SB-T-1102 | 178250-27-6

• 分子结构分类: 有机化合物 - 脂质和类脂质分子 - 异戊烯醇脂质
• 英文名称: SB-T-1102
• 英文别名: 3'-dephenyl-3'-(2-methylpropyl)-10-propanoyldocetaxel；SB-T-1103；3'-dephenyl-3'-(2-methylpropyl)-10-n-propanoyldocetaxel；[(1S,2S,3R,4S,7R,9S,10S,12R,15S)-4-acetyloxy-1,9-dihydroxy-15-[(2R,3S)-2-hydroxy-5-methyl-3-[(2-methylpropan-2-yl)oxycarbonylamino]hexanoyl]oxy-10,14,17,17-tetramethyl-11-oxo-12-propanoyloxy-6-oxatetracyclo[11.3.1.03,10.04,7]heptadec-13-en-2-yl] benzoate
• CAS: 178250-27-6
• 化学式: C₄₄H₆₁NO₁₅
• 分子量: 843.966
• InChiKey: JTFSQGOZNMBTHL-YIFABKNJSA-N

物化性质

• 沸点：
  876.7±65.0 °C(Predicted)
• 密度：
  1.30±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  4.1
• 重原子数：
  60
• 可旋转键数：
  17
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.68
• 拓扑面积：
  231
• 氢给体数：
  4
• 氢受体数：
  15

反应信息

• 作为反应物：
  描述：

  二十二碳六烯酸 、 SB-T-1102 在 4-二甲氨基吡啶 、 达卡巴嗪 作用下， 以 二氯甲烷 为溶剂， 生成 2'-docosahexaenoyl-3'-dephenyl-3'-(2-methylpropyl)-10-propanoyldocetaxel
  参考文献：
  名称：

  Syntheses and evaluation of novel fatty acid-second-generation taxoid conjugates as promising anticancer agents

  摘要：

  Polyunsaturated fatty acids such as docosahexaenoic acid (DHA), linolenic acid, and linoleic acid were linked to the C-2' position of the second-generation taxoids that could overcome MDR caused by overexpressed ABC transporters. The new conjugates, tested in vivo, exhibited strong activity against drug-resistant colon cancer and drug-sensitive ovarian cancer xenografts in mice. Two of the new conjugates, DHA-SB-T-1214 and DHA-SB-T-1213, were found to achieve the total regression of drug-resistant and drug-sensitive tumors, respectively, in the animal models with substantially reduced systemic toxicity. (c) 2005 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2005.10.089
• 作为产物：
  描述：

  7-triethylsilyl-10-propanoyl-10-deacetylbaccatin III 在 palladium on activated charcoal 吡啶 、 氢氟酸 、 氢气 、 lithium hexamethyldisilazane 作用下， 以 四氢呋喃 、 乙酸乙酯 为溶剂， -15.0~30.0 ℃ 、101.33 kPa 条件下， 反应 29.0h， 生成 SB-T-1102
  参考文献：
  名称：

  Syntheses and Structure−Activity Relationships of the Second-Generation Antitumor Taxoids:  Exceptional Activity against Drug-Resistant Cancer Cells

  摘要：

  A series of new 3'-(2-methyl-1-propenyl) and 3'-(2-methylpropyl) taxoids with modifications at C-10 was synthesized by means of the beta-lactam synthon method using 10-modified 7-(triethylsilyl)-10-deacetylbaccatin III derivatives. The new taxoids thus synthesized show excellent cytotoxicity against human ovarian (A121), non-small-cell lung (A549), colon (HT-29), and breast (MCF-7) cancer cell lines. All but one of these new taxoids possess better activity than paclitaxel and docetaxel in the same assay, i.e., the IC50 values of almost all the taxoids are in the subnanomolar level. It is found that a variety of modifications at C-10 is tolerated for the activity against normal cancer cell lines, but the activity against a drug-resistant human breast cancer cell line expressing MDR phenotype (MCF7-R) is highly dependent on the structure of the C-10 modifier. A number of the new taxoids exhibit remarkable activity (IC50 = 2.1-9.1 nM) against MCF7-R. Among these, three new taxoids, SB-T-1213 (4a), SB-T-1214 (4b), and SB-T-1102 (5a), are found to be exceptionally potent, possessing 2 orders of magnitude better activity than paclitaxel and docetaxel. The observed exceptional activity of these taxoids may well be ascribed to an effective inhibition of P-glycoprotein binding by the modified C-10 moieties. The new taxoid SB-T-1213 (4a) shows an excellent activity (T/C = 0% at 12.4 and 7.7 mg/kg/dose, log(10) cell kill = 2.3 and 2.0, respectively) against B16 melanoma in B6D2F(1) mice via intravenous administration.

