Combretastatin A1
(Synonyms: 康普瑞汀A-1) 目录号 : GC43300
An inhibitor of microtubule assembly
Cas No.:109971-63-3
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
Combretastatin A1 is a cis-stilbene originally isolated from C. caffrum that inhibits microtubule assembly (ID50 = 2 µM) by binding to the colchicine binding site on β-tubulin. It inhibits proliferation of hepatocellular carcinoma (IC50s = 9.2-728.2 nM) and other carcinoma cell lines (IC50s = 12.2-2,247 nM). Combretastatin A1 increases apoptosis of HepG2 cells in a GSK3β-dependent manner by decreasing the levels of MCL-1 and β-catenin. It inhibits tumor growth in a hepatocellular carcinoma mouse xenograft model when administered at doses of 2 or 4 mg/kg for 4 weeks. It also enhances the effects of carboplatin , paclitaxel , and cisplatin in murine models of cancer. Combretastatin A1 decreases functional vascular volume within hours in a well-vascularized murine colon adenocarcinoma model.
| Cas No. | 109971-63-3 | SDF | |
| 别名 | 康普瑞汀A-1 | ||
| Canonical SMILES | COC(C(O)=C1O)=CC=C1/C=C\C2=CC(OC)=C(OC)C(OC)=C2 | ||
| 分子式 | C18H20O6 | 分子量 | 332.4 |
| 溶解度 | DMF: 5 mg/ml,DMSO: 5 mg/ml,DMSO:PBS (pH 7.2) (1:1): 0.5 mg/ml,Ethanol: 3 mg/ml | 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 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 3.0084 mL | 15.0421 mL | 30.0842 mL |
| 5 mM | 0.6017 mL | 3.0084 mL | 6.0168 mL |
| 10 mM | 0.3008 mL | 1.5042 mL | 3.0084 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。
Comparative preclinical pharmacokinetic and metabolic studies of the combretastatin prodrugs combretastatin A4 phosphate and A1 phosphate
Clin Cancer Res 2004 Feb 15;10(4):1446-53.PMID:14977848DOI:10.1158/1078-0432.ccr-0518-03.
Purpose: Combretastatin A4 phosphate (CA4P) and its structural analog, Combretastatin A1 phosphate (CA1P), are soluble prodrugs capable of interacting with tubulin and causing rapid vascular shutdown within tumors. CA4P has completed Phase I clinical trials, but recent preclinical studies have shown that CA1P displays a greater antitumor effect than the combretastatin A4 (CA4) analog at equal doses. The aim of this study, therefore, is to compare pharmacokinetics and metabolism of the two compounds to determine whether pharmacokinetics plays a role in their differential activity. Experimental design: NMRI mice bearing MAC29 tumors received injection with either CA4P or CA1P at a therapeutic dose of 150 mg x kg(-1), and profiles of both compounds and their metabolites analyzed by a sensitive and specific liquid chromatography/mass spectroscopy method. Results: The metabolic profile of both compounds is complex, with up to 14 metabolites being detected for Combretastatin A1 (CA1) in the plasma. Many of these metabolites have been identified by liquid chromatography/mass spectroscopy. Initial studies, however, focused on the active components CA4 and CA1, where plasma and tumor areas under the curve were 18.4 and 60.1 microg x h x ml(-1) for CA4, and 10.4 and 13.1 microg x h x ml(-1) for CA1, respectively. In vitro metabolic comparisons of the two compounds strongly suggest that CA1 is metabolized to a more reactive species than the CA4. Conclusions: Although in vitro studies suggest that variable rates of tumor-specific prodrug dephosphorylation may explain these differences in pharmacokinetics profiles, the improved antitumor activity and altered pharmacokinetic profile of CA1 may be due to the formation of a more reactive metabolite.
A Phase 1B Clinical Study of Combretastatin A1 Diphosphate (OXi4503) and Cytarabine (ARA-C) in Combination (OXA) for Patients with Relapsed or Refractory Acute Myeloid Leukemia
Cancers (Basel) 2019 Dec 26;12(1):74.PMID:31888052DOI:10.3390/cancers12010074.
