HTI 286 | 676633-60-6

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: HTI 286
• 英文别名: 4-{[2-(3-Cyclohexyl-3-methyl-2-methylamino-butyrylamino)-3,3-dimethyl-butyryl]-methyl-amino}-2,5-dimethyl-hex-2-enoic acid；(E,4S)-4-[[(2S)-2-[[(2S)-3-cyclohexyl-3-methyl-2-(methylamino)butanoyl]amino]-3,3-dimethylbutanoyl]-methylamino]-2,5-dimethylhex-2-enoic acid
• CAS: 676633-60-6
• 化学式: C₂₇H₄₉N₃O₄
• 分子量: 479.704
• InChiKey: AXRDAMYRXLDSEK-PSRNMDMQSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.7
• 重原子数：
  34
• 可旋转键数：
  11
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.81
• 拓扑面积：
  98.7
• 氢给体数：
  3
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  L-脯氨酸甲酯 、 HTI 286 在 1-羟基苯并三唑 、 1-(3-二甲基氨基丙基)-3-乙基碳二亚胺 、 N,N-二异丙基乙胺 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 生成 methyl (2S)-1-[(E,4S)-4-[[(2S)-2-[[(2S)-3-cyclohexyl-3-methyl-2-(methylamino)butanoyl]amino]-3,3-dimethylbutanoyl]-methylamino]-2,5-dimethylhex-2-enoyl]pyrrolidine-2-carboxylate
  参考文献：
  名称：

  D-piece modifications of the hemiasterlin analog HTI-286 produce potent tubulin inhibitors

  摘要：

  Modifications of the D-piece carboxylic acid group of the hemiasterlin analog HTI-286 gave tubulin inhibitors which were potent cytotoxic agents in taxol resistant cell lines expressing P-glycoprotein. Amides derived from proline had potency comparable to HTI-286. Reduction of the carboxylic acid to ketones and alcohols or its conversion to acidic heterocycles also gave potent analogs. Synthetic modifications of the carboxylic acid could be carried out selectively using a wide range of synthetic reagents. Proline analog 3 was found to be effective in a human xenograft model in athymic mice. (C) 2004 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2004.05.005
• 作为产物：
  描述：

  (S)-2-((叔丁氧基羰基)(甲基)氨基)-3-甲基-3-苯基丁酸 在 platinum(II) oxide lithium hydroxide 、 benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate 、 氢气 、 溶剂黄146 、 N,N-二异丙基乙胺 作用下， 以 甲醇 、 N,N-二甲基甲酰胺 为溶剂， 反应 15.0h， 生成 HTI 286
  参考文献：
  名称：

  Synthesis and Biological Activity of Analogues of the Antimicrotubule Agent N,β,β-Trimethyl-l-phenylalanyl-N-[(1S,2E)-3-carboxy-1-isopropylbut-2-enyl]- N¹,3-dimethyl-l-valinamide (HTI-286)

  摘要：

  Hemiasterlin (1), a tripeptide isolated from marine sponges, induces microtubule depolymerization and mitotic arrest in cells. HTI-286 (2), an analogue from an initial study of the hemiasterlins, is presently in clinical trials. In addition to its potent antitumor effects, 2 has the advantage of circumventing the P-glycoprotein-mediated resistance that hampers the efficacy of other antimicrotubule agents such as paclitaxel and vincristine in animal models. This paper describes an in-depth study of the structure-activity relationships of analogues of 2, their effects on microtubule polymerization, and their in vitro and in vivo anticancer activity. Regions of the molecule necessary for potent activity are identified. Groups tolerant of modification, leading to novel analogues, are reported. Potent analogues identified through in vivo studies in tumor xenograft models include one superior analogue, HTI-042 (48).

  DOI：

  10.1021/jm040056u

文献信息

• Hemiasterlin Derivative Having Cysteine Residue
  申请人：Sumitomo Dainippon Pharma Co., Ltd.

