Name: Combretastatin A4
Brand: BOC Sciences
Price: 499 USD
Availability: MadeToOrder

Synonyms

1-(3,4,5-trimethoxyphenyl)-2-(3'-hydroxy-4'-methoxyphenyl)ethene

IUPAC Name

2-methoxy-5-[(Z)-2-(3,4,5-trimethoxyphenyl)ethenyl]phenol

Canonical SMILES

COC1=C(C=C(C=C1)C=CC2=CC(=C(C(=C2)OC)OC)OC)O

InChI

InChI=1S/C18H20O5/c1-20-15-8-7-12(9-14(15)19)5-6-13-10-16(21-2)18(23-4)17(11-13)22-3/h5-11,19H,1-4H3/b6-5-

InChIKey

HVXBOLULGPECHP-WAYWQWQTSA-N

Density

1.184 g/cm3

Solubility

Soluble to 100 mm in ethanol and to 100 mm in DMSO

Melting Point

84.5-85.5°C

Appearance

White to off-white powder

Shipping

Room temperature

Storage

- 20 °C

Pictograms

Corrosive; Acute Toxic

Signal Word

Danger

In Vitro

Multi-action' Pt(IV) derivatives of cisplatin with combretastatin A4 (CA4) bioactive ligands that are conjugated to Pt(IV) by carbonate are unique because the ligand (IC50 < 10 nM) is dramatically 1000-folds more cytotoxic than cisplatin in vitro. The Pt(IV)-CA4 prodrugs were as cytotoxic as CA4 itself, indicating that the platinum moiety probably plays an insignificant role in triggering cytotoxicity, suggesting that the Pt(IV)-CA4 complexes act as prodrugs for CA4 rather than as true multi-action prodrugs.

In Vivo

In vivo tests (Lewis lung carcinoma) show that ctc-[Pt(NH3)2(PhB)(CA4)Cl2] inhibited tumor growth by 93% compared to combretastatin A4 (CA4) (67%), cisplatin (84%), and 1:1:1 cisplatin/CA4/PhB (85%) while displaying <5% body weight loss compared to cisplatin (20%) or CA4 (10%). In this case, and perhaps with other extremely potent bioactive ligands, platinum(IV) acts merely as a self-immolative carrier triggered by reduction in the cancer cell with only a minor contribution to cytotoxicity. The vascular shutdown induced by administration of 100 mg/kg of combretastatin A4 phosphate results in extensive cell loss in the 24 hrs following treatment, however this is not translated into any significant effect on tumour growth. The continued growth of the tumour is attributed to an actively proliferating population of cells at the periphery of the tumour, which are dependent on normal tissue vasculature for their survival.

NCT Number	Condition Or Disease	Phase	Start Date	Sponsor	Status
NCT01052363	Central Nervous System Tumors	Phase 1	2017-02-09	West Virginia University	Withdrawn (No funding)
NCT00113438	Cancer	Phase 2	2011-11-01	Mateon Therapeutics	Completed
NCT00060242	Head and Neck Cancer	Phase 2	2010-06-11	Case Comprehensive Cancer Center	Completed
NCT01023295	Polypoidal Choroidal Vasculopathy	Phase 2	2011-11-01	Mateon Therapeutics	Completed
NCT02055690	Ovarian Neoplasms	Phase 1, Phase 2	2021-05-17	The Christie NHS Foundation Trust	Terminated (Safety)

Combretastatin A4 is a stilbene-based natural product derivative and a potent ADC cytotoxin employed as an ADC payload in antibody-drug conjugates. Its primary mechanism involves binding to the colchicine-binding site of tubulin, inhibiting microtubule polymerization, disrupting cytoskeletal dynamics, and inducing cell cycle arrest in the G2/M phase. This leads to apoptosis in proliferating tumor cells. The chemical structure of Combretastatin A4 allows conjugation to monoclonal antibodies via cleavable or non-cleavable linkers, enabling selective intracellular delivery in ADC applications.

In antibody-drug conjugates, Combretastatin A4 is covalently linked to antibodies using linker chemistries designed to maintain systemic stability and prevent premature payload release. The ADC remains inactive during circulation and is internalized into target cells expressing specific antigens via receptor-mediated endocytosis. Intracellular enzymatic or chemical cleavage releases the active payload, which binds tubulin, disrupts microtubule formation, and triggers apoptosis. This targeted delivery ensures cytotoxicity is confined to tumor cells, enhancing the precision and reproducibility of the antitumor effect.

