阿多来新 | 110314-48-2

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吲哚及其衍生物
• 中文名称: 阿多来新
• 英文名称: adozelesin
• 英文别名: N-[2-(3-methyl-7-oxo-5,10-diazatetracyclo[7.4.0.01,12.02,6]trideca-2(6),3,8-triene-10-carbonyl)-1H-indol-5-yl]-1-benzofuran-2-carboxamide
• CAS: 110314-48-2
• 化学式: C₃₀H₂₂N₄O₄
• 分子量: 502.529
• InChiKey: BYRVKDUQDLJUBX-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.4
• 重原子数：
  38
• 可旋转键数：
  3
• 环数：
  8.0
• sp3杂化的碳原子比例：
  0.17
• 拓扑面积：
  111
• 氢给体数：
  3
• 氢受体数：
  4

ADMET

代谢

铝通过口服或吸入暴露后吸收不良，基本上不通过皮肤吸收。铝的生物利用度受到铝化合物的影响，以及存在可以与铝形成络合物并增强或抑制其吸收的饮食成分的影响。铝在血液中与各种配体结合并分布到每个器官，其中在骨骼和肺组织中浓度最高。在生物体中，铝被认为存在四种不同形式：作为自由离子，作为低分子量络合物，作为物理结合的大分子络合物，以及作为共价结合的大分子络合物。吸收的铝主要通过尿液排出，较少部分通过胆汁排出，而未吸收的铝则通过粪便排出。（L739）

Aluminum is poorly absorbed following either oral or inhalation exposure and is essentially not absorbed dermally. The bioavailability of aluminum is strongly influenced by the aluminum compound and the presence of dietary constituents which can complex with aluminum and enhance or inhibit its absorption. Aluminum binds to various ligands in the blood and distributes to every organ, with highest concentrations found in bone and lung tissues. In living organisms, aluminum is believed to exist in four different forms: as free ions, as low-molecular-weight complexes, as physically bound macromolecular complexes, and as covalently bound macromolecular complexes. Absorbed aluminum is excreted principally in the urine and, to a lesser extent, in the bile, while unabsorbed aluminum is excreted in the faeces. (L739)

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 毒性总结

铝的主要靶器官是中枢神经系统和骨骼。铝与饮食中的磷结合，并影响胃肠道对磷的吸收。体内磷负荷的减少会导致骨软化（由于骨骼矿化缺陷导致的骨质疏松）和佝偻病。铝的神经毒性被认为涉及多种机制。细胞骨架蛋白功能的变化，如磷酸化、蛋白水解、运输和合成的改变，被认为是其中一个原因。铝可能通过影响血脑屏障的通透性、胆碱能活性、信号转导途径、脂质过氧化以及损害神经元谷氨酸一氧化氮-环磷酸鸟苷酸途径，以及由于类似的配位化学性质和随后的竞争性相互作用，干扰必需微量元素的代谢，从而诱导神经行为效应。有研究表明，铝与雌激素受体的相互作用增加了雌激素相关基因的表达，从而促进了乳腺癌的进展（A235），但研究尚未能够建立铝与乳腺癌风险增加之间的明确联系（A15468）。某些铝盐通过激活炎症小体来诱导免疫反应。（L739, A235, A236）

The main target organs of aluminum are the central nervous system and bone. Aluminum binds with dietary phosphorus and impairs gastrointestinal absorption of phosphorus. The decreased phosphate body burden results in osteomalacia (softening of the bones due to defective bone mineralization) and rickets. Aluminum's neurotoxicity is believed to involve several mechanisms. Changes in cytoskeletal protein functions as a results of altered phosphorylation, proteolysis, transport, and synthesis are believed to be one cause. Aluminum may induce neurobehavioral effects by affecting permeability of the blood-brain barrier, cholinergic activity, signal transduction pathways, lipid peroxidation, and impair neuronal glutamate nitric oxide-cyclic GMP pathway, as well as interfere with metabolism of essential trace elements because of similar coordination chemistries and consequent competitive interactions. It has been suggested that aluminum's interaction with estrogen receptors increases the expression of estrogen-related genes and thereby contributes to the progression of breast cancer (A235), but studies have not been able to establish a clear link between aluminum and increased risk of breast cancer (A15468). Certain aluminum salts induce immune responses by activating inflammasomes. (L739, A235, A236)

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 致癌物分类

未列入国际癌症研究机构(IARC)名录。国际癌症研究机构将铝生产归类为对人类有致癌风险（第1组），但并未将铝本身视为人类致癌物。（L135）有人提出铝制抗汗剂的使用与乳腺癌风险增加之间存在关联（A235），但研究并未能确立明确的联系（A15468）。

Not listed by IARC. IARC classified aluminum production as carcinogenic to humans (Group 1), but did not implicate aluminum itself as a human carcinogen. (L135) A link between use of aluminum-containing antiperspirants and increased risk of breast cancer has been proposed (A235), but studies have not been able to establish a clear link (A15468).

