2-({2-[(4-tert-butoxycarbonylamino-1-methyl-1H-pyrrole-2-carbonyl)amino]thiazole-4-carbonyl}amino)thiazole-4-carboxylic acid ethyl ester | 292071-62-6

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 英文名称: 2-({2-[(4-tert-butoxycarbonylamino-1-methyl-1H-pyrrole-2-carbonyl)amino]thiazole-4-carbonyl}amino)thiazole-4-carboxylic acid ethyl ester
• 英文别名: 2-({2-[(4-tert-Butoxycarbonylamino-1-methyl-1H-pyrrole-2-carbonyl)-amino]-thiazole-4-carbonyl}-amino)-thiazole-4-carboxylic acid ethyl ester；ethyl 2-[[2-[[1-methyl-4-[(2-methylpropan-2-yl)oxycarbonylamino]pyrrole-2-carbonyl]amino]-1,3-thiazole-4-carbonyl]amino]-1,3-thiazole-4-carboxylate
• CAS: 292071-62-6
• 化学式: C₂₁H₂₄N₆O₆S₂
• 分子量: 520.59
• InChiKey: CNECVOSYWUAONL-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.8
• 重原子数：
  35
• 可旋转键数：
  10
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.33
• 拓扑面积：
  210
• 氢给体数：
  3
• 氢受体数：
  10

反应信息

• 作为反应物：
  描述：

  2-({2-[(4-tert-butoxycarbonylamino-1-methyl-1H-pyrrole-2-carbonyl)amino]thiazole-4-carbonyl}amino)thiazole-4-carboxylic acid ethyl ester 在 盐酸 、 4-二甲氨基吡啶 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 作用下， 以 1,4-二氧六环 、 二氯甲烷 、 水 为溶剂， 反应 0.5h， 生成 (11aS)-8-(3-{5-[4-(4-ethoxycarbonylthiazol-2-ylcarbamoyl)-thiazol-2-ylcarbamoyl]-1-methyl-1H-pyrrol-3-ylcarbamoyl}propoxy)-7-methoxy-5-oxo-11-(tetrahydropyran-2-yloxy)-2,3,11,11a-tetrahydro-1H,5H-pyrrolo[2,1-c][1,4]benzodiazepine-10-carboxylic acid allyl ester
  参考文献：
  名称：

  An Extended Pyrrolobenzodiazepine–Polyamide Conjugate with Selectivity for a DNA Sequence Containing the ICB2 Transcription Factor Binding Site

  摘要：

  The binding of nuclear factor Y (NF-Y) to inverted CCAAT boxes (ICBs) within the promoter region of DNA topoisomerase II alpha results in control of cell differentiation and cell cycle progression. Thus, NF-Y inhibitory small molecules could be employed to inhibit the replication of cancer cells. A library of pyrrolobenzodiazepine (PBD) C8-conjugates consisting of one PBD unit attached to tri-heterocyclic polyamide fragments was designed and synthesized. The DNA-binding affinity and sequence selectivity of each compound were evaluated in DNA thermal denaturation and DNase I footprinting assays, and the ability to inhibit binding of NF-Y to ICB1 and ICB2 was studied using an electrophoretic mobility shift assay (EMSA). 3a was found to be a potent inhibitor of NF-Y binding, exhibiting a 10-fold selectivity for an ICB2 site compared to an ICB1-containing sequence, and showing low nanomolar cytotoxicity toward human tumor cell lines. Molecular modeling and computational studies have provided details of the covalent attachment process that leads to formation of the PBD-DNA adduct, and have allowed the preference of 3a for ICB2 to be rationalized.

  DOI：

  10.1021/jm4001852
• 作为产物：
  描述：

  2-氨基噻唑-4-甲酸乙酯 在 4-二甲氨基吡啶 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 三氟乙酸 作用下， 以 二氯甲烷 、 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 456.5h， 生成 2-({2-[(4-tert-butoxycarbonylamino-1-methyl-1H-pyrrole-2-carbonyl)amino]thiazole-4-carbonyl}amino)thiazole-4-carboxylic acid ethyl ester
  参考文献：
  名称：

  An Extended Pyrrolobenzodiazepine–Polyamide Conjugate with Selectivity for a DNA Sequence Containing the ICB2 Transcription Factor Binding Site