Applications of Combretastatin A4 include incorporation into ADCs targeting both solid tumors and hematologic malignancies with defined antigen expression. Its chemical compatibility with various linker systems allows optimization of conjugation efficiency, intracellular release kinetics, and pharmacokinetics. Combretastatin A4 exhibits defined cytotoxic activity in tubulin-expressing tumor cells, supporting the development of ADCs with mechanistically precise antimitotic activity and targeted tumor cell elimination. Its predictable microtubule-disrupting mechanism enables consistent evaluation of ADC performance in preclinical models and facilitates rational ADC design for clinical translation.

1.Combretastatins: more than just vascular targeting agents?

Greene LM1, Meegan MJ2, Zisterer DM2. J Pharmacol Exp Ther. 2015 Nov;355(2):212-27. doi: 10.1124/jpet.115.226225. Epub 2015 Sep 9.

Several prodrugs of the naturally occurring combretastatins have undergone extensive clinical evaluation as vascular targeting agents (VTAs). Their increased selectivity toward endothelial cells together with their innate ability to rapidly induce vascular shutdown and inhibit tumor growth at doses up to 10-fold less than the maximum tolerated dose led to the clinical evaluation of combretastatins as VTAs. Tubulin is well established as the molecular target of the combretastatins and the vast majority of its synthetic derivatives. Furthermore, tubulin is a highly validated molecular target of many direct anticancer agents routinely used as front-line chemotherapeutics. The unique vascular targeting properties of the combretastatins have somewhat overshadowed their development as direct anticancer agents and the delineation of the various cell death pathways and anticancer properties associated with such chemotherapeutics. Moreover, the ongoing clinical trial of OXi4503 (combretastatin-A1 diphosphate) together with preliminary preclinical evaluation for the treatment of refractory acute myelogenous leukemia has successfully highlighted both the indirect and direct anticancer properties of combretastatins.

2.Stepwise pH-responsive nanoparticles containing charge-reversible pullulan-based shells and poly(β-amino ester)/poly(lactic-co-glycolic acid) cores as carriers of anticancer drugs for combination therapy on hepatocellular carcinoma.

Zhang C1, An T1, Wang D1, Wan G1, Zhang M2, Wang H1, Zhang S1, Li R1, Yang X1, Wang Y3. J Control Release. 2016 Mar 28;226:193-204. doi: 10.1016/j.jconrel.2016.02.030. Epub 2016 Feb 16.

Stepwise pH-responsive nanoparticle system containing charge reversible pullulan-based (CAPL) shell and poly(β-amino ester) (PBAE)/poly(lactic-co-glycolic acid) (PLAG) core is designed to be used as carriers of paclitaxel (PTX) and combretastatin A4 (CA4) for combining antiangiogenesis and chemotherapy to treat hepatocellular carcinoma (HCC). CAPL-coated PBAE/PLGA (CAPL/PBAE/PLGA) nanoparticles displayed step-by-step responses to weakly acidic tumor microenvironment (pH ≈6.5) and endo/lysosome (pH ≈5.5) respectively through the cleavage of β-carboxylic amide bond in CAPL and the "proton-sponge" effect of PBAE, thus realized the efficient and orderly releases of CA4 and PTX. In human HCC HepG2 cells and human umbilical vein endothelial cells, CAPL/PBAE/PLGA nanoparticles significantly enhanced synergistic effects of PTX and CA4 on cell proliferation and cell migration. In HepG2 tumor-bearing mice, CAPL/PBAE/PLGA nanoparticles showed excellent tumor-targeting capability and remarkably increased inhibitory effects of PTX and CA4 on tumor growth and angiogenesis.

3.Combretastatin A-4 Conjugated Antiangiogenic Micellar Drug Delivery Systems Using Dendron-Polymer Conjugates.