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 健康影响

铝针对神经系统，导致神经系统性能下降，并与血脑屏障功能改变有关。体内铝的积累可能导致骨骼或脑部疾病。高水平的铝与阿尔茨海默病有关。少数人对铝过敏，在接触或摄入含有铝的产品时，会经历接触性皮炎、消化紊乱、呕吐或其他症状。

Aluminum targets the nervous system and causes decreased nervous system performance and is associated with altered function of the blood-brain barrier. The accumulation of aluminum in the body may cause bone or brain diseases. High levels of aluminum have been linked to Alzheimer's disease. A small percentage of people are allergic to aluminium and experience contact dermatitis, digestive disorders, vomiting or other symptoms upon contact or ingestion of products containing aluminium. (L739, L740)

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 暴露途径

口服（L739）；吸入（L739）

Oral (L739) ; inhalation (L739)

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 症状

吸入铝尘会导致咳嗽和胸部X光异常。一小部分人对铝过敏，接触含铝产品或摄入后会经历接触性皮炎、消化系统紊乱、呕吐或其他症状。

Inhalating aluminum dust causes coughing and abnormal chest X-rays. A small percentage of people are allergic to aluminium and experience contact dermatitis, digestive disorders, vomiting or other symptoms upon contact or ingestion of products containing aluminium. (L739, L740)

来源:Toxin and Toxin Target Database (T3DB)

反应信息

• 作为反应物：
  描述：

  阿多来新 生成 N-[2-[4-hydroxy-8-(hydroxymethyl)-1-methyl-7,8-dihydro-3H-pyrrolo[3,2-e]indole-6-carbonyl]-1H-indol-5-yl]-1-benzofuran-2-carboxamide
  参考文献：
  名称：

  WARPEHOSKI, M. A.;GEBHARD, I.;KELLY, R. C.;KRUEGER, W. C.;LI, L. H.;MCGOV+, J. MED. CHEM., 31,(1988) N 3, 590-603

  摘要：

  DOI：
• 作为产物：
  描述：

  [6-[5-(1-benzofuran-2-carbonylamino)-1H-indole-2-carbonyl]-1-methyl-4-phenylmethoxy-7,8-dihydro-3H-pyrrolo[3,2-e]indol-8-yl]methyl methanesulfonate 以16%的产率得到
  参考文献：
  名称：

  WARPEHOSKI, M. A.;GEBHARD, I.;KELLY, R. C.;KRUEGER, W. C.;LI, L. H.;MCGOV+, J. MED. CHEM., 31,(1988) N 3, 590-603

  摘要：

  DOI：

文献信息

• Stereoelectronic factors influencing the biological activity and DNA interaction of synthetic antitumor agents modeled on CC-1065
  作者：M. A. Warpehoski、I. Gebhard、R. C. Kelly、W. C. Krueger、L. H. Li、J. P. McGovren、M. D. Prairie、N. Wicnienski、W. Wierenga

  DOI：10.1021/jm00398a017

  日期：1988.3

  on the potent antitumor antibiotic CC-1065 (1), are described. Many of these synthetic analogues are significantly more effective than 1 against murine tumors. In particular, compound 27 exhibits high activity and potency. Structure-activity analysis supports a molecular mechanism for biological action involving hydrophobic interaction of the drug with DNA and acid-catalyzed alkylation of DNA.

  描述了以有效的抗肿瘤抗生素CC-1065（1）为模型的一系列新型螺环丙基化合物的合成，理化性质和生物学活性。这些合成类似物中的许多对鼠类肿瘤的疗效明显优于1。特别地，化合物27表现出高活性和效力。结构活性分析支持生物学作用的分子机制，涉及药物与DNA的疏水相互作用和酸催化的DNA烷基化。
• NOVEL B7-H3 BINDING MOLECULES, ANTIBODY DRUG CONJUGATES THEREOF AND METHODS OF USE THEREOF
  申请人：MacroGenics, Inc.

