Vinblastine
Overview
Description
Vinblastine is a vinca alkaloid derived from the Madagascar periwinkle plant, Catharanthus roseus . It is primarily used as a chemotherapy medication to treat various types of cancer, including Hodgkin’s lymphoma, non-small-cell lung cancer, bladder cancer, brain cancer, melanoma, and testicular cancer . This compound works by inhibiting cell division, making it an effective antineoplastic agent .
Mechanism of Action
Target of Action
Vinblastine primarily targets microtubules in the cell . Microtubules are a component of the cell’s cytoskeleton and play a crucial role in maintaining cell shape, enabling cell motility, and most importantly, in cell division . This compound also targets tumor-associated macrophages (TAMs) , influencing their polarization state .
Mode of Action
This compound binds to the microtubular proteins of the mitotic spindle, leading to the crystallization of the microtubule . This interaction inhibits mitosis at the metaphase, causing mitotic arrest or cell death . In the context of TAMs, this compound can reset these macrophages from an immune-suppressive M2-like phenotype to a proinflammatory M1-like phenotype .
Biochemical Pathways
This compound affects the microtubule dynamics , disrupting the formation of spindle fibers, which are responsible for the alignment and separation of chromosomes during cell division . This disruption leads to mitotic arrest and ultimately, cell death . In TAMs, this compound induces the activation of the NF-κB-Cyba axis to generate reactive oxygen species, thus polarizing TAMs to the M1 phenotype .
Pharmacokinetics
The pharmacokinetics of this compound is primarily driven by ABCB1-mediated efflux and CYP3A4 metabolism , creating potential for drug-drug interaction . The data were consistent with a three-compartment open model system with the following values: α phase: t 1/2 = 3.90 ± 1.46 min; Vc = 16.8 ± 7.1 liters. β phase: t 1/2 = 53.0 ± 13.0 min; V β = 79.0 ± 52.0 liters; γ phase: t 1/2 = 1173.0 ± 65.0 min; V γ = 1656.0 ± 717.0 liters .
Result of Action
The result of this compound’s action at the molecular level is the disruption of microtubule dynamics , leading to mitotic arrest and cell death . At the cellular level, this compound causes a shift in the polarization of TAMs from an immune-suppressive M2-like phenotype to a proinflammatory M1-like phenotype, promoting an antitumor immune response .
Action Environment
The action, efficacy, and stability of this compound can be influenced by various environmental factors. For instance, the presence of other drugs can impact the effectiveness of this compound due to potential drug-drug interactions . Additionally, the tumor microenvironment can influence the action of this compound, particularly its ability to reset TAMs from the M2 phenotype to the M1 phenotype .
Biochemical Analysis
Biochemical Properties
Vinblastine plays a crucial role in biochemical reactions by interacting with microtubular proteins of the mitotic spindle. It binds to tubulin, a protein that is essential for the formation of microtubules, thereby inhibiting their polymerization and inducing depolymerization of formed tubules . This interaction leads to mitotic arrest and cell death. Additionally, this compound may interfere with nucleic acid and protein synthesis by blocking the utilization of glutamic acid . The compound also exhibits immunosuppressive activity .
Cellular Effects
This compound exerts significant effects on various types of cells and cellular processes. It primarily affects rapidly dividing cells, such as cancer cells, by inhibiting their ability to divide and proliferate . This compound disrupts the formation of the mitotic spindle, leading to mitotic arrest and apoptosis . It also influences cell signaling pathways, gene expression, and cellular metabolism by interfering with microtubule dynamics . The compound’s impact on microtubules affects intracellular transport, cell shape, and motility, ultimately leading to cell death .
Molecular Mechanism
The molecular mechanism of this compound involves its binding to tubulin, which inhibits microtubule formation and disrupts the mitotic spindle . This disruption prevents the proper separation of chromosomes during cell division, leading to mitotic arrest at metaphase and subsequent cell death . This compound also interferes with nucleic acid and protein synthesis by blocking the utilization of glutamic acid . The compound’s interaction with microtubules and its ability to induce depolymerization are key to its antineoplastic activity .
Temporal Effects in Laboratory Settings
In laboratory settings, the effects of this compound change over time. The compound is known to be stable under standard storage conditions, but its activity can degrade over extended periods . Long-term studies have shown that this compound can cause persistent changes in cellular function, including alterations in cell cycle progression and induction of apoptosis . In vitro and in vivo studies have demonstrated that this compound’s antitumor effects are sustained over time, with continued inhibition of tumor growth and metastasis .
