143-67-9

Basic information

• Product Name: Vinblastine sulfate
• Synonyms: 29060le;exal;nsc49842;rozevinsulfate;velban;velbe;vincaleukoblastine,sulfate(1:1)(salt);VINBLASTINE SULFATE SALT
• CAS NO: 143-67-9
• Molecular Formula: C₄₆H₅₈N₄O₉*H₂O₄S
• Molecular Weight: 909.05
• EINECS: 205-606-0
• Product Categories: Active Pharmaceutical Ingredients;APIs;VINBLASTINE SULPHATE;Intermediates & Fine Chemicals;Pharmaceuticals;Caspases/Apoptosis;Chiral Reagents;Heterocycles;chemical reagent;pharmaceutical intermediate;phytochemical;reference standards from Chinese medicinal herbs (TCM).;standardized herbal extract;VELBAN;Antineoplastic;Anti-cancer & immunity;Inhibitors
• Mol File: 143-67-9.mol
• Article Data: 3

Chemical Properties

• Melting Point: 267 °C (dec.)(lit.)
• Appearance: white/powder
• Density: 1.37 g/cm³
• Storage Temp.: 2-8°C
• Solubility: H2O: 10 mg/mL
• Water Solubility: >=1 g/100 mL at 24.5 ºC
• Merck: 13,10044
• BRN: 3659812
• CAS DataBase Reference: Vinblastine sulfate(CAS DataBase Reference)
• NIST Chemistry Reference: Vinblastine sulfate(143-67-9)
• EPA Substance Registry System: Vinblastine sulfate(143-67-9)

Safety Data

• Hazard Codes: Xn,T
• Statements: 22-37/38-41-61-36/37/38-63-23/24/25
• Safety Statements: 26-36/39-53-45-37/39-36/37/39
• RIDADR: 1544
• WGK Germany: 3
• RTECS: YY8400000
• F: 8-10
• HazardClass: 6.1(a)
• PackingGroup: II
• Hazardous Substances Data: 143-67-9(Hazardous Substances Data)

Usage

Description

Vinblastine sulfate, also known as Velban, is a dimeric alkaloid derived from the plant Catharanthus roseus (Madagascar periwinkle). It is a white to off-white crystalline powder with antineoplastic properties, acting as a microtubule disrupter and inducing apoptosis. Vinblastine sulfate is used therapeutically to treat various types of cancer by disrupting microtubule formation and function during mitosis and interfering with glutamic acid metabolism.

Uses

Used in Anticancer Applications:
Vinblastine sulfate is used as an antineoplastic agent for the treatment of various cancers, including Hodgkin's disease, lymphosarcoma, reticulum cell sarcoma, neuroblastoma, choriocarcinoma, carcinoma of the breast, lung, oral cavity, testis, bladder, acute and chronic leukemia, histiocytosis, and mycosis fungoides. It modulates several oncological signaling pathways, exerting inhibitory effects on tumor growth and progression.
Used in Pharmaceutical Industry:
Vinblastine sulfate is used as a key component in the development of novel drug delivery systems to enhance its applications and efficacy against cancer cells. Various organic and metallic nanoparticles have been employed as carriers for vinblastine sulfate delivery, aiming to improve its delivery, bioavailability, and therapeutic outcomes.

Originator

Velban ,Lilly ,US ,1961

Therapeutic Function

Cancer chemotherapy

Air & Water Reactions

Water soluble..Rapidly hydrolyzes.

Reactivity Profile

Vinblastine sulfate is sensitive to light, hydrolysis, oxidation, and heat. Vinblastine sulfate is very hygroscopic. .

Health Hazard

SYMPTOMS: Symptoms of exposure to Vinblastine sulfate include temporary mental depression, paresthesias, loss of deep-tendon reflexes, headache, convulsions, psychoses; dysfunction of the autonomic nervous system, with marked constipation, paralytic ileus, urinary retention, bilateral pain and tenderness of the parotid glands associated with dryness of the mouth, sinus tachycardia; nausea, vomiting, anorexia, diarrhea; loss of hair, vesicular mucositis of the mouth, and dermatitis.

Biological Activity

Anticancer agent; microtubule disrupter. Induces apoptosis in cultured hepatocytes and human lymphoma cells.