  公开号：US20210171641A1

  公开（公告）日：2021-06-10

  The present invention is directed to novel B7-H3-binding molecules capable of binding to human and non-human B7-H3, and in particular to such molecules that are cross-reactive with B7-H3 of a non-human primate (e.g., a cynomolgus monkey). The invention additionally pertains to B7-H3-binding molecules that comprise Variable Light Chain and/or Variable Heavy Chain (VH) Domains that have been humanized and/or deimmunized so as to exhibit a reduced immunogenicity upon administration to recipient subjects. The invention particularly pertains to bispecific, trispecific or multispecific B7-H3-binding molecules, including bispecific diabodies, BiTEs, bispecific antibodies, trivalent binding molecules, etc. that comprise: (i) such B7-H3-binding Variable Domains and (ii) a domain capable of binding to an epitope of a molecule present on the surface of an effector cell. The invention is also directed to pharmaceutical compositions that contain any of such B7-H3-binding molecules, and to methods involving the use of any of such B7-H3-binding molecules in the treatment of cancer and other diseases and conditions. The invention also particularly pertains to a molecule that comprises the human B7-H3 binding domain of a humanized anti-human B7-H3 antibody conjugated to at least one drug moiety (a “B7-H3-ADC”). The invention is also directed to pharmaceutical compositions that contain such B7-H3-ADCs, and to methods involving the use of any of such B7-H3-ADCs in the treatment of cancer and other diseases and conditions.
• [EN] NOVEL B7-H3 BINDING MOLECULES, ANTIBODY DRUG CONJUGATES THEREOF AND METHODS OF USE THEREOF<br/>[FR] NOUVELLES MOLÉCULES DE LIAISON À B7-H3, LEURS CONJUGUÉS ANTICORPS-MÉDICAMENTS ET LEURS PROCÉDÉS D'UTILISATION
  申请人：MACROGENICS INC

  公开号：WO2017180813A1

  公开（公告）日：2017-10-19

  The present invention is directed to novel B7-H3-binding molecules capable of binding to human and non-human B7-H3, and in particular to such molecules that are cross-reactive with B7-H3 of a non-human primate (e.g., a cynomolgus monkey). The invention additionally pertains to B7-H3-binding molecules that comprise Variable Light Chain and/or Variable Heavy Chain (VH) Domains that have been humanized and/or deimmunized so as to exhibit a reduced immunogenicity upon administration to recipient subjects. The invention particularly pertains to bispecific, trispecific or multispecific B7-H3-binding molecules, including bispecific diabodies, BiTEs, bispecific antibodies, trivalent binding molecules, etc. that comprise: (i) such B7-H3-binding Variable Domains and (ii) a domain capable of binding to an epitope of a molecule present on the surface of an effector cell. The invention also particularly pertains to a molecule that comprises the human B7-H3 binding domain of a humanized anti-human B7-H3 antibody conjugated to at least one drug moiety (a "B7-H3-ADC").
• [EN] SMART DRUG DELIVERY SYSTEM AND PHARMACEUTICAL KIT FOR DUAL NUCLEAR MEDICAL CYTOTOXIC THERANOSTICS<br/>[FR] SYSTÈME D'ADMINISTRATION DE MÉDICAMENT INTELLIGENT ET KIT PHARMACEUTIQUE POUR THÉRANOSTIQUE CYTOTOXIQUE MÉDICALE NUCLÉAIRE DOUBLE<br/>[DE] SMART-DRUG-DELIVERY-SYSTEM UND PHARMAZEUTISCHES KIT FÜR DUALE NUKLEARMEDIZINISCH-CYTOTOXISCHE THERANOSTIK
  申请人：UNIV MAINZ JOHANNES GUTENBERG

  公开号：WO2021123013A1

  公开（公告）日：2021-06-24

  Ein Smart-Drug-Delivery-System für duale nuklearmedizinisch-cytotoxische Theranostik umfasst – eine erste Verbindung mit der Struktur: oder – eine zweite Verbindung mit der Struktur Chel—S—TV und eine dritte Verbindung mit der Struktur CT—L—TV; wobei in der ersten, zweiten und dritten Verbindung Chel ein Rest eines Chelators für die Komplexierung eines Radioisotops; CT ein Rest einer cytotoxischen Verbindung; TV ein biologischer Targetingvektor; L1 und L jeweils ein Linker; S1, S2 und S jeweils ein Spacer ist.