  摘要：

  The binding of nuclear factor Y (NF-Y) to inverted CCAAT boxes (ICBs) within the promoter region of DNA topoisomerase II alpha results in control of cell differentiation and cell cycle progression. Thus, NF-Y inhibitory small molecules could be employed to inhibit the replication of cancer cells. A library of pyrrolobenzodiazepine (PBD) C8-conjugates consisting of one PBD unit attached to tri-heterocyclic polyamide fragments was designed and synthesized. The DNA-binding affinity and sequence selectivity of each compound were evaluated in DNA thermal denaturation and DNase I footprinting assays, and the ability to inhibit binding of NF-Y to ICB1 and ICB2 was studied using an electrophoretic mobility shift assay (EMSA). 3a was found to be a potent inhibitor of NF-Y binding, exhibiting a 10-fold selectivity for an ICB2 site compared to an ICB1-containing sequence, and showing low nanomolar cytotoxicity toward human tumor cell lines. Molecular modeling and computational studies have provided details of the covalent attachment process that leads to formation of the PBD-DNA adduct, and have allowed the preference of 3a for ICB2 to be rationalized.

  DOI：

  10.1021/jm4001852

文献信息

• Alkyl 4- [4- (5-Oxo-2,3,5, 11A-Tetrahydo-5H-Pyrrolo [2, 1-C] [1,4] Benzodiazepine-8-Yloxy) -Butyrylamino]-1H-Pyrrole-2-Carboxylate Derivatives and Related Compounds For the Treatment of a Proliferative Disease
  申请人：Howard Philip Wilson

  公开号：US20080214525A1

  公开（公告）日：2008-09-04

  A compound of formula (I); or a salt or solvate thereof, wherein: the dotted line indicates the optional presence of a double bond between C2 and C3; R 2 is selected from —H, —OH, =0, ═CH 2 , —CN, —R, OR, halo, ═CH—R, O—SO 2 —R, CO 2 R and COR; R 7 is selected from H, R, OH, OR, SH, SR, NH 2 , NHR, NRR′, nitro, Me 3 Sn and halo, where R and R′ are independently selected from optionally substituted C 1-7 alkyl, C 3-20 heterocyclyl and C 5-20 aryl groups; R 10 and R 11 either together form a double bond, or are selected from H and YR Y , where Y is selected from O, S and NH and R is H or C 1-7 alkyl or H and SO x M, where x is 2 or 3 and M is a monovalent pharmaceutically acceptable cation; each X is independently a heteroarylene group; n is from 1 to 6; and R E is C 1-4 alkyl. The compound is useful for the treatment of proliferative diseases.

  化合物的公式（I）；或其盐或溶剂化物，其中：虚线表示C2和C3之间的双键是可选的；R2选择自-H，-OH，=0，═CH2，-CN，-R，OR，卤基，═CH-R，O-SO2-R，CO2R和COR；R7选择自H，R，OH，OR，SH，SR，NH2，NHR，NRR'，硝基，Me3Sn和卤基，其中R和R'独立选择自可选取代的C1-7烷基，C3-20杂环基和C5-20芳基基团；R10和R11要么一起形成双键，要么选择自H和YRY，其中Y选择自O，S和NH，R为H或C1-7烷基或H和SOxM，其中x为2或3，M为一价的药用可接受阳离子；每个X独立地是杂芳基基团；n为1至6；以及RE为C1-4烷基。该化合物可用于治疗增殖性疾病。
• Alkyl 4- [4- (5-oxo-2,3,5, 11a-tetrahydo-5H-pyrrolo [2, 1-c] [1,4] benzodiazepine-8-yloxy)-butyrylamino]-1H-pyrrole-2-carboxylate derivatives and related compounds for the treatment of a proliferative disease
  申请人：Howard Philip Wilson

  公开号：US08637664B2

  公开（公告）日：2014-01-28

  A compound of formula (I); or a salt or solvate thereof, wherein: the dotted line indicates the optional presence of a double bond between C2 and C3; R2 is selected from —H, —OH, =0, ═CH2, —CN, —R, OR, halo, ═CH—R, O—SO2—R, CO2R and COR; R7 is selected from H, R, OH, OR, SH, SR, NH2, NHR, NRR′, nitro, Me3Sn and halo, where R and R′ are independently selected from optionally substituted C1-7 alkyl, C3-20 heterocyclyl and C5-20 aryl groups; R10 and R11 either together form a double bond, or are selected from H and YRY, where Y is selected from O, S and NH and R is H or C1-7 alkyl or H and SOxM, where x is 2 or 3 and M is a monovalent pharmaceutically acceptable cation; each X is independently a heteroarylene group; n is from 1 to 6; and RE is C1-4 alkyl. The compound is useful for the treatment of proliferative diseases.

