长春新碱
描述
Vincristine is a vinca alkaloid derived from the Madagascar periwinkle plant, Catharanthus roseus . It is a chemotherapy medication used to treat various types of cancer, including acute lymphocytic leukemia, Hodgkin’s disease, non-Hodgkin’s lymphoma, neuroblastoma, and small cell lung cancer . Vincristine works by inhibiting cell division, making it a crucial component in cancer treatment regimens .
作用机制
Target of Action
Vincristine, a vinca alkaloid, primarily targets the protein tubulin, a key component of the microtubules in cells . Microtubules play a crucial role in maintaining cell structure and function, particularly during cell division .
Mode of Action
Vincristine binds to tubulin, inhibiting the polymerization of tubulin dimers and preventing the formation of microtubules . This interaction disrupts the formation of the mitotic spindle, a structure essential for chromosome separation during cell division . As a result, cells are arrested at metaphase, a stage in mitosis, leading to cell death .
Biochemical Pathways
The primary biochemical pathway affected by vincristine is the cell cycle, specifically the M and S phases . By disrupting microtubule dynamics, vincristine causes mitotic arrest, halting the cell cycle and leading to cell death . This disruption can also interfere with amino acid, cyclic AMP, and glutathione metabolism, as well as calmodulin-dependent Ca2±transport ATPase activity, and cellular respiration .
Pharmacokinetics
The pharmacokinetics of vincristine involve its absorption, distribution, metabolism, and excretion (ADME). Vincristine is administered intravenously, bypassing the absorption phase . It is metabolized primarily in the liver by the CYP3A5 enzyme . Vincristine’s neurotoxicity, a dose-limiting factor, is thought to be influenced by genetic variations in drug-metabolizing enzymes and transporters .
Result of Action
The molecular effect of vincristine’s action is the disruption of microtubule formation, leading to cell cycle arrest . On a cellular level, this results in the death of rapidly dividing cells, particularly cancer cells . This can also affect healthy cells, leading to side effects such as peripheral neuropathy .
Action Environment
Environmental factors can influence the action and efficacy of vincristine. For instance, the presence of other drugs used in combination therapies can impact vincristine’s effectiveness and toxicity profile . Additionally, genetic variations in patients can influence the drug’s metabolism and transport, potentially affecting its efficacy and toxicity .
科学研究应用
Vincristine has a wide range of scientific research applications, particularly in the fields of chemistry, biology, medicine, and industry . In chemistry, it is used as a model compound for studying the mechanisms of alkaloid biosynthesis and the development of new synthetic methodologies . In biology, vincristine is used to study cell division and the effects of microtubule inhibition on cellular processes . In medicine, it is a key component of chemotherapy regimens for various cancers, helping to inhibit the growth and spread of cancer cells . In industry, vincristine is used in the development of new drug formulations and delivery systems to improve its efficacy and reduce side effects .
生化分析
Biochemical Properties
Vincristine is a vinca alkaloid that binds to the microtubular proteins of the mitotic spindle . This interaction leads to the crystallization of the microtubule and mitotic arrest or cell death . Vincristine has some immunosuppressant effect . The vinca alkaloids are considered to be cell cycle phase-specific .
Cellular Effects
Vincristine works by stopping the cancer cells from separating into 2 new cells, thereby stopping the growth of the cancer . It achieves this through a process that disrupts the formation of microtubules, which affects cell division and eventually leads to apoptosis .
Molecular Mechanism
The molecular mechanism of Vincristine involves its binding to the tubulin protein, stopping the tubulin dimers from polymerizing to form microtubules . This causes the cell to be unable to separate its chromosomes during the metaphase . The cell then undergoes apoptosis . The vincristine molecule inhibits leukocyte production and maturation .
Temporal Effects in Laboratory Settings
It is known that within 15 to 30 minutes after injection, over 90% of the drug is distributed from the blood into tissue, where it remains tightly, but not irreversibly, bound .
Dosage Effects in Animal Models
In animal models, vincristine has shown high efficiency (86.6%) for treatment of transmissible venereal tumor in canines at the dose of 0.5 mg/m^2 of body surface (IV), on 7-14 days intervals . One tumor (6.6%) was refractory to vincristine, while at the treatment beginning a mass reduction was observed .
Metabolic Pathways
Vincristine may interfere with amino acid, cyclic AMP, and glutathione metabolism . It may also interfere with calmodulin-dependent Ca^2+ -transport ATPase activity, cellular respiration, and nucleic acid and lipid biosynthesis .
Transport and Distribution
Vincristine is transported and distributed within cells and tissues primarily through the bloodstream . It is given intravenously and can be administered through a drip into the arm or hand . Over 90% of the drug is distributed from the blood into tissue within 15 to 30 minutes after injection .