  公开号：US20220144889A1

  公开（公告）日：2022-05-12

  A compound represented by formula (1): wherein b represents an integer of 1 to 5; X represents —NH— or —CO—; Z represents a group represented, for example, by formula (Z-1); R 1 represents a hydrogen atom or (AB) m ; AB represents a particular amino acid residue, and when there is a plurality of ABs, each AB may be the same as or different from each other and ABs are bonded to each other via an amide bond; m represents an integer of 1 to 9; R 2 represents a hydroxy group or (AC) g ; AC represents a particular amino acid residue, and when there is a plurality of ACs, each AC may be the same as or different from each other and ACs are bonded to each other via an amide bond; and g represents an integer of 1 to 9, or a salt thereof.

  化合物的化学式为（1）：其中b表示1至5的整数；X表示—NH—或—CO—；Z表示由化学式（Z-1）表示的基团；R1表示氢原子或(AB)m；AB表示特定的氨基酸残基，当存在多个AB时，每个AB可以相同或不同，并且AB通过酰胺键相互连接；m表示1至9的整数；R2表示羟基或(AC)g；AC表示特定的氨基酸残基，当存在多个AC时，每个AC可以相同或不同，并且AC通过酰胺键相互连接；g表示1至9的整数；或其盐。
• Method of treating resistant tumors
  申请人：Wyeth Holdings Corporation

  公开号：US20040121965A1

  公开（公告）日：2004-06-24

  The invention provides a method of treating or inhibiting the growth of or eradicating a tumor in a mammal in need thereof wherein said tumor is resistant to at least one chemotherapeutic agent which method comprises providing to said mammal an effective amount of a compound of Formula II or a pharmaceutically acceptable salt thereof.

  本发明提供了一种治疗或抑制哺乳动物体内对至少一种化疗药物产生耐药性的肿瘤生长或根除肿瘤的方法，该方法包括向该哺乳动物提供有效量的公式II化合物或其药学上可接受的盐。
• Hemiasterlin Derivatives and Antibody-Drug Conjugates Including Same
  申请人：Sumitomo Dainippon Pharma Co., Ltd.

  公开号：US20200247845A1

  公开（公告）日：2020-08-06

  A compound represented by formula (1): wherein AA represents a particular amino acid residue or a C 1-6 alkyl ester thereof, and when there is a plurality of AAs, each AA may be the same as or different from each other and AAs are bonded to each other via an amide bond; an N-terminal nitrogen atom of (AA) m forms an amide bond together with carbonyl (a); Q represents an unsubstituted phenyl group, or a group represented by formula (Q-1), formula (Qa-2), formula (Qa-3), formula (Qa-4), formula (Qa-5), formula (Qa-6) or formula (Qa-7); R 1a and R 1b each independently represent a hydrogen atom or a C 1-6 alkyl group; and m represents an integer of 1 to 10, or a salt thereof.
• Antibody-Drug Conjugates Including Hemiasterlin Derivative
  申请人：Sumitomo Dainippon Pharma Co., Ltd.

  公开号：US20200247847A1

  公开（公告）日：2020-08-06

  A compound represented by formula (1-1): wherein b represents an integer of 1 to 5; and Z is a group represented by formula (Z-1), formula (Z-2), formula (Z-3), formula (Za-1), formula (Za-2), formula (Za-3), formula (Za-4) or formula (Za-5), or a salt thereof.
• [EN] METHOD OF TREATING RESISTANT TUMORS<br/>[FR] METHODE DE TRAITEMENT DE TUMEURS RESISTANTES
  申请人：WYETH CORP

  公开号：WO2004026293A2

  公开（公告）日：2004-04-01

  The invention provides a method of treating or inhibiting the growth of or eradicating a tumor in a mammal in need thereof wherein said tumor is resistant to at least one chemotherapeutic agents which method comprises providing to said mammal an effective amount of a compound of Formula II or a pharmaceutically acceptable salt thereof.