  DOI：

  10.1021/jm9604080

文献信息

• Drug conjugates
  申请人：Ojima Iwao

  公开号：US20050232928A1

  公开（公告）日：2005-10-20

  A compound having the formula Y-A-Z, wherein: A is a 5, 6, or 7 member ring that is monocyclic or is fused to 1 to 3 additional 4 to 8 member rings; wherein ring A and, independently, the fused additional rings are carbocyclic or heterocyclic, and saturated or unsaturated, wherein unsaturated rings are aromatic or non-aromatic; wherein Y and Z are substituents at adjacent positions on ring A; Y represents: Z represents: X and E represent O, S, or NR a or NR b ; each of a, b, c, d, e and f independently represents 0 or 1; a+c equals 0, 1, or 2; b+d equals 0, 1, or 2; a+b+c+d+e+f equals 1, 2, or 3; provided that when f is 1, then d is 1, and when d is 0, then f is 0; and when both e and b are 0, then neither R 1 nor R 1 is chloro or bromo; v represents 0 or 1, provided that when v is 0, then J is hydrogen, a metal ion, or a quaternary ammonium ion; and X is O and G is H; either G is hydrogen, a metal ion, a quaternary ammonium ion, lower alkyl, or comprised of a pharmaceutically active chemical compound or the precursor thereof; or X-G represents a carbonyl-activating group; J is lower alkyl, aryl, heteroaryl, omega-hydroxycarbonyl-(lower alkyl), omega-(lower alkoxy)carbonyl-(lower alkyl), omega-(X-G)-carbonyl-(lower alkyl) group, or comprised of a specific binding agent; and R a , R b , R 1 , R 2 , R 3 , R 4 are as defined in the specification.

  具有Y-A-Z分子式的化合物，其中：A是一个5、6或7成员环，可以是单环的，也可以与1至3个额外的4至8成员环融合；其中环A和额外融合的环独立地可以是碳环或杂环，饱和或不饱和，不饱和环可以是芳香的或非芳香的；其中Y和Z是环A上相邻位置的取代基；Y代表：Z代表：X和E代表O、S或NRa或NRb；a、b、c、d、e和f中的每一个独立地代表0或1；a+c等于0、1或2；b+d等于0、1或2；a+b+c+d+e+f等于1、2或3；条件是当f为1时，d为1，当d为0时，f为0；当e和b都为0时，R1和R1都不是氯或溴；v代表0或1，条件是当v为0时，J为氢、金属离子或季铵离子；X为O且G为H；G为氢、金属离子、季铵离子、低碳基，或由药用活性化学化合物或其前体组成；或者X-G代表一个羰基活化基团；J为低碳基、芳基、杂环基、ω-羟基羰基-(低碳基)、ω-(低烷氧基)羰基-(低碳基)、ω-(X-G)-羰基-(低碳基)基团，或由特异结合剂组成；而Ra、Rb、R1、R2、R3、R4如规范中所定义。
• Syntheses and Structure−Activity Relationships of the Second-Generation Antitumor Taxoids:  Exceptional Activity against Drug-Resistant Cancer Cells
  作者：Iwao Ojima、John C. Slater、Evelyne Michaud、Scott D. Kuduk、Pierre-Yves Bounaud、Patricia Vrignaud、Marie-Christine Bissery、Jean M. Veith、Paula Pera、Ralph J. Bernacki

  DOI：10.1021/jm9604080

  日期：1996.1.1

  A series of new 3'-(2-methyl-1-propenyl) and 3'-(2-methylpropyl) taxoids with modifications at C-10 was synthesized by means of the beta-lactam synthon method using 10-modified 7-(triethylsilyl)-10-deacetylbaccatin III derivatives. The new taxoids thus synthesized show excellent cytotoxicity against human ovarian (A121), non-small-cell lung (A549), colon (HT-29), and breast (MCF-7) cancer cell lines. All but one of these new taxoids possess better activity than paclitaxel and docetaxel in the same assay, i.e., the IC50 values of almost all the taxoids are in the subnanomolar level. It is found that a variety of modifications at C-10 is tolerated for the activity against normal cancer cell lines, but the activity against a drug-resistant human breast cancer cell line expressing MDR phenotype (MCF7-R) is highly dependent on the structure of the C-10 modifier. A number of the new taxoids exhibit remarkable activity (IC50 = 2.1-9.1 nM) against MCF7-R. Among these, three new taxoids, SB-T-1213 (4a), SB-T-1214 (4b), and SB-T-1102 (5a), are found to be exceptionally potent, possessing 2 orders of magnitude better activity than paclitaxel and docetaxel. The observed exceptional activity of these taxoids may well be ascribed to an effective inhibition of P-glycoprotein binding by the modified C-10 moieties. The new taxoid SB-T-1213 (4a) shows an excellent activity (T/C = 0% at 12.4 and 7.7 mg/kg/dose, log(10) cell kill = 2.3 and 2.0, respectively) against B16 melanoma in B6D2F(1) mice via intravenous administration.
• Syntheses and evaluation of novel fatty acid-second-generation taxoid conjugates as promising anticancer agents
  作者：Larissa Kuznetsova、Jin Chen、Liang Sun、Xinyuan Wu、Antonella Pepe、Jean M. Veith、Paula Pera、Ralph J. Bernacki、Iwao Ojima

  DOI：10.1016/j.bmcl.2005.10.089

  日期：2006.2

  Polyunsaturated fatty acids such as docosahexaenoic acid (DHA), linolenic acid, and linoleic acid were linked to the C-2' position of the second-generation taxoids that could overcome MDR caused by overexpressed ABC transporters. The new conjugates, tested in vivo, exhibited strong activity against drug-resistant colon cancer and drug-sensitive ovarian cancer xenografts in mice. Two of the new conjugates, DHA-SB-T-1214 and DHA-SB-T-1213, were found to achieve the total regression of drug-resistant and drug-sensitive tumors, respectively, in the animal models with substantially reduced systemic toxicity. (c) 2005 Elsevier Ltd. All rights reserved.