Subcellular Localization
The subcellular localization of Vincristine is primarily at the mitotic spindle, where it binds to the microtubular proteins . This binding leads to the crystallization of the microtubule and mitotic arrest or cell death .
准备方法
Vincristine is primarily obtained from the natural alkaloid plant source, Catharanthus roseus . The extraction process involves isolating the compound from the plant material, followed by purification steps to obtain the active ingredient . Industrial production methods often involve the use of advanced extraction techniques and purification processes to ensure the compound’s efficacy and safety .
化学反应分析
Vincristine undergoes various chemical reactions, including oxidation, reduction, and substitution . Common reagents used in these reactions include oxidizing agents, reducing agents, and nucleophiles . The major products formed from these reactions depend on the specific conditions and reagents used . For example, oxidation of vincristine can lead to the formation of different oxidized derivatives, while reduction can yield reduced forms of the compound .
相似化合物的比较
These compounds share a similar mechanism of action, targeting microtubule formation and inhibiting cell division . vincristine is unique in its specific clinical applications and its relatively lower bone marrow suppression compared to other vinca alkaloids . Vinblastine, for example, is used to treat different types of cancer and has a different toxicity profile . Vindesine and vinflunine are also used in cancer treatment but have distinct pharmacokinetic properties and clinical uses .
属性
CAS 编号 |
57-22-7 |
|---|---|
分子式 |
C46H56N4O10 |
分子量 |
825.0 g/mol |
IUPAC 名称 |
methyl (10S,11R,12R)-11-acetyloxy-12-ethyl-4-[(13S,15S,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]-8-formyl-10-hydroxy-5-methoxy-8,16-diazapentacyclo[10.6.1.01,9.02,7.016,19]nonadeca-2,4,6,13-tetraene-10-carboxylate |
InChI |
InChI=1S/C46H56N4O10/c1-7-42(55)22-28-23-45(40(53)58-5,36-30(14-18-48(24-28)25-42)29-12-9-10-13-33(29)47-36)32-20-31-34(21-35(32)57-4)50(26-51)38-44(31)16-19-49-17-11-15-43(8-2,37(44)49)39(60-27(3)52)46(38,56)41(54)59-6/h9-13,15,20-21,26,28,37-39,47,55-56H,7-8,14,16-19,22-25H2,1-6H3/t28-,37?,38?,39-,42+,43-,44?,45+,46+/m1/s1 |
InChI 键 |
OGWKCGZFUXNPDA-DLBZMDDPSA-N |
杂质 |
3'-hydroxyvincristine; 4'-deoxyvincristine; N-desmethylvinblastine; deacetylvincristine; deacetylvinblastine; vinblastine; leurosine; formylleurosine |
SMILES |
CCC1(CC2CC(C3=C(CCN(C2)C1)C4=CC=CC=C4N3)(C5=C(C=C6C(=C5)C78CCN9C7C(C=CC9)(C(C(C8N6C=O)(C(=O)OC)O)OC(=O)C)CC)OC)C(=O)OC)O |
手性 SMILES |
CC[C@@]1(C[C@@H]2C[C@@](C3=C(CCN(C2)C1)C4=CC=CC=C4N3)(C5=C(C=C6C(=C5)C78CCN9C7[C@@](C=CC9)([C@H]([C@@](C8N6C=O)(C(=O)OC)O)OC(=O)C)CC)OC)C(=O)OC)O |
规范 SMILES |
CCC1(CC2CC(C3=C(CCN(C2)C1)C4=CC=CC=C4N3)(C5=C(C=C6C(=C5)C78CCN9C7C(C=CC9)(C(C(C8N6C=O)(C(=O)OC)O)OC(=O)C)CC)OC)C(=O)OC)O |
外观 |
White to off-white, odorless amorphous or crystalline powder |
颜色/形态 |
Blades from methanol |
熔点 |
424 to 428 °F (NTP, 1992) 218-220 °C |
| 57-22-7 | |
物理描述 |
Vincristine appears as a white crystalline solid. Melting point 218 °C. Used as an antineoplastic. |
保质期 |
STERILE SOLN IN EITHER H2O OR PHYSIOLOGICAL SALINE STORED IN REFRIGERATOR FOR UP TO 2 WK WITHOUT SIGNIFICANT LOSS OF POTENCY |
溶解度 |
WHITE TO SLIGHTLY YELLOW, AMORPHOUS OR CRYSTALLINE POWDER; ODORLESS, HYGROSCOPIC; FREELY SOL IN WATER /VINCRISTINE SULFATE USP/ |
同义词 |
cellcristin Citomid Farmistin Leurocristine Oncovin Oncovine Onkocristin PFS, Vincasar Sulfate, Vincristine Vincasar Vincasar PFS Vincristin Bristol Vincristin medac Vincristine Vincristine Sulfate Vincrisul Vintec |
产品来源 |
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
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