CCI-779 | 162635-04-3

• 物质功能分类: 生物化工 - 抑制剂 - PI3K/Akt/mTOR抑制剂(PI3K/Akt/mTOR)
• 分子结构分类: 有机化合物 - 苯丙烷和聚酮 - 大环内酯内酰胺
• 英文名称: CCI-779
• 英文别名: (1R,2R,4S)-4-[(2R)-2-[(1R,9S,12S,15R,18R,19R,21R,23S,30S,32S,35R)-1,18-dihydroxy-19,30-dimethoxy-15,17,21,23,29,35-hexamethyl-2,3,10,14,20-pentaoxo-11,36-dioxa-4-azatricyclo[30.3.1.0^{4,9}]hexatriaconta-16,24,26,28-tetraen-12-yl]propyl]-2-methoxycyclohexyl 3-hydroxy-2-(hydroxymethyl)-2-methylpropanoate；[(1R,2R,4S)-4-[(2R)-2-[(1R,9S,12S,15R,16E,18R,19R,21R,23S,24E,26E,28E,30S,35R)-1,18-dihydroxy-19,30-dimethoxy-15,17,21,23,29,35-hexamethyl-2,3,10,14,20-pentaoxo-11,36-dioxa-4-azatricyclo[30.3.1.04,9]hexatriaconta-16,24,26,28-tetraen-12-yl]propyl]-2-methoxycyclohexyl] 3-hydroxy-2-(hydroxymethyl)-2-methylpropanoate
• CAS: 162635-04-3
• 化学式: C₅₆H₈₇NO₁₆
• 分子量: 1030.3
• InChiKey: CBPNZQVSJQDFBE-HGVVHKDOSA-N

物化性质

• 熔点：
  99-101°C
• 沸点：
  1048.4±75.0 °C(Predicted)
• 密度：
  1.21
• 闪点：
  587.8℃
• 溶解度：
  易溶于可溶于氯仿、甲醇。
• 颜色/状态：
  White to off-white powder
• 解离常数：
  No ionizable functional groups

计算性质

• 辛醇/水分配系数(LogP)：
  5.6
• 重原子数：
  73
• 可旋转键数：
  11
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.75
• 拓扑面积：
  242
• 氢给体数：
  4
• 氢受体数：
  16

ADMET

代谢

主要由人类肝脏中的细胞色素P450 3A4代谢。同样有效的代谢物西罗莫司是人类静脉输注后的主要代谢物。在体外进行的坦西莫司代谢研究中观察到的其他代谢途径包括羟基化、还原和去甲基化。

Primarily metabolized by cytochrome P450 3A4 in the human liver. Sirolimus, an equally potent metabolite, is the primary metabolite in humans following IV infusion. Other metabolic pathways observed in <i>in vitro</i> temsirolimus metabolism studies include hydroxylation, reduction and demethylation.

来源:DrugBank

代谢

西罗莫司是替西莫司的活性代谢物，是人类静脉给药后主要的代谢物。其余代谢物在血浆中的放射性不到10%。

Sirolimus, an active metabolite of temsirolimus, is the principal metabolite in humans following intravenous treatment. The remainder of the metabolites account for less than 10% of radioactivity in the plasma.

来源:Hazardous Substances Data Bank (HSDB)

代谢

Temsirolimus 通过水解代谢为西罗莫司，后者是主要的活性代谢物。Temsirolimus 和西罗莫司均通过细胞色素 P-450（CYP）同工酶 3A4 进行代谢。尽管 Temsirolimus 被代谢为西罗莫司，但 Temsirolimus 本身具有抗肿瘤活性，并不被认为是一种前药。

Temsirolimus is metabolized by hydrolysis to sirolimus, the principal active metabolite. Both temsirolimus and sirolimus also are metabolized by cytochrome P-450 (CYP) isoenzyme 3A4. Although temsirolimus is metabolized to sirolimus, temsirolimus itself exhibits antitumor activity and is not considered a prodrug.

来源:Hazardous Substances Data Bank (HSDB)

代谢

体外代谢研究了替西罗莫司（雷帕霉素-42-[2,2-双-(羟甲基)]-丙酸酯），一种抗肿瘤药物，使用人肝微粒体以及重组人细胞色素P450酶，即CYP3A4、1A2、2A6、2C8、2C9、2C19和2E1。通过液相色谱-串联质谱（LC-MS/MS或MS/MS/MS）检测到15个代谢物。CYP3A4被确定为主要负责该化合物代谢的酶。与重组CYP3A4孵育的替西罗莫司产生了大多数与人肝微粒体孵育时检测到的代谢物，这些代谢物用于大规模制备。通过硅胶色谱后接着半制备反相色谱高效液相色谱，分离和纯化了单个代谢物，用于结构鉴定和生物活性研究。通过正负质谱（MS）和MS/MS光谱方法，将次要代谢物（峰1-7）鉴定为羟基化或去甲基化的巨环环开替西罗莫司衍生物。由于这些化合物不稳定且仅以微量存在，因此未进行进一步研究。通过结合LC-MS、MS/MS、MS/MS/MS和NMR技术，确定了六个主要代谢物为36-羟基替西罗莫司（M8）、35-羟基替西罗莫司（M9）、开环的11-羟基替西罗莫司（M10和M11）、N-氧化物替西罗莫司（M12）和32-O-去甲基替西罗莫司（M13）。与母体化合物相比，这些代谢物对LNCaP细胞增殖的活性显著降低。

The in vitro metabolism of temsirolimus, (rapamycin-42-[2,2-bis-(hydroxymethyl)]-propionate), an antineoplastic agent, was studied using human liver microsomes as well as recombinant human cytochrome P450s, namely CYP3A4, 1A2, 2A6, 2C8, 2C9, 2C19, and 2E1. Fifteen metabolites were detected by liquid chromatography (LC)-tandem mass spectrometry (MS/MS or MS/MS/MS). CYP3A4 was identified as the main enzyme responsible for the metabolism of the compound. Incubation of temsirolimus with recombinant CYP3A4 produced most of the metabolites detected from incubation with human liver microsomes, which was used for large-scale preparation of the metabolites. By silica gel chromatography followed by semipreparative reverse-phase high-performance liquid chromatography, individual metabolites were separated and purified for structural elucidation and bioactivity studies. The minor metabolites (peaks 1-7) were identified as hydroxylated or desmethylated macrolide ring-opened temsirolimus derivatives by both positive and negative mass spectrometry (MS) and MS/MS spectroscopic methods. Because these compounds were unstable and only present in trace amounts, no further investigations were conducted. Six major metabolites were identified as 36-hydroxyl temsirolimus (M8), 35-hydroxyl temsirolimus (M9), 11-hydroxyl temsirolimus with an opened hemiketal ring (M10 and M11), N- oxide temsirolimus (M12), and 32-O-desmethyl temsirolimus (M13) using combined LC-MS, MS/MS, MS/MS/MS, and NMR techniques. Compared with the parent compound, these metabolites showed dramatically decreased activity against LNCaP cellular proliferation. </