Cereblon; Apoptosis; E3 ligase

(S)-沙利度胺处理会导致 U266 细胞的细胞活力降低，IC50 为 362 μM[1]。 (S)-沙利度胺治疗以剂量依赖性方式增加 U266 细胞的凋亡[1]。参与细胞凋亡和血管生成的基因已经改变了表达谱，但细胞凋亡基因发生了最显着的变化。特别是，IB 激酶表达减少了两倍，同时 NF-B 表达减少了四倍。 (S)-沙利度胺可提高 Bax:Bcl-2 比率，同时还可提高 I-kB 蛋白水平并降低 NF-kB 活性。当与其他细胞毒性药物联合使用时，(S)-沙利度胺可显着降低 Bcl-2 的表达，从而增加了增强细胞毒性作用的可能性[1]。

只要鸡胚胎直接接触该药物，沙利度胺就确实会导致肢体缩小缺陷。最好的方法包括将沙利度胺浸泡的珠子植入邻近肢体区域的胚胎中，或将沙利度胺播种到假定的雏鸡肢体区域中，然后将外植体移植到宿主胚胎体细胞上。沙利度胺对移植到宿主胚胎中的鸡肢具有剂量依赖性作用。 (S)-沙利度胺的致畸性也高于(R)-沙利度胺[1]。

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在沙利度胺灾难的早期历史中，鸡胚被“淘汰”，因为它们对沙利度酰胺的研究很有用。得出这一结论的一个原因是，许多早期实验都有缺陷。我们进行了一系列实验，将鸡胚暴露于沙利度胺中。我们的数据显示，只要胚胎直接接触药物，沙利度胺确实会导致鸡胚肢体减少缺陷。最有用的技术是将沙利度胺浸泡过的珠子植入紧邻肢体区域的胚胎中，或将假定的鸡肢体区域浸泡在沙利度酰胺中，然后将外植体移植到宿主胚胎细胞中。沙利度胺以剂量反应方式影响移植到宿主胚胎的鸡肢体。此外，S-沙利度胺和S-EM12比R-沙利度酰胺和R-EM12更具致畸性。[2]

s-沙利度胺已被证明对多发性骨髓瘤有效。尽管它具有抗血管生成和促凋亡作用，但其主要治疗作用机制尚不清楚。我们研究了在U266 MM细胞系中用s-沙利度胺培养后，与这些细胞过程相关的基因表达的变化。用s-沙利度胺（0-1000微M）培养细胞，并在第3天评估细胞参数，包括凋亡。从在IC（50）浓度的s-沙利度胺下培养24小时的细胞中提取RNA，并通过微阵列方法研究基因表达的变化。在用s-沙利度胺培养的U266细胞中观察到细胞存活率降低（IC（50）:362微M），这反映在凋亡的显著增加上（例如，第3天的200微M：40.3+/-3.1%对第0天的3.2+/-0.4%；P<0.001）。参与血管生成和凋亡的基因的表达谱发生了变化，但凋亡基因的变化最为显著。特别是，I-κB激酶的表达降低了两倍，这与NF-κB表达降低了四倍有关。这些数据与免疫印迹分析相关，免疫印迹分析显示I-kappaB蛋白水平显著升高，NF-κB活性降低。此外，Bax:Bcl-2比值显著增加。我们的数据表明，血管生成和凋亡基因和蛋白质都受到s-沙利度胺的影响。此外，s-沙利度胺显著降低Bcl-2表达，表明如果与其他细胞毒性药物联合使用，可能会增强细胞毒性作用[1]。

Thalidomide is currently under evaluation as an anti-angiogenic agent in cancer treatment, alone and in combination with cytotoxic agents. Thalidomide is a racemate with known pharmacologic and pharmacokinetic enantioselectivity. In a previous study with thalidomide combination chemotherapy, we found evidence of anti-tumour synergy. In this study, we examined whether the synergy involved altered pharmacokinetics of thalidomide enantiomers. Adult female F344 rats were implanted with 9L gliosarcoma tumours intracranially, subcutaneously (flank), or both. Effectiveness of oral thalidomide alone, and with intraperitoneal BCNU or cisplatin combination chemotherapy, was assessed after several weeks treatment. Presumed pseudo steady-state serum, tumour and other tissues, collected after treatment, were assayed for R- and S-thalidomide by chiral HPLC. Both serum and tissue concentrations of R-thalidomide were 40-50% greater than those of S-thalidomide. Co-administration of BCNU or cisplatin with thalidomide did not alter the concentration enantioselectivity. Poor correlation of concentration with subcutaneous anti-tumour effect was found for individual treatments, and with all treatments for intracranial tumours. The consistency of the enantiomer concentration ratios across treatments strongly suggests that the favourable antitumour outcomes from interactions between thalidomide and the cytotoxic agents BCNU and cisplatin did not have altered enantioselectivity of thalidomide pharmacokinetics as their basis.[3]

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100 mg/kg, p.o.

