Cilengitide CAS 188968-51-6

Cilengitide, CAS number 188968-51-6, molecular formula C27H40N8O7, average molecular weight 588.66. It is a white to beige powder with good water solubility, which can dissolve up to 10mg/ml. In addition, its solubility in DMSO is also high, reaching ≥ 29.43mg/ml. These results indicate that silengeptide has good solubility, which is beneficial for its application in pharmaceutical formulations. The predicted density value is 1.41 ± 0.1g/cm ³, The isoelectric point (PI) is 6.34, and the net charge at pH=7.0 is -0.02. The predicted acidity coefficient (pKa) is 4.01 ± 0.10. The acidity coefficient is an important parameter that describes the acidity and alkalinity of a substance, reflecting its ability to dissociate hydrogen ions in solution. The pKa value indicates that it is relatively stable under neutral or alkaline conditions, while it may be prone to dissociation or degradation under acidic conditions. For example, it is a cyclic pentapeptide with a specific spatial structure and conformation. This spatial structure and conformation have a significant impact on the binding and biological activity of silengeptide to integrins. Belongs to integrin inhibitors. Integrin is a cell surface receptor that participates in various processes of tumor cell dysregulation, including tumor growth, survival, and infiltration, as well as tumor angiogenesis. Silunglutide exerts anti-tumor effects by blocking the binding of integrin to the extracellular matrix, inhibiting integrin mediated signaling processes.

Cilengitide is an important neurotransmitter and peptide drug with extensive pharmacological effects and application prospects. As an integrin inhibitor, silengeptide mainly regulates cellular signaling processes by binding to integrin receptors, thereby exerting various pharmacological effects.

1. Integrin inhibitory effect

As a potent integrin antagonist, it can specifically target integrins on the surface of tumor cells α V β 3 and α V β 5 proteins. Integrin is a cell surface receptor that participates in various processes of tumor cell dysregulation, including tumor growth, survival, infiltration, and tumor angiogenesis. Silunglutide blocks the interaction between integrin and extracellular matrix by binding to integrin receptors, thereby inhibiting integrin mediated signaling processes. This inhibitory effect can inhibit the proliferation, migration, and invasion of tumor cells, induce endothelial cell apoptosis, and thus exert anti-tumor effects.

2. Antitumor effect

The anti-tumor effect is one of its main pharmacological effects. In animal models and clinical trials, it has shown therapeutic potential for various tumors, including glioblastoma, melanoma, lung cancer, etc. By inhibiting integrin mediated signaling, the growth and survival pathways of tumor cells are blocked, thereby inhibiting tumor growth and spread. In addition, it can increase the therapeutic benefits associated with cytotoxic drugs and improve the killing effect on tumor cells.

3. The impact on angiogenesis

Integrins play an important role in the process of angiogenesis. By inhibiting integrin α V β 3 and α V β The activity of 5 can inhibit the proliferation and migration of endothelial cells, thereby inhibiting tumor angiogenesis. This inhibitory effect can block the blood supply of tumor cells, further inhibiting tumor growth and spread.

4. Immunomodulatory effect

It also has an immunomodulatory effect. By binding to integrin receptors, it can affect the activation and function of immune cells, thereby regulating the body's immune response. This immune regulatory effect can enhance the body's anti-tumor immunity and improve treatment effectiveness.

5. Other pharmacological effects

In addition to the aforementioned effects, it also has some other pharmacological effects. For example, it can affect the processes of cell adhesion, migration, and invasion, thereby inhibiting the metastasis and spread of tumor cells. In addition, it can also affect the metabolism and apoptosis of cells, thereby exerting various therapeutic effects.

Overall, its pharmacological properties are mainly reflected in its integrin inhibitory effect, anti-tumor effect, impact on angiogenesis, immunomodulatory effect, and other pharmacological effects. These effects make sildenafil a drug with broad application prospects. However, further research and exploration are needed on its pharmacological mechanisms to gain a deeper understanding of its therapeutic effects and safety in different diseases.

Cilengitide is a cyclic pentapeptide with specific spatial structure and biological activity. The laboratory synthesis of sildenafil usually involves multiple steps, including peptide chain synthesis, cyclization, and purification.