Biochem/physiol Actions

Primary TargetInteraction of tubulin with microtubule-associated proteins, specifically Tau and MAP2

Clinical Use

Vinblastine sulfate is available as a powder in 10-mg vials and as a solution in 10- and 25-mL vials for IV administrationin the treatment of various cancers including Hodgkin’sdisease, lymphocytic lymphoma, histiocytic lymphoma, advancedmycosis fungoides, advanced testicular carcinoma,and Kaposi sarcoma. It has also been used in treating choriocarcinomaand breast cancer when other therapies havefailed.

Side effects

The major toxic effect of vinblastine is a dose-related bone marrow depression. This is more frequent and severe than with the close structural analog, vincristine. Dose-related leukopenia occurs with a nadir of 4 to 10 days and with recovery occurring over another 7 to 14 days. Because of the relatively predictable nadir, it may be possible to administer vinblastine cautiously as often as every 7 to 10 days. Thrombocytopenia typically occurs; however, with standard dosing regimens, serious platelet depressions are infrequent. Erythrocytes are usually only slightly depressed.

Safety Profile

Poison by ingestion, intraperitoneal, and intravenous routes. An experimental teratogen. Human systemic effects by intravenous route: blood leukopenia and hair changes. Experimental reproductive effects. Questionable carcinogen. Human mutation data reported. When heated to decomposition it emits very toxic fumes of NOx and SOx. See also VINCALEUKOBLASTINE and SULFATES.

Veterinary Drugs and Treatments

Vinblastine may be employed in the treatment of lymphomas, carcinomas, mastocytomas, and splenic tumors in small animals. It is more effective than vincristine in the treatment of canine mast cell tumors.

Drug interactions

Potentially hazardous interactions with other drugs Aldesleukin: avoid concomitant use. Antibacterials: toxicity increased by erythromycin - avoid; possible increased risk of ventricular arrhythmias with delamanid. Antiepileptics: phenytoin levels may be reduced. Antifungals: possible increased risk of toxicity with itraconazole; metabolism possibly inhibited by posaconazole (increased risk of neurotoxicity). Antimalarials: avoid with piperaquine with artenimol. Antipsychotics: avoid with clozapine (increased risk of agranulocytosis).

Metabolism

Vinblastine is extensively metabolised mainly in the liver by the CYP3A group of isoenzymes to desacetylvinblastine, which is more active than the parent compound. 33% of the drug is slowly excreted in the urine and 21% in the faeces within 72 hours.

Purification Methods

Crystallise the sulfate from MeOH or EtOH and dry it in vacuo over conc H2SO4. The free base crystallises from EtOH or MeOH m 211-216o (+ 2MeOH .1 H2O) and forms a stable etherate from Et2O with m 201-211o, and [] D +42o (CHCl3), and UV max at 214 and 259nm (log  4.73 and 4.21). The dihydrochloride has m 244-246o(dec)(MeOH). It is a monoamine oxidase B inhibitor and induces microtubule aggregation. It is an antineoplastic drug for Hodgkin’s lymphoma. [Neuss et al. J Am Chem Soc 81 4754 1959, Jong-KeunSon et al. J Med Chem 33 1845 1990, Warfield & Bouck Science 186 1219 1974, Beilstein 26 III/IV 3167.]

Mode of action

Vinblastine binds to tubulin and inhibits microtubule assembly. This inhibition prevents mitotic spindle formation and results in an accumulation of cells in metaphase. Vinblastine is considered cell cycle phase specic for mitosis; however, the cytotoxic effect probably occurs in S phase and is expressed only in M phase. At high doses, direct effects may be expressed in S and G1 phases. Vinblastine is assumed to have stathmokinetic (cell cycle arrest) effects similar to vincristine.

InChI:InChI=1/C46H58N4O9.H2O4S/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;1-5(2,3)4/h10-14,16,21-22,28,37-39,47,54-55H,8-9,15,17-20,23-26H2,1-7H3;(H2,1,2,3,4)/t28?,37-,38+,39+,42-,43+,44+,45-,46-;/m0./s1

Synthetic route

C46H54N4O9 → vinblastine (143-67-9)

Conditions	Yield
With hydrogen; palladium on activated charcoal In ethanol at 20℃; for 0.75h;	89%

exo-catharanthine + vindoline (2182-14-1) → vinblastine (143-67-9)

Conditions	Yield
Stage #1: exo-catharanthine; vindoline With hydrogenchloride; iron(III) chloride; 2,2,2-trifluoroethanol for 2h; Stage #2: With sodium tetrahydroborate; oxygen at 0℃; for 0.5h;	50%