C57BL/6 mice

Metabolism / Metabolites
(-)-thalidomide has known human metabolites that include 5-hydroxy-thalidomide, 5'-Hydroxythalidomide, and (-)-thalidomide arene oxide.

mouse LD50 oral 700 mg/kg BEHAVIORAL: SOMNOLENCE (GENERAL DEPRESSED ACTIVITY) Nature., 215(296), 1967 [PMID:6059519]

[1]. s-thalidomide has a greater effect on apoptosis than angiogenesis in a multiple myeloma cell line. Hematol J. 2004;5(3):247-54.

[2]. The effect of thalidomide in chicken embryos. Birth Defects Res A Clin Mol Teratol. 2009 Aug;85(8):725-31.

[3]. Enantioselectivity of thalidomide serum and tissue concentrations in a rat glioma model and effects of combination treatment with cisplatin and BCNU. J Pharm Pharmacol. 2007 Jan;59(1):105-14.

[4]. Understanding the Thalidomide Chirality in Biological Processes by the Self-disproportionation of Enantiomers. Sci Rep. 2018 Nov 20;8(1):17131.

(S)-thalidomide is a 2-(2,6-dioxopiperidin-3-yl)-1H-isoindole-1,3(2H)-dione that has S-configuration at the chiral centre. It has a role as a teratogenic agent. It is an enantiomer of a (R)-thalidomide.

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Twenty years after the thalidomide disaster in the late 1950s, Blaschke et al. reported that only the (S)-enantiomer of thalidomide is teratogenic. However, other work has shown that the enantiomers of thalidomide interconvert in vivo, which begs the question: why is teratogen activity not observed in animal experiments that use (R)-thalidomide given the ready in vivo racemization ("thalidomide paradox")? Herein, we disclose a hypothesis to explain this "thalidomide paradox" through the in-vivo self-disproportionation of enantiomers. Upon stirring a 20% ee solution of thalidomide in a given solvent, significant enantiomeric enrichment of up to 98% ee was observed reproducibly in solution. We hypothesize that a fraction of thalidomide enantiomers epimerizes in vivo, followed by precipitation of racemic thalidomide in (R/S)-heterodimeric form. Thus, racemic thalidomide is most likely removed from biological processes upon racemic precipitation in (R/S)-heterodimeric form. On the other hand, enantiomerically pure thalidomide remains in solution, affording the observed biological experimental results: the (S)-enantiomer is teratogenic, while the (R)-enantiomer is not.[4]

C13H10N2O4

258.23

258.064

C, 60.47; H, 3.90; N, 10.85; O, 24.78

841-67-8

Thalidomide;50-35-1;Thalidomide-d4;1219177-18-0;(R)-Thalidomide;2614-06-4

92142

Off-white to light brown solid powder

1.503g/cm3

509.7ºC at 760 mmHg

269-271ºC

262.1ºC

1.646

0.354

83.55

1

4

1

19

449

1

C1CC(=O)NC(=O)C1N2C(=O)C3=CC=CC=C3C2=O

UEJJHQNACJXSKW-VIFPVBQESA-N

InChI=1S/C13H10N2O4/c16-10-6-5-9(11(17)14-10)15-12(18)7-3-1-2-4-8(7)13(15)19/h1-4,9H,5-6H2,(H,14,16,17)/t9-/m0/s1

2-[(3S)-2,6-dioxopiperidin-3-yl]isoindole-1,3-dione

(S)-Thalidomide; NSC91730; NSC 91730; (S)-Thalidomide; (-)-Thalidomide; 841-67-8; (S)-(-)-thalidomide; l-Thalidomide; S-(-)-Thalidomide; S-Thalidomide; Thalidomide, (-)-; NSC-91730; l-Thalidomide

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

注意： 本产品在运输和储存过程中需避光。

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)