Sumer Bolu B1, Manavoglu Gecici E1, Sanyal R1,2. Mol Pharm. 2016 Apr 14. [Epub ahead of print]

Employment of polymeric nanomaterials in cancer therapeutics is actively pursued since they often enable drug administration with increased efficacy along with reduced toxic side effects. In this study, drug conjugated micellar constructs are fabricated using triblock dendron-linear polymer conjugates where a hydrophilic linear polyethylene glycol (PEG) chain is flanked by well-defined hydrophobic biodegradable polyester dendrons bearing an antiangiogenic drug, combretastatin-A4 (CA4). Variation in dendron generation is utilized to obtain a library of micellar constructs with varying sizes and drug loadings. In particular, a family of drug appended dendron-polymer conjugates based on polyester dendrons of generations ranging from G1 to G3 and 10 kDa linear PEG were obtained using [3 + 2] Huisgen type "click" chemistry. The final constructs benefit from PEG's hydrophilicity and antibiofouling character, as well as biodegradable nature of the hydrophobic polyester dendrons.

4.Synthesis and Evaluation of 131I-Skyrin as a Necrosis Avid Agent for Potential Targeted Radionuclide Therapy of Solid Tumors.

Wang C1,2, Jin Q2, Yang S2, Zhang D2, Wang Q2,3, Li J1,2, Song S4, Sun Z5, Ni Y6, Zhang J2, Yin Z1. Mol Pharm. 2015 Dec 17. [Epub ahead of print]

An innovative anticancer approach targeted to necrotic tissues, which serves as a noncancerous and generic anchor, may present a breakthrough. Necrosis avid agents with a flat conjugate aromatic structure selectively accumulate in necrotic tissues, but they easily form aggregates that undesirably distribute to normal tissues. In this study, skyrin, a dianthraquinone compound with smaller and distorted π-cores and thus decreased aggregates as compared with hypericin (Hyp), was designed to target necrosis for tumor therapy. Aggregation studies of skyrin by UV/vis spectroscopy showed a smaller self-association constant with skyrin than with Hyp. Skyrin was labeled by iodine-131 with a radiochemical purity of 98% and exhibited good stability in rat serum for 72 h. In vitro cell uptake studies showed significant difference in the uptake of 131I-skyrin by necrotic cells compared to normal cells (P < 0.05). Compared in rats with liver and muscle necrosis, radiobiodistribution, whole-body autoradiography, and SPECT/CT studies revealed higher accumulation of 131I-skyrin in necrotic liver and muscle (p < 0.

HNMR

HPLC

What is Combretastatin A4?

Combretastatin A4 is a tubulin-binding cytotoxic agent used as a payload in antibody-drug conjugates. Its mechanism involves disrupting microtubule dynamics, leading to mitotic arrest and cell death, making it valuable in targeted cancer therapy research.

9/7/2020

Dear team, how does Combretastatin A4 function in ADCs?

In ADCs, Combretastatin A4 is delivered selectively to antigen-positive cells via the conjugated antibody. Once internalized, it destabilizes microtubules, causing cell cycle arrest and apoptosis while sparing non-target cells.

22/9/2019

Dear team, which linkers are suitable for Combretastatin A4 conjugation?

Both cleavable and non-cleavable linkers can be used with Combretastatin A4. Cleavable linkers respond to intracellular triggers, facilitating controlled payload release, while non-cleavable linkers retain cytotoxicity after antibody degradation.

19/8/2022

What safety protocols are required for Combretastatin A4?

Combretastatin A4 must be handled under standard cytotoxic compound safety protocols, including gloves, lab coats, and containment systems, to prevent accidental exposure during handling, storage, or conjugation procedures.

19/9/2018

Good morning! Is Combretastatin A4 commonly used in preclinical ADC studies?

Yes, Combretastatin A4 is widely applied in preclinical ADC studies to assess potency, stability, and delivery efficiency. Its tubulin-targeting mechanism allows researchers to evaluate microtubule-mediated cytotoxic effects in vitro and in vivo.

23/4/2022

— Dr. Kevin Wallace, Senior Scientist (USA)

Combretastatin A4 supplied by BOC Sciences met our expectations for purity and solubility, supporting cytotoxicity assays.

19/8/2022

— Dr. Kevin Mitchell, Principal Investigator (USA)

Combretastatin A4 supplied by BOC Sciences showed excellent stability and purity, critical for our ADC payload studies.

23/4/2022

— Ms. Annika Schmidt, R&D Manager (Germany)

We received detailed CoA and QC data with Combretastatin A4, facilitating seamless integration into our conjugation workflow.

19/9/2018

— Dr. Oliver Grant, Biochemist (UK)

The consistency and solubility of Combretastatin A4 batches allowed smooth optimization of our linker chemistry.