3,14-三甲基-1的酰化制备了一系列顺式-1,2-二羟基-1,2-二氢苯并[b]醋栗碱二酸半酯和二氨基甲酸酯。 ,2,3,14-四氢-7H-苯并[b]吡喃并[3,2-h]吖啶-7-酮。二氨基甲酸酯的细胞毒性取决于位置 1 和 2 处酯化基团的空间位阻。二酸半酯表现出显着的体外细胞毒性活性，并诱导细胞周期扰动，类似于使用 cis-1,2-diacetoxy-1,2- 获得的结果。二氢苯并[b]acronycine (S23906-1)目前正处于临床前开发阶段。 cis-1-乙酰氧基-2-半戊二酰氧基-1,2-二氢苯并[b]acronycine是该系列中最有前途的化合物，当针对植入小鼠的C38结肠腺癌进行测试时，可完全抑制肿瘤生长。
• Benzo[b]pyrano[3,2-h]acridin-7-one compounds
  申请人：LES LABORATOIRES SERVIER

  公开号：US20040063702A1

  公开（公告）日：2004-04-01

  A method for treating a living body afflicted with a cancer selected from lung and ovarian carcinoma, comprising the step of administering to the living animal body an amount of a compound selected from those of formula (I): 1 wherein: X and Y represent group selected from hydrogen, halogen, mercapto, cyano, nitro, alkyl, trihaloalkyl, trihaloalkylcarbonylamino, —ORa, —NRaRb, —NRa—C(O)-T 1 , —O—C(O)-T 1 , —O-T 2 -NRaRb, —O-T 2 -ORa, —NRa-T 2 -NRaRb, —NRa-T 2 -ORa and —NRa-T 2 -CO 2 Ra wherein Ra, Rb, T 1 , T 2 are as defined in the description, or X and Y together form a methylenedioxy or ethylenedioxy, R 1 represents hydrogen or alkyl, R 2 represents a group selected from hydrogen, —ORa, —NRaRb, —NRa—C(O)-T 1 , —O—C(O)-T 1 , —O-T 2 -NRaRb, —O-T 2 -ORa, —NRa-T 2 -NRaRb, —NRa-T 2 -ORa and —NRa-T 2 -CO 2 Ra wherein Ra, Rb, T 1 and T 2 are as defined hereinbefore, R 3 and R 4 represent hydrogen or alkyl, W represents a group of formula —CH(R 5 )—CH(R 6 )—, —CH═C(R 7 )—, —C(R 7 )═CH— or —C(O)—CH(R 8 )— wherein R 5 , R 6 , R 7 and R 8 are as defined in the description, their isomers and N-oxides, and addition salts thereof with a pharmaceutically acceptable acid or base, and medicinal products containing the same are useful in the treatment of cancer.

  一种治疗患有肺癌和卵巢癌的生物体的方法，包括向生物体内注射一定量的化合物，所述化合物的选择公式为(I)中的一种：其中，X和Y代表从氢、卤素、巯基、氰基、硝基、烷基、三卤代烷基、三卤代烷基羰基氨基、-ORa、-NRaRb、-NRa-C(O)-T1、-O-C(O)-T1、-O-T2-NRaRb、-O-T2-ORa、-NRa-T2-NRaRb、-NRa-T2-ORa和-NRa-T2-CO2Ra中选择的基团，其中Ra、Rb、T1和T2如上所述，或X和Y共同形成亚甲二氧基或乙二氧基，R1代表氢或烷基，R2代表从氢、-ORa、-NRaRb、-NRa-C(O)-T1、-O-C(O)-T1、-O-T2-NRaRb、-O-T2-ORa、-NRa-T2-NRaRb、-NRa-T2-ORa和-NRa-T2-CO2Ra中选择的基团，其中Ra、Rb、T1和T2如上所述，R3和R4代表氢或烷基，W代表公式-CH(R5)-CH(R6)-、-CH═C(R7)-、-C(R7)═CH-或-C(O)-CH(R8)-中的一种基团，其中R5、R6、R7和R8如上所述，它们的异构体和N-氧化物，以及与药学上可接受的酸或碱形成的加合物盐，和含有它们的药物制剂在癌症治疗中有用。
• New benzo [b] pyrano [3,2-h] acridin-7-one compounds
  申请人：——

  公开号：US20030073841A1

  公开（公告）日：2003-04-17

  A compound selected from those of formula (I): 1 wherein: X and Y represent group selected from hydrogen, halogen, mercapto, cyano, nitro, alkyl, trihaloalkyl, trihaloalkylcarbonylamino, —ORa, —NRaRb, —NRa—C(O)-T 1 , —O—C(O)-T 1 , —O-T 2 -NRaRb, —O-T 2 ORa, —NRa-T 2 NRaRb, —NRa-T 2 -ORa and —NRa-T 2 -CO 2 Ra wherein Ra, Rb, T 1 , T 2 are as defined in the description, or X and Y together form a methylenedioxy or ethylenedioxy, R 1 represents hydrogen or alkyl, R 2 represents a group selected from hydrogen, —ORa, —NRaRb, —NRa—C(O)-T 1 , —O—C(O)-T 1 , —O-T 2 -NRaRb, —O-T 2 -ORa, —NRa-T 2 -NRaRb, —NRa-T 2 -ORa and —NRa-T 2 -CO 2 Ra wherein Ra, Rb, T 1 and T 2 are as defined hereinbefore, R 3 and R 4 represent hydrogen or alkyl, W represents a group of formula —CH(R 5 )—CH(R 6 )—, —CH═C(R 7 )—, —C(R 7 )═CH— or —C(O)—CH(R 8 )— wherein R 5 , R 6 , R 7 and R 8 are as defined in the description, their isomers and N-oxides, and addition salts thereof with a pharmaceutically acceptable acid or base, and medicinal products containing the same which are useful in the treatment of cancer.

  从式(I)中选择的化合物：其中，X和Y代表氢，卤素，巯基，氰基，硝基，烷基，三卤代烷基，三卤代烷基羰基氨基，-ORa，-NRaRb，-NRa-C（O）-T1，-O-C（O）-T1，-O-T2-NRaRb，-O-T2ORa，-NRa-T2NRaRb，-NRa-T2-ORa和-NRa-T2-CO2Ra，其中Ra，Rb，T1，T2如描述中所定义，或X和Y共同形成甲基二氧或乙基二氧基，R1代表氢或烷基，R2代表从氢，-ORa，-NRaRb，-NRa-C（O）-T1，-O-C（O）-T1，-O-T2-NRaRb，-O-T2-ORa，-NRa-T2-NRaRb，-NRa-T2-ORa和-NRa-T2-CO2Ra中选择的基团，其中Ra，Rb，T1和T2如前所述定义，R3和R4代表氢或烷基，W代表式为-CH（R5）-CH（R6）-，-CH═C（R7）-，-C（R7）═CH-或-C（O）-CH（R8）的基团，其中R5，R6，R7和R8如描述中所定义，它们的异构体和N-氧化物，以及与药学上可接受的酸或碱形成的加合物盐，以及含有它们的医药产品，可用于癌症的治疗。