Tubulysin
目录号 : GC37835
Tubulysin 家族的次级代谢产物最初是从粘细菌 Archangium geophyra 和 Angiococcus disciformis 中分离出来的。 这些化合物是有效的微管去稳定剂，其皮摩尔范围内的 IC50 值对抗许多包括具有多药抗性的癌细胞系。Tubulysins 由于严重毒性而具有有限的治疗效用，Tubulysins 是结合到小分子药物缀合物 (SMDC) 递送系统中的理想候选者。
Cas No.:1943604-24-7
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >98.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
Tubulysin family of secondary metabolites are originally isolated from the myxobacteria Archangium geophyra and Angiococcus disciformis. These compounds are potent microtubule destabilizing agents with IC50 values in the picomolar range against many cancer cell lines, including those with multidrug resistant properties. Tubulysins have limited therapeutic utility due to severe toxicity, so Tubulysins are ideal candidates to be incorporated into molecule drug conjugate (SMDC) delivery system[1].
[1]. Leamon CP, et al. Prostate-Specific Membrane Antigen-Specific Antitumor Activity of a Self-Immolative Tubulysin Conjugate. Bioconjug Chem. 2019 Jun 19;30(6):1805-1813.
| Cas No. | 1943604-24-7 | SDF | |
| Canonical SMILES | O=C(O)[C@@H](C)C[C@@H](NC(C1=CSC([C@H](OC(C)=O)C[C@@H](N(COC(CC(C)C)=O)C([C@@H](NC([C@@H]2N(C)CCCC2)=O)[C@@H](C)CC)=O)C(C)C)=N1)=O)CC3=CC=C(C)C=C3 | ||
| 分子式 | C44H67N5O9S | 分子量 | 842.1 |
| 溶解度 | Soluble in DMSO | 储存条件 | Store at -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
 |
1 mg | 5 mg | 10 mg |
| 1 mM | 1.1875 mL | 5.9375 mL | 11.8751 mL |
| 5 mM | 0.2375 mL | 1.1875 mL | 2.375 mL |
| 10 mM | 0.1188 mL | 0.5938 mL | 1.1875 mL |
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
| 第二步：请输入动物体内配方组成（配方适用于不溶于水的药物；不同批次药物配方比例不同，请联系GLPBIO为您提供正确的澄清溶液配方） | ||||||||||
| % DMSO % % Tween 80 % saline | ||||||||||
| 计算重置 | ||||||||||
计算结果:
工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL saline，混匀澄清。
1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
3. 以上所有助溶剂都可在 GlpBio 网站选购。
Structure-activity relationships of Tubulysin analogues
Bioorg Med Chem Lett 2020 Jul 15;30(14):127241.PMID:32527543DOI:10.1016/j.bmcl.2020.127241.
The tubulysins are an emerging antibody-drug conjugate (ADC) payload that maintain potent anti-proliferative activity against cells that exhibit the multi-drug resistant (MDR) phenotype. These drugs possess a C-11 acetate known to be hydrolytically unstable in plasma, and loss of the acetate significantly attenuates cytotoxicity. Structure-activity relationship studies were undertaken to identify stable C-11 Tubulysin analogues that maintain affinity for tubulin and potent cytotoxicity. After identifying several C-11 alkoxy analogues that possess comparable biological activity to Tubulysin M with significantly improved plasma stability, additional analogues of both the Ile residue and N-terminal position were synthesized. These studies revealed that minor changes within the tubulin binding site of Tubulysin can profoundly alter the activity of this chemotype, particularly against MDR-positive cell types.
Tubulysin Synthesis Featuring Stereoselective Catalysis and Highly Convergent Multicomponent Assembly
Org Lett 2020 Jul 17;22(14):5396-5400.PMID:32584589DOI:10.1021/acs.orglett.0c01718.
A concise and modular total synthesis of the highly potent N14-desacetoxytubulysin H (1) has been accomplished in 18 steps in an overall yield of up to 30%. Our work highlights the complexity-augmenting and route-shortening power of diastereoselective multicomponent reaction (MCR) as well as the role of bulky ligands to perfectly control both the regioselective and diastereoselective synthesis of tubuphenylalanine in just two steps. The total synthesis not only provides an operationally simple and step economy but will also stimulate major advances in the development of new Tubulysin analogues.
Improving Antibody-Tubulysin Conjugates through Linker Chemistry and Site-Specific Conjugation
ChemMedChem 2021 Apr 8;16(7):1077-1081.PMID:33369163DOI:10.1002/cmdc.202000889.
Tubulysins have emerged in recent years as a compelling drug class for delivery to tumor cells via antibodies. The ability of this drug class to exert bystander activity while retaining potency against multidrug-resistant cell lines differentiates them from other microtubule-disrupting agents. Tubulysin M, a synthetic analogue, has proven to be active and well tolerated as an antibody-drug conjugate (ADC) payload, but has the liability of being susceptible to acetate hydrolysis at the C11 position, leading to attenuated potency. In this work, we examine the ability of the drug-linker and conjugation site to preserve acetate stability. Our findings show that, in contrast to a more conventional protease-cleavable dipeptide linker, the β-glucuronidase-cleavable glucuronide linker protects against acetate hydrolysis and improves ADC activity in vivo. In addition, site-specific conjugation can positively impact both acetate stability and in vivo activity. Together, these findings provide the basis for a highly optimized delivery strategy for Tubulysin M.
Total synthesis of Tubulysin U and N14-desacetoxytubulysin H
Org Biomol Chem 2020 Jul 22;18(28):5349-5353.PMID:32643750DOI:10.1039/d0ob01109f.
A concise and efficient procedure for the total synthesis of Tubulysin U and N14-desacetoxytubulysin H has been developed with high stereoselectivity on a gram scale. This synthesis features an elegant cascade one-pot process to install the challenging thiazole moiety and the employment of stereoselective reductions and a series of high-yield mild reactions to ensure the requisite stereochemistry, reaction scale, and yield and to avoid the vexing epimerization occurring during peptide formation.
Cytotoxic simplified Tubulysin analogues
J Med Chem 2008 Mar 27;51(6):1530-3.PMID:18314944DOI:10.1021/jm701321p.
An efficient route for the synthesis of the Tubulysin family of antimitotic peptides was developed. Simplified Tubulysin analogues were synthesized to define the minimum pharmacophore required for cytotoxicity. Simplified Tubulysin analogues retain significant cytotoxicity and reveal important preliminary structure-activity relationships.