(+)-(9R)-3-oxo-9-methoxycarbonylindolizino<8,7-b>indole (124096-76-0) → vinblastine (143-67-9)

Conditions

Yield

Multi-step reaction with 7 steps 1.1: triethylamine; dmap / dichloromethane / 14 h / 20 °C 2.1: lithium diisopropyl amide / tetrahydrofuran / 12 h 3.1: trifluoroacetic acid / dichloromethane / 16 h 4.1: trimethoxonium tetrafluoroborate; 2,6-di-tert-butyl-pyridine / dichloromethane / 12 h 4.2: 0.5 h 5.1: [bis(trifluoromethanesulfonyl)imidate](triphenylphosphine)gold(I); 2-bromopyridine-N-oxide; methanesulfonic acid; silver trifluoromethanesulfonate / 5 h / 20 °C 5.2: 3 h / 20 °C 6.1: potassium tert-butylate / tetrahydrofuran / 2 h 7.1: hydrogenchloride; 2,2,2-trifluoroethanol; iron(III) chloride / 2 h 7.2: 0.5 h / 0 °C View Scheme

C19H18N2O3 → vinblastine (143-67-9)

Conditions

Yield

Multi-step reaction with 4 steps 1.1: trimethoxonium tetrafluoroborate; 2,6-di-tert-butyl-pyridine / dichloromethane / 12 h 1.2: 0.5 h 2.1: [bis(trifluoromethanesulfonyl)imidate](triphenylphosphine)gold(I); 2-bromopyridine-N-oxide; methanesulfonic acid; silver trifluoromethanesulfonate / 5 h / 20 °C 2.2: 3 h / 20 °C 3.1: potassium tert-butylate / tetrahydrofuran / 2 h 4.1: hydrogenchloride; 2,2,2-trifluoroethanol; iron(III) chloride / 2 h 4.2: 0.5 h / 0 °C View Scheme

C19H20N2O2 → vinblastine (143-67-9)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: [bis(trifluoromethanesulfonyl)imidate](triphenylphosphine)gold(I); 2-bromopyridine-N-oxide; methanesulfonic acid; silver trifluoromethanesulfonate / 5 h / 20 °C 1.2: 3 h / 20 °C 2.1: potassium tert-butylate / tetrahydrofuran / 2 h 3.1: hydrogenchloride; 2,2,2-trifluoroethanol; iron(III) chloride / 2 h 3.2: 0.5 h / 0 °C View Scheme

C19H20N2O3 → vinblastine (143-67-9)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: potassium tert-butylate / tetrahydrofuran / 2 h 2.1: hydrogenchloride; 2,2,2-trifluoroethanol; iron(III) chloride / 2 h 2.2: 0.5 h / 0 °C View Scheme

C21H24N2O5 → vinblastine (143-67-9)

Conditions

Yield

Multi-step reaction with 6 steps 1.1: lithium diisopropyl amide / tetrahydrofuran / 12 h 2.1: trifluoroacetic acid / dichloromethane / 16 h 3.1: trimethoxonium tetrafluoroborate; 2,6-di-tert-butyl-pyridine / dichloromethane / 12 h 3.2: 0.5 h 4.1: [bis(trifluoromethanesulfonyl)imidate](triphenylphosphine)gold(I); 2-bromopyridine-N-oxide; methanesulfonic acid; silver trifluoromethanesulfonate / 5 h / 20 °C 4.2: 3 h / 20 °C 5.1: potassium tert-butylate / tetrahydrofuran / 2 h 6.1: hydrogenchloride; 2,2,2-trifluoroethanol; iron(III) chloride / 2 h 6.2: 0.5 h / 0 °C View Scheme

C24H26N2O5 → vinblastine (143-67-9)

Conditions

Yield

Multi-step reaction with 5 steps 1.1: trifluoroacetic acid / dichloromethane / 16 h 2.1: trimethoxonium tetrafluoroborate; 2,6-di-tert-butyl-pyridine / dichloromethane / 12 h 2.2: 0.5 h 3.1: [bis(trifluoromethanesulfonyl)imidate](triphenylphosphine)gold(I); 2-bromopyridine-N-oxide; methanesulfonic acid; silver trifluoromethanesulfonate / 5 h / 20 °C 3.2: 3 h / 20 °C 4.1: potassium tert-butylate / tetrahydrofuran / 2 h 5.1: hydrogenchloride; 2,2,2-trifluoroethanol; iron(III) chloride / 2 h 5.2: 0.5 h / 0 °C View Scheme

diiodomethane (75-11-6) + vinblastine (143-67-9) → C47H61N4O9(1+)*I(1-) + vinamidine + cyclovinblastine