Dosage Effects in Animal Models
The effects of this compound vary with different dosages in animal models. At lower doses, this compound effectively inhibits tumor growth without causing significant toxicity . At higher doses, the compound can cause dose-limiting toxicities, such as myelosuppression and neurotoxicity . Studies have shown that this compound’s therapeutic index is narrow, and careful dose optimization is required to balance efficacy and toxicity . Threshold effects have been observed, where increasing the dose beyond a certain point does not significantly enhance antitumor activity but increases adverse effects .
Metabolic Pathways
This compound is primarily metabolized by hepatic cytochrome P450 3A isoenzymes . The compound undergoes extensive hepatic metabolism, resulting in the formation of active and inactive metabolites . The primary metabolic pathway involves the conversion of this compound to desacetylthis compound, which retains antineoplastic activity . The metabolism of this compound can be influenced by factors such as hepatic dysfunction and concomitant use of potent inhibitors of cytochrome P450 3A isoenzymes .
Transport and Distribution
This compound is transported and distributed within cells and tissues through various mechanisms. The compound is extensively bound to tissue and formed peripheral blood elements . It is primarily transported via the bloodstream and distributed to various tissues, including tumors . This compound’s distribution is influenced by factors such as plasma protein binding and tissue-specific binding . The compound’s transport is mediated by ABCB1 efflux transporters, which play a role in its pharmacokinetics and potential drug-drug interactions .
Subcellular Localization
This compound’s subcellular localization is primarily within the cytoplasm, where it interacts with microtubules . The compound’s binding to tubulin and its effects on microtubule dynamics are critical for its antineoplastic activity . This compound’s localization to the mitotic spindle and its ability to induce depolymerization are essential for its mechanism of action . Additionally, this compound’s effects on intracellular transport and cell shape are mediated by its interaction with microtubules .
Preparation Methods
Synthetic Routes and Reaction Conditions: Vinblastine can be synthesized through a complex biosynthetic pathway involving the coupling of vindoline and catharanthine . This process has been successfully replicated in engineered yeast, which can produce the necessary precursors . The synthetic route involves multiple steps, including the formation of strictosidine, followed by the production of catharanthine and vindoline, and their subsequent coupling to form this compound .
Industrial Production Methods: Industrial production of this compound typically involves the extraction of vindoline and catharanthine from Catharanthus roseus, followed by their chemical coupling . Advances in synthetic biology have enabled the production of these alkaloids in engineered yeast, providing a more sustainable and scalable method .
Chemical Reactions Analysis
Types of Reactions: Vinblastine undergoes various chemical reactions, including oxidation, reduction, and substitution .
Common Reagents and Conditions:
Reduction: Reduction reactions can be carried out using hydrogen gas in the presence of a palladium catalyst.
Substitution: Substitution reactions often involve nucleophiles such as hydroxide ions or amines.
Major Products: The major products formed from these reactions depend on the specific conditions and reagents used. For example, oxidation can lead to the formation of various oxidized derivatives, while reduction can yield reduced forms of this compound .
Scientific Research Applications
Vinblastine has a wide range of scientific research applications:
Chemistry: It is used as a model compound to study the synthesis and modification of complex alkaloids.
Biology: Researchers use this compound to investigate cell division and microtubule dynamics.
Medicine: this compound is a critical component of chemotherapy regimens for treating various cancers.
Comparison with Similar Compounds
These compounds share a similar mechanism of action but differ in their chemical structures and clinical applications . For example:
Vincristine: Used primarily to treat leukemia and lymphoma.
Vindesine: Used in the treatment of various cancers, including melanoma and lung cancer.
Vinflunine: Primarily used for bladder cancer.
Vinblastine is unique in its specific combination of vindoline and catharanthine, which contributes to its distinct pharmacological profile and therapeutic applications .