  化合物的式子（I）或其盐或溶剂化物，其中：虚线表示C2和C3之间的双键是可选的；R2从—H，—OH，=0，═CH2，—CN，—R，OR，卤素，═CH—R，O—SO2—R，CO2R和COR中选择；R7从H，R，OH，OR，SH，SR，NH2，NHR，NRR'，硝基，Me3Sn和卤素中选择，其中R和R'分别从选择性取代的C1-7烷基，C3-20杂环基和C5-20芳基中独立选择；R10和R11要么一起形成双键，要么从H和YRY中选择，其中Y从O，S和NH中选择，R是H或C1-7烷基或H和SOxM，其中x为2或3，M是单价的药用可接受阳离子；每个X都是独立的杂芳基基团；n为1到6；RE是C1-4烷基。该化合物用于治疗增生性疾病。
• ALKYL 4- [4- (5-OXO-2, 3, 5, 11A-TETRAHYD0-5H-PYRR0L0 [2, 1-C][1, 4]BENZODIAZEPINE-8-YLOXY) -BUTYRYLAMINO]-1H-PYRROLE-2-CARBOXYLATE DERIVATIVES AND RELATED COMPOUNDS FOR THE TREATMENT OF A PROLIFERATIVE DISEASE
  申请人：Spirogen Limited

  公开号：EP1931671B1

  公开（公告）日：2009-04-08
• US8637664B2
  申请人：——

  公开号：US8637664B2

  公开（公告）日：2014-01-28
• [EN] ALKYL 4- [4- (5-OXO-2, 3, 5, 11A-TETRAHYD0-5H-PYRR0L0 [2, 1-C] [1, 4] BENZODIAZEPINE-8-YLOXY) -BUTYRYLAMINO]-1H-PYRROLE-2-CARBOXYLATE DERIVATIVES AND RELATED COMPOUNDS FOR THE TREATMENT OF A PROLIFERATIVE DISEASE<br/>[FR] DERIVES D'ALKYLE 4-[4-(5-OXO-2, 3, 5, 11A-TETRAHYDRO-5H-PYRROLO [2, 1-C] [1, 4] BENZODIAZEPINE-8-YLOXY) -BUTYRYLAMINO]-1H-PYRROLE-2-CARBOXYLATE ET COMPOSES ASSOCIES DESTINES AU TRAITEMENT D'UNE MALADIE HYPERPLASIQUE
  申请人：SPIROGEN LTD

  公开号：WO2007039752A1

  公开（公告）日：2007-04-12

  [EN] A compound of formula (I); or a salt or solvate thereof, wherein: the dotted line indicates the optional presence of a double bond between C2 and C3; R² is selected from -H, -OH, =0, =CH₂, -CN, -R, OR, halo, =CH-R, O-SO₂-R, CO₂R and COR; R⁷ is selected from H, R, OH, OR, SH, SR, NH₂, NHR, NRR', nitro, Me₃Sn and halo, where R and R' are independently selected from optionally substituted C_1-7 alkyl, C_3-20 heterocyclyl and C_5-20 aryl groups; R¹⁰ and R¹¹ either together form a double bond, or are selected from H and YR^Y, where Y is selected from O, S and NH and R^Y is H or C_1-7 alkyl or H and SO_xM, where x is 2 or 3, and M is a monovalent pharmaceutically acceptable cation; each X is independently a heteroarylene group; n is from 1 to 6; and R^E is C_1-4 alkyl. The compound is useful for the treatment of proliferative diseases.
  [FR] L'invention concerne un composé représenté par la formule générale (I) ou un sel ou solvate de ce composé. Dans cette formule, la ligne pointillée désigne la présence éventuelle d'une double liaison entre C2 et C3 ; R² désigne un groupe sélectionné dans l'ensemble comprenant -H, -OH, =0, =CH₂, -CN, -R, OR, halo, =CH-R, O-SO₂-R, CO₂R et COR; R⁷ désigne un groupe sélectionné dans l'ensemble comprenant H, R, OH, OR, SH, SR, NH₂, NHR, NRR', nitro, Me₃Sn et halo, R et R' désignant indépendamment un groupe sélectionné dans l'ensemble comprenant les groupes éventuellement substitués alkyle C_1-7, hétérocyclyle C_3-20 et aryle C_5-20 ; R¹⁰ et R¹¹ forment une double liaison, ou désignent des groupes sélectionnés dans l'ensemble comprenant H et YR^Y, Y désignant un groupe sélectionné dans l'ensemble comprenant O, S et NH et R^Y désignant un groupe sélectionné dans l'ensemble comprenant H ou alkyle C_1-7 ou H et SO_xM, x valant 2 ou 3, et M désignant un cation monovalent de qualité pharmaceutique ; chaque X désigne indépendamment un groupe hétéroarylène ; n vaut entre 1 et 6 compris ; et R^E désigne un groupe alkyle C_1-4. Le composé de l'invention est utile pour le traitement de maladies hyperplasiques.