2,6-bis(3-chloropropionamido)anthracene-9,10-dione | 72966-79-1

• 分子结构分类: 有机化合物 - 苯类化合物 - 蒽
• 英文名称: 2,6-bis(3-chloropropionamido)anthracene-9,10-dione
• 英文别名: 3-chloro-N-[6-(3-chloropropanoylamino)-9,10-dioxoanthracen-2-yl]propanamide
• CAS: 72966-79-1
• 化学式: C₂₀H₁₆Cl₂N₂O₄
• 分子量: 419.264
• InChiKey: VEPZBTUPEBGMGG-UHFFFAOYSA-N

物化性质

• 熔点：
  186 °C(Solv: ethanol (64-17-5))
• 沸点：
  762.1±60.0 °C(Predicted)
• 密度：
  1.491±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.3
• 重原子数：
  28
• 可旋转键数：
  6
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.2
• 拓扑面积：
  92.3
• 氢给体数：
  2
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  2,6-bis(3-chloropropionamido)anthracene-9,10-dione 在 三氟乙酸 作用下， 以 乙醇 为溶剂， 反应 18.0h， 生成 2,6-bis(1,3-diaminopropano-3-propionamido)anthracene-9,10-dione
  参考文献：
  名称：

  Cleavage of abasic sites in DNA by intercalator-amines

  摘要：

  Anthraquinone and naphthalene diimide intercalators with amine-containing side chains cleave plasmid DNA at abasic sites (apurinic or apyrimidinic (AP) sites). The intercalator-amine is substantially more effective than the amine itself; many intercalators with diamine side chains cleave most of the abasic sites at micromolar concentration (30 min at 37 degrees C). Intercalators with two amino moieties in the side chain are more efficient than those with one, arguing for a role for each of two amines in the cleavage mechanism. Side chains ending in tertiary amines are somewhat more effective than those ending in primary amines, indicating that imine formation is not required for cleavage at the abasic site. We also report a systematic study of abasic site cleavage by polyamines, including piperidine, spermine, spermidine and 12 other di-, tri- and tetra-amines. For polyamines as well as intercalatoramines, examples with three carbon atoms between neighboring nitrogens atoms cleave most efficiently. This may reflect a particularly favorable geometry for proton abstraction for these species. The effect of nitrogen-nitrogen spacing on the pK(a) values of the nitrogens may contribute as well. Overall, cleavage of plasmid DNA at adventitious abasic sites by intercalator-amines bearing two nitrogens in a single side chain occurs readily. (C) 1999 Elsevier Science Ltd. All rights reserved.

  DOI：

  10.1016/s0968-0896(99)00193-5
• 作为产物：
  描述：

  2,6-二氨基蒽醌 、 3-氯丙酰氯 反应 5.0h， 以95%的产率得到2,6-bis(3-chloropropionamido)anthracene-9,10-dione
  参考文献：
  名称：

  2、6 蒽醌衍生物对端粒 DNA 序列的分子识别导致热稳定性并诱导癌细胞凋亡

  摘要：

  根据目前的研究，抗癌蒽醌会影响端粒破坏，并可能与触发细胞凋亡信号的 G-四链体 DNA 相互作用。本研究代表了与实验室合成的基于哌啶的蒽醌衍生物 2, 6- 双 [(3-哌啶基)乙酰氨基)] 蒽-9,10- 结合后，癌细胞中氧化应激、晚期细胞凋亡和诱导衰老的生物物理学研究二酮 (N1P) 和 2, 6-双[哌啶基)丙酰胺基]蒽-9,10-二酮 (N2P)，具有 G-四链体 DNA。我们采用生物物理方法来探索合成蒽醌衍生物与四链体 DNA 序列的相互作用，以影响 K 和 Na 阳离子存在下的生物活性。 N2P 和 N1P 的结合亲和力分别为 = 5.8 × 10 M 和 = 1.0 × 10 M，导致低/高色度，红移 5–7 nm，显着的荧光猝灭和椭圆度变化，导致外部结合两者都是 G-四链体 DNA 的配体。与 K 环境 (Δ = 21 °C) 相比，Na 环境 (Δ = 34 °C) 中配体结合诱导的

  DOI：

  10.1016/j.ijbiomac.2022.08.156

文献信息

• Novel, Water-Soluble Carboranyl Derivatives of Anthraquinones, Flourenones, and Sulfones:  A Synthetic Investigation
  作者：Kamesh Vyakaranam、Geeta Rana、Artie Ratanasuwan、Sumathy N. Hosmane、John A. Maguire、Narayan S. Hosmane