Properties
CAS No. |
865-21-4 |
|---|---|
Molecular Formula |
C46H58N4O9 |
Molecular Weight |
811.0 g/mol |
IUPAC Name |
methyl (9R,10S,11R,12R,19R)-11-acetyloxy-12-ethyl-4-[(13S,15R,17S)-17-ethyl-17-hydroxy-13-methoxycarbonyl-1,11-diazatetracyclo[13.3.1.04,12.05,10]nonadeca-4(12),5,7,9-tetraen-13-yl]-10-hydroxy-5-methoxy-8-methyl-8,16-diazapentacyclo[10.6.1.01,9.02,7.016,19]nonadeca-2,4,6,13-tetraene-10-carboxylate |
InChI |
InChI=1S/C46H58N4O9/c1-8-42(54)23-28-24-45(40(52)57-6,36-30(15-19-49(25-28)26-42)29-13-10-11-14-33(29)47-36)32-21-31-34(22-35(32)56-5)48(4)38-44(31)17-20-50-18-12-16-43(9-2,37(44)50)39(59-27(3)51)46(38,55)41(53)58-7/h10-14,16,21-22,28,37-39,47,54-55H,8-9,15,17-20,23-26H2,1-7H3/t28-,37-,38+,39+,42-,43+,44?,45-,46-/m0/s1 |
InChI Key |
JXLYSJRDGCGARV-JQQWJEIDSA-N |
SMILES |
CCC1(CC2CC(C3=C(CCN(C2)C1)C4=CC=CC=C4N3)(C5=C(C=C6C(=C5)C78CCN9C7C(C=CC9)(C(C(C8N6C)(C(=O)OC)O)OC(=O)C)CC)OC)C(=O)OC)O |
Isomeric SMILES |
CC[C@@]1(C[C@H]2C[C@@](C3=C(CCN(C2)C1)C4=CC=CC=C4N3)(C5=C(C=C6C(=C5)C78CCN9[C@H]7[C@@](C=CC9)([C@H]([C@@]([C@@H]8N6C)(C(=O)OC)O)OC(=O)C)CC)OC)C(=O)OC)O |
Canonical SMILES |
CCC1(CC2CC(C3=C(CCN(C2)C1)C4=CC=CC=C4N3)(C5=C(C=C6C(=C5)C78CCN9C7C(C=CC9)(C(C(C8N6C)(C(=O)OC)O)OC(=O)C)CC)OC)C(=O)OC)O |
Color/Form |
Solvated needles from methanol |
melting_point |
211-216 °C |
| 865-21-4 | |
physical_description |
Solid |
shelf_life |
SOLN MAY BE STORED IN REFRIGERATOR FOR PERIODS OF 30 DAYS WITHOUT SIGNIFICANT LOSS OF POTENCY /VINBLASTINE SULFATE/ |
solubility |
Negligible ODORLESS & HYGROSCOPIC; WHITE TO SLIGHTLY YELLOW, AMORPHOUS OR CRYSTALLINE POWDER; FREELY SOL IN WATER /VINBLASTINE SULFATE/ Practically insoluble in water, petroleum ether; soluble in alcohols, acetone, ethyl acetate, chloroform |
Synonyms |
cellblastin Lemblastine Sulfate, Vinblastine Velban Velbe Vinblastin Hexal Vinblastina Lilly Vinblastine Vinblastine Sulfate Vinblastinsulfat-Gry Vincaleukoblastine |
vapor_pressure |
1.03X10-27 mm Hg at 25 °C (est) |
Origin of Product |
United States |
Retrosynthesis Analysis
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Strategy Settings
| Precursor scoring | Relevance Heuristic |
|---|---|
| Min. plausibility | 0.01 |
| Model | Template_relevance |
| Template Set | Pistachio/Bkms_metabolic/Pistachio_ringbreaker/Reaxys/Reaxys_biocatalysis |
| Top-N result to add to graph | 6 |
Feasible Synthetic Routes
A: Vinblastine is a microtubule inhibitor that exerts its anticancer effects primarily by binding to tubulin, a protein crucial for microtubule formation [, , , , , , , , ]. Microtubules are essential for various cellular processes, including cell division (mitosis), intracellular transport, and maintaining cell shape. By disrupting microtubule dynamics, this compound leads to mitotic arrest, ultimately resulting in cell death.
A: While all Vinca alkaloids target microtubules, vinflunine and vinorelbine, newer members of this class, exhibit distinct effects on microtubule dynamics compared to this compound []. Unlike this compound, these newer agents do not increase the time microtubules spend in an attenuated state. They also have a less pronounced inhibitory effect on microtubule treadmilling compared to this compound. These differences might contribute to the unique efficacy and toxicity profiles of these drugs.
A: Research suggests that this compound might influence the interaction between calmodulin, a calcium-binding protein, and stable tubule only polypeptide (STOP), a microtubule-associated protein []. This interaction is involved in regulating microtubule dynamics, and its disruption by this compound could further contribute to the drug's antimitotic activity.
A: Studies in rats demonstrate that this compound can inhibit ferritin clearance from circulation and stimulate the release of endogenous ferritin into the serum and bile []. This effect suggests a potential interaction with iron metabolism, although the exact mechanisms remain unclear.
