[(1S,2S,3R,4S,7R,9S,10S,12R,15S)-15-[(2R,3S)-2-[2-[2-[[5-[2-[[4-[2-[2-[2-[2-[5-[(3aS,4S,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]ethoxy]ethoxy]ethoxy]ethylamino]-6-[[1-[2-[2-[2-[2-[4-[[2-[2-[[(19S)-19-ethyl-14,18-dioxo-17-oxa-3,13-diazapentacyclo[11.8.0.02,11.04,9.015,20]henicosa-1(21),2,4,6,8,10,15(20)-heptaen-19-yl]oxy]-2-oxoethyl]phenyl]disulfanyl]pentanoylamino]ethoxy]ethoxy]ethoxy]ethyl]triazol-4-yl]methylamino]-1,3,5-triazin-2-yl]amino]ethylamino]-5-oxopentan-2-yl]disulfanyl]phenyl]acetyl]oxy-5-methyl-3-[(2-methylpropan-2-yl)oxycarbonylamino]hex-4-enoyl]oxy-4-acetyloxy-12-(cyclopropanecarbonyloxy)-1,9-dihydroxy-10,14,17,17-tetramethyl-11-oxo-6-oxatetracyclo[11.3.1.03,10.04,7]heptadec-13-en-2-yl] benzoate | 1613697-44-1

• 分子结构分类: 有机化合物 - 生物碱及其衍生物 - 喜树碱
• 英文名称: [(1S,2S,3R,4S,7R,9S,10S,12R,15S)-15-[(2R,3S)-2-[2-[2-[[5-[2-[[4-[2-[2-[2-[2-[5-[(3aS,4S,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]ethoxy]ethoxy]ethoxy]ethylamino]-6-[[1-[2-[2-[2-[2-[4-[[2-[2-[[(19S)-19-ethyl-14,18-dioxo-17-oxa-3,13-diazapentacyclo[11.8.0.02,11.04,9.015,20]henicosa-1(21),2,4,6,8,10,15(20)-heptaen-19-yl]oxy]-2-oxoethyl]phenyl]disulfanyl]pentanoylamino]ethoxy]ethoxy]ethoxy]ethyl]triazol-4-yl]methylamino]-1,3,5-triazin-2-yl]amino]ethylamino]-5-oxopentan-2-yl]disulfanyl]phenyl]acetyl]oxy-5-methyl-3-[(2-methylpropan-2-yl)oxycarbonylamino]hex-4-enoyl]oxy-4-acetyloxy-12-(cyclopropanecarbonyloxy)-1,9-dihydroxy-10,14,17,17-tetramethyl-11-oxo-6-oxatetracyclo[11.3.1.03,10.04,7]heptadec-13-en-2-yl] benzoate
• CAS: 1613697-44-1
• 化学式: C₁₂₅H₁₆₁N₁₇O₃₁S₅
• 分子量: 2558.08
• InChiKey: WPGHIYHIBYOXDG-AWQZLHAASA-N

物化性质

• 密度：
  1.43±0.1 g/cm3(Temp: 20 °C; Press: 760 Torr)(predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  8.7
• 重原子数：
  178
• 可旋转键数：
  74
• 环数：
  17.0
• sp3杂化的碳原子比例：
  0.57
• 拓扑面积：
  738
• 氢给体数：
  11
• 氢受体数：
  45