1.Synthesis of peptide chains

• Step 1: Protect the activation of amino acids

Firstly, it is necessary to select appropriate protective groups to protect the required amino acids, in order to prevent unnecessary reactions during peptide chain synthesis. Subsequently, the protected amino acids are reacted with activation reagents (such as N-hydroxysuccinimide ester) to generate corresponding amino acid activation intermediates.

Example of chemical equation:

R-AA-OH+NHS → R-AA-O-NSU

Among them, R represents the side chain of amino acids, AA represents amino acids, and NHS is N-hydroxysuccinimide.

• Step 2: Formation of peptide bonds

React the activated amino acid intermediate with the next amino acid (or its activated form) to form a peptide bond. This step is usually carried out in the presence of appropriate solvents and catalysts (such as bases).

Example of chemical equation:

R₁-AA₁-O-NSU+R₂-AA₂-OH → R₁-AA₁-CO-NH-R₂-AA₂-OH

Among them, R ₁ and R ₂ represent the side chains of two adjacent amino acids, while AA ₁ and AA ₂ represent two adjacent amino acids.

• Step 3: Gradually extend the peptide chain

Repeat step 2 and gradually connect the required amino acids to the peptide chain until a complete linear peptide chain is synthesized. Each step needs to ensure complete reaction and remove unreacted amino acids and by-products.

2.Cyclization of peptide chains

• Step 4: Select the appropriate cyclization method

Silunglutide is a cyclic pentapeptide, therefore it needs to form a loop at both ends of the peptide chain. Common cyclization methods include intramolecular acylation, thioester method, etc. The choice of method depends on the specific sequence of the peptide chain and the structure of the desired ring.

• Step 5: Cyclization reaction

Place the linear peptide chain under appropriate conditions (such as temperature, pH, solvent, etc.) to undergo cyclization reaction. This step usually takes a longer time to complete to ensure complete cyclization.

Example of chemical equation (using intramolecular acylation as an example):

R₁-AA₁-CO-NH-R₂-AA₂-CO-NH-NH-R₃-AA₃-CO-NH-R₄-R₄-AA₄-CO-NH-R₅-AA₅-OH →

R₁-AA₁-CO-NH-R₂-AA₂-CO-NH-R₃-AA₃-CO-NH-R₄-R₄-AA₄-CO-NH-R₅-AA₅-CO-NH-R₁

3.Purification and identification

• Step 6: Purification

The unreacted raw materials, by-products and other impurities are removed by appropriate purification methods (such as high performance liquid chromatography, gel filtration, etc.) to obtain silengitide with high purity.

• Step 7: Identification

Use multiple methods (such as mass spectrometry, nuclear magnetic resonance, etc.) to identify the purified product and ensure that its structure and purity meet the requirements.

Cilengitide (EMD 121974) is a cyclic pentapeptide integrin inhibitor developed by Merck KGaA in Germany, mainly used to inhibit tumor angiogenesis and cancer treatment. Its discovery stems from in-depth research on the cell adhesion molecule integrin, especially the role of α v β 3 and α v β 5 integrins in tumor growth and metastasis. Integrins are an important class of cell surface receptors that mediate the interaction between cells and extracellular matrix (ECM), affecting cell migration, proliferation, and survival. In 1986, scientists such as Richard Hynes and Erkki Ruoslahti first systematically described the integrin family and found that they play a critical role in tumor invasion and metastasis. In the 1990s, research found that α v β 3 and α v β 5 integrins were highly expressed in vascular endothelial cells and played a key role in tumor angiogenesis. The theory of "anti angiogenic therapy" proposed by Judah Folkman further promotes the development of drugs targeting integrins, as inhibiting these receptors may block the blood supply of tumors, thereby inhibiting their growth. Integrins bind to ECM proteins such as fibronectin and fibronectin by recognizing the arginine glycine aspartate (RGD) sequence. Therefore, scientists began designing small molecule or peptide inhibitors containing RGD sequences to competitively block integrin function. In 1994, scientists from the Max Planck Institute in Germany collaborated with Merck to develop a series of high affinity integrin inhibitors based on cyclic RGD peptides. Through structural optimization, they found that circular conformation can enhance the stability and binding ability of peptides. Among numerous candidate molecules, Cilengitide (initially named EMD 121974) stands out due to its high selectivity towards α v β 3 and α v β 5 integrins and excellent pharmacokinetic properties. Its chemical structure is a cyclic pentapeptide (c (RGDef (N-Me) V)), which improves metabolic stability through methylation modification.

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