  DOI：10.1021/om020387+

  日期：2002.9.1

  CH3, C6H5] (14−16) in 49−78% yields as new carborane derivatives of anthraquinones, flourenones, and sulfones. The decapitation reaction of the closo-carborane species (3−8, 10−12, 14−16) with KOH in refluxing ethanol (C2H5OH) produced the corresponding open cage (nido) compounds (3a−8a, 10a−12a, 14a−16a) that are robust and water-soluble species, a requirement to impart lower toxicity for an effective

  据报道，有新的功能化的蒽醌，氟酮和砜的水溶性碳硼烷基衍生物。的Monolithiation Ó -carborane，甲基Ò -carborane，或苯基ö -carborane以及它们与合适的chloroamides（后续反应1，2，9，或13蒽，flourenone的），和砜制备1,5（或2 ，6） -双3- [2-（1-R-1,2- dicarba-闭合碳-dodecaboranyl）]丙酰胺}蒽-9,10-二酮[R = H，CH 3，C 6 H ^ 5 ]（3 - 8），2,7-双3- [2-（1-R-1,2-dicarba-闭合碳-dodecaboranyl）]丙酰胺} -9- flourenone [R = H，CH 3，C 6 H ^ 5 ]（10 - 12），和双4- [2-（1-R-1,2- dicarba-闭合碳- dodecaboranyl）]}苯基砜[R = H，CH
• Synthesis and Human Telomerase Inhibition of a Series of Regioisomeric Disubstituted Amidoanthraquinones
  作者：Hsu-Shan Huang、In-Been Chen、Kuo-Feng Huang、Wei-Chih Lu、Fu-Ying Shieh、Yi-Yuan Huang、Fong-Chun Huang、Jing-Jer Lin

  DOI：10.1248/cpb.55.284

  日期：——

  Telomerase is the enzymatic activity that maintains the ends of eukaryotic chromosomes. Telomerase activity is detected in most tumor cells whereas it is low or undetectable in most normal somatic cells. Expression of the telomerase catalytic component, the human telomerase reverse transcriptase (hTERT), is believed to be controlled primarily at the level of transcription. Because of this selective expression property of telomerase, it has been touted as a specific target for antitumor chemotherapeutics. However, a concern for the applicability of telomerase inhibitors is that they require a long lag time for telomeres to be shortened to critical length before cancer cells stop proliferating. Here we investigate telomerase inhibitory, cytotoxicity and the hTERT repressing effects on a number of synthesized 2,6-diamidoanthraquinones and 1,5-diamidoanthraquinones as compared to their disubstituted homologues. We found that several of the 1,5-diamidoanthraquinones and 2,6-diamidoanthraquinones inhibited telomerase activity effectively with IC50 at the sub-micro to micro molar range and caused acute cytotoxicity to cancer cells with EC50 similar or better than that of mitoxantrone. Particularly, 2,6-diamidoanthraquinone with 2-ethylaminoacetamido side chains 33, even though not affecting cell proliferation, showed to be endowed with a strong telomerase effect, probably related to a marked stabilization of the G-quadruplex-binding structure. The results suggested that these compounds caused multiple effects to cancer cells. More significantly, they overcome the long lag period problem of classical telomerase inhibitors that they are also potent cytotoxic agents. These results greatly expand the potential of tricyclic anthraquinone pharmacophore in preventive and/or curative therapy.

  端粒酶是维持真核染色体末端的酶活性。在大多数肿瘤细胞中都能检测到端粒酶活性，而在大多数正常体细胞中，端粒酶活性很低或检测不到。端粒酶催化成分人类端粒酶逆转录酶（hTERT）的表达被认为主要受转录水平的控制。由于端粒酶的这种选择性表达特性，它被誉为抗肿瘤化疗药物的特异性靶点。然而，端粒酶抑制剂的适用性令人担忧，因为在癌细胞停止增殖之前，端粒需要较长的滞后时间才能缩短到临界长度。在这里，我们研究了一些合成的 2,6-二氨基蒽醌和 1,5-二氨基蒽醌与它们的二取代同系物相比所具有的端粒酶抑制作用、细胞毒性和 hTERT 抑制作用。我们发现，其中几种 1,5-二氨基蒽醌和 2,6-二氨基蒽醌能有效抑制端粒酶活性，其 IC50 在亚微量至微量摩尔范围内，对癌细胞的急性细胞毒性 EC50 与米托蒽醌相似或更高。特别是带有 2- 乙氨基乙酰氨基侧链 33 的 2,6-二氨基蒽醌，虽然不影响细胞增殖，但却具有很强的端粒酶作用，这可能与 G-四联体结合结构的明显稳定有关。研究结果表明，这些化合物对癌细胞具有多重作用。更重要的是，这些化合物克服了传统端粒酶抑制剂滞后期长的问题，它们同时也是强效的细胞毒剂。这些结果大大拓展了三环蒽醌类药物在预防和/或治疗方面的潜力。
• Molecular Modeling Studies on G-Quadruplex Complexes of Telomerase Inhibitors:  Structure−Activity Relationships
  作者：Martin A. Read、Alexis A. Wood、John R. Harrison、Sharon M. Gowan、Lloyd R. Kelland、Harvinder S. Dosanjh、Stephen Neidle