反应信息

• 作为产物：
  描述：

  (S)-4-ethyl-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-4-yl 2-(2-((1-azido-13-oxo-3,6,9-trioxa-12-azaheptadecan-16-yl)disulfaneyl)phenyl)acetate 、 [(1S,2S,3R,4S,7R,9S,10S,12R,15S)-15-[(2R,3S)-2-[2-[2-[[5-[2-[[4-[2-[2-[2-[2-[5-[(3aS,4S,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]ethoxy]ethoxy]ethoxy]ethylamino]-6-(prop-2-ynylamino)-1,3,5-triazin-2-yl]amino]ethylamino]-5-oxopentan-2-yl]disulfanyl]phenyl]acetyl]oxy-5-methyl-3-[(2-methylpropan-2-yl)oxycarbonylamino]hex-4-enoyl]oxy-4-acetyloxy-12-(cyclopropanecarbonyloxy)-1,9-dihydroxy-10,14,17,17-tetramethyl-11-oxo-6-oxatetracyclo[11.3.1.03,10.04,7]heptadec-13-en-2-yl] benzoate 在 copper(ll) sulfate pentahydrate 、 维生素 C 作用下， 以 四氢呋喃 、 二氯甲烷 、 水 为溶剂， 反应 14.0h， 以92%的产率得到[(1S,2S,3R,4S,7R,9S,10S,12R,15S)-15-[(2R,3S)-2-[2-[2-[[5-[2-[[4-[2-[2-[2-[2-[5-[(3aS,4S,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]ethoxy]ethoxy]ethoxy]ethylamino]-6-[[1-[2-[2-[2-[2-[4-[[2-[2-[[(19S)-19-ethyl-14,18-dioxo-17-oxa-3,13-diazapentacyclo[11.8.0.02,11.04,9.015,20]henicosa-1(21),2,4,6,8,10,15(20)-heptaen-19-yl]oxy]-2-oxoethyl]phenyl]disulfanyl]pentanoylamino]ethoxy]ethoxy]ethoxy]ethyl]triazol-4-yl]methylamino]-1,3,5-triazin-2-yl]amino]ethylamino]-5-oxopentan-2-yl]disulfanyl]phenyl]acetyl]oxy-5-methyl-3-[(2-methylpropan-2-yl)oxycarbonylamino]hex-4-enoyl]oxy-4-acetyloxy-12-(cyclopropanecarbonyloxy)-1,9-dihydroxy-10,14,17,17-tetramethyl-11-oxo-6-oxatetracyclo[11.3.1.03,10.04,7]heptadec-13-en-2-yl] benzoate
  参考文献：
  名称：

  Design, Synthesis, and Biological Evaluations of Tumor-Targeting Dual-Warhead Conjugates for a Taxoid–Camptothecin Combination Chemotherapy

  摘要：

  Novel tumor-targeting dual-warhead conjugates, 2 (DW-1) and 3 (DW-2), which consist of a next-generation taxoid, 1 (SB-T-1214), and camptothecin as two warheads, self-immolative disulfide linkers for drug release, biotin as the tumor-targeting moiety, and 1,3,5-triazine as the tripod splitter module, were designed and synthesized. The potency of 2 was evaluated against MX-1, MCF-7, ID8, L1210FR (BR+, biotin receptor overexpressed) and WI38 (BR-, normal) cell lines in the absence and presence of glutathione (GSH), which is an endogenous thiol that triggers drug release inside the cancer cells. With the GSH and resuspension protocol, 2 exhibited IC50 values of 3.22-9.80 nM against all BR+ cancer cell lines, and 705 nM against WI38. Thus, there was a two orders of magnitude higher selectivity to cancer cells. Also, a clear cooperative effect was observed for the taxoid-camptothecin combination when two drugs were delivered to the cancer cells specifically in the form of a dual-warhead conjugate.

  DOI：

  10.1021/jm500631u

文献信息

• Therapeutic agent for treating tumors
  申请人：THE RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK

  公开号：US10280183B2

  公开（公告）日：2019-05-07

  The present disclosure relates to a therapeutic agent of the formula: Z—C(═O)—(CH2)n-Φ-S—S—(CRR′)m-(CH2)p-C(═O)—NH—(CH2)q-NH—Y[NH—(CH2)r-X-T-W][NH—(CH2—CH—O)t(CH2)s-NH—V]  Formula I or a pharmaceutically acceptable salt thereof, useful for treating tumors, including cancers. Where the compound of Formula I also contains a radionuclide or an imaging agent or both, the compound of formula I is a theranostic agent useful for treating and diagnosing tumors, including cancers.

  本公开涉及一种式的治疗剂： Z-C(═O)-(CH2)n-Φ-S-S-(CRR′)m-( )p-C(═O)-NH-( )q-NH-Y[NH-( )r-X-T-W][NH-( -CH-O)t( )s-NH-V] 式 I 或其药学上可接受的盐，可用于治疗肿瘤，包括癌症。如果式 I 的化合物还含有放射性核素或成像剂或两者兼有，则式 I 的化合物是一种治疗和诊断肿瘤（包括癌症）的治疗剂。
• THERAPEUTIC AGENT FOR TREATING TUMORS
  申请人：THE RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK

  公开号：US20170166591A1

  公开（公告）日：2017-06-15

  The present disclosure relates to a therapeutic agent of the formula: Z—C(═O)—(CH 2 ) n -Φ-S—S—(CRR′) m -(CH 2 ) p —C(═O)—NH—(CH 2 ) q —NH—Y[NH—(CH 2 ) r —X-T-W][NH—(CH 2 —CH—O) t (CH 2 ) s —NH—V]  Formula I or a pharmaceutically acceptable salt thereof, useful for treating tumors, including cancers. Where the compound of Formula I also contains a radionuclide or an imaging agent or both, the compound of formula I is a theranostic agent useful for treating and diagnosing tumors, including cancers.