Conditions	Yield
With diethylzinc In hexane; dichloromethane at 0 - 20℃; Inert atmosphere;	A 18% B n/a C n/a

vinblastine (143-67-9) → desacetylvinblastine monohydrazide (55383-37-4)

Conditions	Yield
With hydrogenchloride; sodium nitrite In methanol; water at 0℃; for 0.2h; pH=7.6;

vinblastine (143-67-9) → (S)-2-vinblastine desacetyl hydrazide

Conditions	Yield
Multi-step reaction with 2 steps 1: hydrogenchloride; sodium nitrite / water; methanol / 0.2 h / 0 °C / pH 7.6 2: dichloromethane / 0 - 20 °C / Inert atmosphere View Scheme

Upstream product

• 2182-14-1 vindoline 
• 124096-76-0 (+)-(9R)-3-oxo-9-methoxycarbonylindolizino<8,7-b>indole 

Downstream Products

• 854758-10-4 12'-(4-trifluoromethylphenylamino)-3-(tert-butyl-dimethylsilanyloxy)vinblastine 
• 854758-08-0 12'-(4-methoxyphenylamino)-3-(tert-butyl-dimethylsilanyloxy)vinblastine 
• 854758-07-9 12'-(phenylamino)-3-(tert-butyl-dimethylsilanyloxy)vinblastine 
• 854756-57-3 12'-(4-methoxybenzylsulfanyl)vinblastine 
• 854756-99-3 12'-(2-hydroxyphenylsulfanyl)vinblastine 
• 854756-04-0 12'-(3-methoxyphenyl)vinblastine 
• 854756-10-8 12'-(3-hydroxyphenyl)vinblastine 
• 854756-08-4 12'-(3-fluorophenyl)vinblastine 
• 55383-37-4 desacetylvinblastine monohydrazide 
• 55383-37-4 desacetylvinblastine hydrazide 
• 55383-37-4 4-Desacetyl-VLB C-3 carbohydrazid 
• 3352-69-0 vindesine 

Relevant articles and documents

Enantioselective synthesis of: Iboga alkaloids and vinblastine via rearrangements of quaternary ammoniums

An efficient and novel strategy for the enantioselective syntheses of various iboga alkaloids has been developed. The salient features include a gold-catalyzed oxidation of a terminal alkyne followed by cyclization, a Stevens rearrangement and a tandem sequence that combines the gold-catalyzed oxidation, cyclization and [1,2]-shift. The catharanthine analogs provided by our approach were further converted to the vinca alkaloid vinblastine and its analogs, which confirmed the remarkable sensitivity of the cytotoxicity to the C20′ substituent of vinblastine.

Methods for stabilizing biologically active agents encapsulated in biodegradable controlled-release polymers

Methods for reducing or inhibiting the irreversible inactivation of water-soluble biologically active agents in biodegradable polymeric delivery systems which are designed to release such agents over a prolonged period of time, such as PLGA delivery systems are provided. The method comprises preparing a PLGA delivery systems whose microclimate, i.e. the pores where the active agent resides, uniformly or homogenously maintain a pH of between 3 and 9, preferably between 4 and 8, more preferably between 5 and 7.5 during biodegradation. Depending on the size of the delivery system, and the initial bulk permeability of the polymer, this result is achieved by (a) incorporating a water-soluble carrier into the delivery system, (b) incorporating a select basic additive (or antacid) into the delivery system, (c) incorporating both a water soluble carrier and a select basic additive into the delivery system, (d) adding a pore forming molecule for increasing the rate of release of low molecular weight monomers and oligomers into the delivery system, (e) using a PLGA polymer with reduced glycolide content, i.e. PLGA with from 100% to 75% lactide and 0 to 25% glycolide) (f) using a microencapsulation method that yields a more extensive pore-network, e.g. oil-in-oil emulsion-solvent extraction as opposed to water-in-oil-in water-solvent evaporation method, and (g) combinations thereof.