  DOI：10.1021/jm990287e

  日期：1999.11.1

  Inhibition of the ability of the enzyme telomerase to add telomeric repeats to the end of chromosomes is a novel target for potential anticancer therapy. This paper examines the hypothesis that compounds possessing a planar aromatic chromophore inhibit telomerase via stabilization of, and binding to, a folded guanine quadruplex structure. Two series of telomerase inhibitors have been designed based on the 2,6-disubstituted amidoanthracene-9,10-dione and a,6-disubstituted acridine chromophores in order to investigate structure-activity relationships between biological activity and substituent group size. The relative binding energies between these compounds and the folded human telomere DNA quadruplex were determined using molecular simulation methods, involving explicitly solvated structures. The results obtained are in excellent agreement with the biological activity as measured in vitro using a modified TRAP assay and in general agreement with the ranking order of binding enthalpies found in isothermal titration calorimetry studies. This broad agreement provides strong support for the hypothesis that guanine quadruplexes are the primary target for telomerase inhibitors with extended planar chromophores.
• Anthracene-9,10-diones as potential anticancer agents. Synthesis, DNA-binding, and biological studies on a series of 2,6-disubstituted derivatives
  作者：Mavis Agbandje、Terence C. Jenkins、Robert McKenna、Anthony P. Reszka、Stephen Neidle

  DOI：10.1021/jm00086a010

  日期：1992.4

  A series of 2,6-bis(omega-aminoalkanamido)anthracene-9,10-diones (9,10-anthraquinones), of general formula Ar(NHCO(CH2)nNR2)2, where Ar = anthracene-9,10-dione and n = 1 or 2, have been synthesized by treatment of the corresponding bis(omega-haloalkanamido) derivatives with appropriate secondary amines. The DNA-binding properties of these compounds were evaluated by thermal denaturation studies, unwinding of closed-circular DNA, determination of association constants in solution, and examined by molecular modeling. A representative compound in the series has been examined by X-ray crystallography. In vitro cytotoxicity data is reported for the compounds and some indications of structure-activity relationships have been discerned. In particular, those compounds with two methylene links (n = 2) in each side chain separating the amide and terminal amine moieties have superior activity and, in general, enhanced DNA binding characteristics. It is postulated that the mode of reversible binding of these compounds to DNA involves the side chains occupying both major and minor grooves and, further, that this may confer cytotoxic properties which are distinct from those of previously reported anthracene-9,10-dione cytotoxins.
• 1,4- and 2,6-Disubstituted Amidoanthracene-9,10-dione Derivatives as Inhibitors of Human Telomerase
  作者：Philip J. Perry、Sharon M. Gowan、Anthony P. Reszka、Paolo Polucci、Terence C. Jenkins、Lloyd R. Kelland、Stephen Neidle

  DOI：10.1021/jm9801105

  日期：1998.8.1

  A number of 1,4- and 2,6-difunctionalized amidoanthracene-9, l0-diones have been prepared. We have examined their in vitro cytotoxicity in several tumor cell lines and their ability to inhibit the telomere-addition function of the human telomerase enzyme together with their inhibition of the Taq polymerase enzyme. Compounds with -(CH2)(2)- side chains terminating in basic groups such as piperidine show inhibition of telomerase at (IC50)-I-tel levels of 4-11 mu M. These are thus among the most potent nonnucleoside telomerase inhibitors reported to date. Cytotoxicity levels in human tumor cell lines were at comparable levels for several compounds. Implications for amidoanthracene-9,10-dione telomerase inhibitors as potential anticancer agents are discussed.