Combretastatin A1 (OXi4503) is a dual-function drug with vascular disrupting and cytotoxic properties that has exhibited single-agent anti-leukemia activity in murine xenograft models of acute myeloid leukemia (AML) and in a prior Phase 1A clinical study for relapsed/refractory (R/R) AML. The purpose of the present multicenter Phase 1B study was to define the maximum tolerated dose (MTD) and safety profile of OXi4503 and cytarabine (ARA-C) administered in combination (OXA). At four centers, 29 patients with R/R AML or myelodysplastic syndrome (MDS) were treated with OXA. The most common grade 3/4 treatment-emergent adverse events (AEs) were febrile neutropenia (28%), hypertension (17%), thrombocytopenia (17%), and anemia (14%). There were no treatment-emergent grade 5 AEs. Drug-related serious adverse events (SAEs) developed in 4/29 patients (14%) and included febrile neutropenia (N = 2), pneumonia/acute respiratory failure (N = 1), and hypotension (N = 1). 9.76 mg/m2 was defined as the MTD of OXi4503 when administered in combination with 1 g/m2 ARA-C. In 26 evaluable AML patients, there were 2 complete remissions (CR), 2 complete remissions with incomplete count recovery (CRi) and one partial response (PR), for an overall response rate (ORR) of 19%. The median overall survival (OS) time for the four patients who achieved a CR/CRi was 528 days (95% CI: 434-NA), which was significantly longer than the median OS time of 113 days (95% CI: 77-172) for the remaining 22 patients who did not achieve a CR/CRi (Log Rank Chi Square = 11.8, p-value = 0.0006). The safety and early evidence of efficacy of the OXA regimen in R/R AML patients warrant further investigation in a Phase 2 clinical study.
A concise synthesis of pyrazole analogues of Combretastatin A1 as potent anti-tubulin agents
ChemMedChem 2013 Apr;8(4):633-43.PMID:23436706DOI:10.1002/cmdc.201200561.
Combretastatin A1 (CA1) binds to the β-subunit at the colchicine binding site of tubulin and inhibits polymerization. As such, it is both an antitumor agent and a vascular disrupting agent. It has been shown to be at least tenfold more potent than combretastatin A4 (CA4) in terms of vascular shutdown, which correlates with its metabolism to reactive ortho-quinone species that are assumed to be directly cytotoxic in tumor cells. A series of 3,4-diarylpyrazoles were concisely synthesized, one of which, 3-methoxy-6-[4-(3,4,5-trimethoxyphenyl)-1H-pyrazol-3-yl]benzene-1,2-diol (27), proved to be a cytotoxic anti-tubulin agent with low nanomolar potency. We also report that combretastatins, including CA1, CA4, and 27, are effective against mesothelioma cell lines and therefore have significant clinical promise. Metabolism experiments demonstrate that 27 retains the ability to form ortho-quinone species, while the pyrazole ring shows high metabolic stability, suggesting that this compound might result in better pharmacokinetic profiles than CA1, with similar pharmacodynamic properties and clinical potential.
Quantitative determination of the anticancer prodrug Combretastatin A1 phosphate (OXi4503, CA1P), the active CA1 and its glucuronide metabolites in human urine and of CA1 in plasma by HPLC with mass spectrometric detection
J Chromatogr B Analyt Technol Biomed Life Sci 2012 Jun 1;898:1-6.PMID:22578514DOI:10.1016/j.jchromb.2012.03.040.
Validated methods for the determination of CA1, the active agent derived from the prodrug CA1P, in human plasma and urine, and of CA1P and three glucuronides CA1G1, CA1G2 and CA1DG in human urine were developed using LC-MS. Plasma CA1 was extracted using solid phase extraction and validated over the range 5-1000 nM. Urine samples were analysed without extraction, and the assays validated over the range 50-2000 nM (CA1P), 25-2000 nM (CA1), 50-40,000 nM (CA1G1 and CA1G2) and 25-4000 nM (CA1DG). The mean correlation coefficient (r²) was ≥ 0.997 for all assays. The intra-day and inter-day accuracy and precision were within the generally accepted criteria for bioanalytical methods (<15%). Mean recovery of CA1 from plasma was 101%, and 97% from urine. Mean urine recovery of CA1P was 98%, CA1G1 96%, CA1G2 93% and CA1DG 93%. The method was applied to plasma and urine samples from a recently completed clinical trial of the prodrug. Peak plasma concentrations of up to 470 nM CA1 were seen. The majority of drug-related material measured in urine comprised of the two monoglucuronides; CA1 and the diglucuronide were about 10-fold lower. No CA1P was detectable in urine.
Differential cytotoxicity of combretastatins A1 and A4 in two daunorubicin-resistant P388 cell lines
Cancer Chemother Pharmacol 1990;26(1):79-81.PMID:2322992DOI:10.1007/BF02940301.
Combretastatin A4, a novel anti-mitotic agent was effective against two P388 cell lines with acquired resistance to daunorubicin. In contrast, Combretastatin A1, a close structural analogue of A4, showed a high degree of cross-resistance. Combretastatin A1 was also more efficient at increasing intracellular daunorubicin concentrations in both resistant cell lines. Neither agent was capable of altering anthracycline accumulation in the parental (sensitive) cell line. We propose that the cross-resistance to Combretastatin A1 occurs, at least in part, as a result of the increased affinity of the drug-efflux process operative in these resistant cells for Combretastatin A1 vs Combretastatin A4. Hence, Combretastatin A4 may play a role in the treatment of tumours with acquired resistance to the anthracycline antibiotics.