ANone: The molecular formula of this compound is C46H58N4O9, and its molecular weight is 811.0 g/mol.
A: Modifying this compound's structure can significantly impact its activity and potency. For example, creating C20' urea and thiourea derivatives of this compound led to some derivatives exhibiting up to 10-fold greater potency than this compound itself []. This finding highlights the potential for developing more effective this compound analogs through structural modifications.
A: While specific details on this compound's ADME profile are not provided in the research papers, one study mentions that this compound can be detected in the urine of dogs undergoing chemotherapy []. This finding suggests that renal excretion might be one of the elimination pathways for this compound.
A: Studies demonstrate that flubendazole, an antihelmintic drug with microtubule-inhibiting properties, displays synergistic effects when combined with this compound in preclinical models of leukemia []. This combination therapy resulted in enhanced tumor growth delay compared to either drug alone, suggesting potential benefits for treating these hematologic malignancies.
A: Clinical trials investigating weekly this compound administration in children with recurrent or refractory low-grade gliomas demonstrated sustained responses with manageable toxicity [, ]. This finding suggests this compound could be a valuable treatment option for this patient population.
A: Research using a naturally-occurring canine model of invasive urothelial carcinoma indicated that combining this compound with piroxicam, a non-selective cyclooxygenase inhibitor, significantly improved remission rates and progression-free survival compared to this compound alone []. This study highlights the potential of combination therapies in enhancing this compound's efficacy.
A: Overexpression of P-glycoprotein, a transmembrane protein that pumps drugs out of cells, is one mechanism of resistance to this compound and other drugs [, , , ]. This overexpression can limit the intracellular accumulation of this compound, thereby reducing its efficacy.
A: Studies using renal cell carcinoma cell lines revealed that exposure to this compound can alter the expression of beta 1 integrins, specifically VLA-2, which are involved in cell adhesion and migration []. This finding suggests that this compound might influence the metastatic potential of tumor cells.
A: Research exploring the use of this compound-loaded platelets (VLP) for treating platelet-phagocytizing tumors shows that VLPs could potentially deliver this compound specifically to tumor sites, as evidenced by higher drug levels in tumor-infiltrated bone marrow compared to peripheral blood [].
A: Research suggests that a single nucleotide polymorphism (SNP) in the promoter region of the CEP72 gene (TT allele at rs924607) is associated with an increased risk of vincristine-induced peripheral neuropathy []. This finding could potentially guide personalized chemotherapy approaches by identifying patients at higher risk of developing this side effect.
A: Radioimmunoassay is one method mentioned in the research papers for measuring this compound concentrations in biological samples []. Additionaly, liquid chromatography-electrospray ionization-tandem mass spectrometry (LC-ESI-MS/MS) is a highly sensitive and specific method for quantifying this compound and other chemotherapeutic drugs in biological matrices, such as urine [].
A: Yes, matrix-assisted laser desorption/ionization-ion mobility separation-mass spectrometry imaging (MALDI-IMS-MS) has been successfully employed to visualize the distribution of this compound in whole-body tissue sections []. This technique allows for the detection and localization of both the parent drug and its metabolites, providing valuable insights into drug distribution and pharmacokinetics.
A: Studies evaluating the biodegradability of this compound, vincristine, and vindesine using the closed bottle test (CBT) and Zahn-Wellens test (ZWT) indicated that these compounds exhibit low biodegradability in aquatic environments []. This finding highlights potential concerns regarding the persistence of these drugs in the environment and their possible ecological impact.
A: Yes, this compound is a known substrate of P-glycoprotein (P-gp), a transmembrane efflux transporter responsible for pumping drugs out of cells [, , , ]. This interaction can lead to reduced intracellular drug accumulation and contribute to drug resistance.
A: Yes, several compounds have been identified that can modulate this compound's interaction with P-glycoprotein. For example, staurosporine derivatives, particularly NA-382, have shown the ability to enhance this compound accumulation in adriamycin-resistant P388 (P388/ADR) cells by inhibiting P-gp activity []. Similarly, the isoquinolinesulfonamide compound H-87 has been shown to reverse this compound resistance in rat ascites hepatoma AH66 cells by inhibiting the binding of this compound to P-gp [].
A: Flubendazole, an antihelmintic drug, has emerged as a potential alternative to this compound in treating leukemia and myeloma []. It inhibits tubulin polymerization through a distinct mechanism and shows efficacy even in this compound-resistant cells. Moreover, flubendazole displays synergistic effects when combined with this compound in preclinical models, suggesting its potential as both an alternative and a synergistic agent.
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