Cilengitide CAS 188968-51-6

Cilengitide, CAS naj npawb 188968-51-6, molecular mis C27H40N8O7, qhov nruab nrab molecular hnyav 588.66. Nws yog xim dawb rau beige hmoov nrog dej solubility zoo, uas tuaj yeem yaj mus txog 10mg / ml. Tsis tas li ntawd, nws cov solubility hauv DMSO kuj yog siab, nce siab dua lossis sib npaug li 29.43mg / ml. Cov txiaj ntsig no qhia tau hais tias silengeptide muaj cov solubility zoo, uas yog qhov zoo rau nws daim ntawv thov hauv cov tshuaj formulations. Tus nqi kwv yees qhov ceev yog 1.41 ± 0.1g / cm³, isoelectric point (PI) yog 6.34, thiab tus nqi them ntawm pH =7.0 yog -0.02. Kev kwv yees acidity coefficient (pKa) yog 4.01 ± 0.10. Lub acidity coefficient yog ib qho tseem ceeb parameter uas piav txog cov acidity thiab alkalinity ntawm ib yam khoom, xav txog nws lub peev xwm los dissociate hydrogen ions nyob rau hauv kev daws. Tus nqi pKa qhia tau hais tias nws yog qhov ruaj khov nyob rau hauv nruab nrab lossis alkaline tej yam kev mob, thaum nws tuaj yeem raug cuam tshuam los yog degradation nyob rau hauv acidic tej yam kev mob. Piv txwv li, nws yog ib tug cyclic pentapeptide nrog ib tug tshwj xeeb spatial qauv thiab conformation. Cov qauv spatial thiab conformation no muaj feem cuam tshuam rau kev khi thiab kev ua haujlwm lom neeg ntawm silengeptide rau integrins. belongs rau integrin inhibitors. Integrin yog lub cell nto receptor uas koom nrog ntau yam txheej txheem ntawm qog cell dysregulation, nrog rau cov qog loj hlob, ciaj sia taus, thiab infiltration, nrog rau cov qog angiogenesis. Silunglutide tawm dag zog los tiv thaiv qog nqaij hlav los ntawm kev thaiv kev khi ntawm integrin mus rau extracellular matrix, inhibiting integrin mediated signaling processes.

Cilengitideyog ib qho tseem ceeb neurotransmitter thiab peptide tshuaj nrog nws kim heev pharmacological teebmeem thiab daim ntawv thov prospects. Raws li ib qho integrin inhibitor, silengeptide feem ntau tswj cov txheej txheem ntawm tes taw qhia los ntawm kev khi rau integrin receptors, yog li ua rau muaj ntau yam teebmeem tshuaj.

1. Integrin inhibitory nyhuv

Raws li ib tug muaj zog integrin antagonist, nws muaj peev xwm tshwj xeeb integrins nyob rau saum npoo ntawm cov qog hlwb V 3 thiab V 5 proteins. Integrin yog lub cell nto receptor uas koom nrog ntau yam txheej txheem ntawm qog cell dysregulation, nrog rau cov qog loj hlob, ciaj sia taus, infiltration, thiab qog angiogenesis. Silunglutide thaiv kev cuam tshuam ntawm integrin thiab extracellular matrix los ntawm kev khi rau integrin receptors, yog li inhibiting integrin mediated signaling processes. Cov nyhuv inhibitory no tuaj yeem cuam tshuam qhov kev loj hlob, kev tsiv teb tsaws, thiab kev cuam tshuam ntawm cov qog hlwb, ua rau endothelial cell apoptosis, thiab yog li siv los tiv thaiv- qog nqaij hlav.

2. Antitumor nyhuv

Cov tshuaj tiv thaiv-cov nyhuv qog yog ib qho ntawm nws cov tshuaj pharmacological tseem ceeb. Hauv cov qauv tsiaj thiab kev sim tshuaj, nws tau pom tias muaj peev xwm kho tau rau ntau yam qog nqaij hlav, suav nrog glioblastoma, melanoma, mob ntsws cancer, thiab lwm yam. Los ntawm inhibiting integrin mediated signaling, txoj kev loj hlob thiab ciaj sia ntawm cov qog hlwb raug thaiv, yog li inhibiting qog loj hlob thiab kis tau. Tsis tas li ntawd, nws tuaj yeem txhim kho cov txiaj ntsig kho mob cuam tshuam nrog cov tshuaj cytotoxic thiab txhim kho cov nyhuv tua ntawm cov qog hlwb.

3. Qhov cuam tshuam rau angiogenesis

Integrins ua lub luag haujlwm tseem ceeb hauv cov txheej txheem ntawm angiogenesis. Los ntawm inhibiting integrin V 3 thiab V Cov kev ua ntawm 5 tuaj yeem inhibit qhov kev loj hlob thiab kev tsiv teb tsaws ntawm cov hlwb endothelial, yog li inhibiting qog angiogenesis. Cov nyhuv inhibitory no tuaj yeem thaiv cov ntshav ntawm cov qog hlwb, ntxiv inhibiting qog loj hlob thiab kis tau.

4. Immunomodulatory nyhuv

Nws kuj muaj cov nyhuv immunomodulatory. Los ntawm kev khi rau integrin receptors, nws tuaj yeem cuam tshuam rau kev ua haujlwm thiab kev ua haujlwm ntawm lub cev tiv thaiv kab mob, yog li tswj hwm lub cev tiv thaiv kab mob. Cov tshuaj tiv thaiv kab mob no tuaj yeem txhim kho lub cev tiv thaiv- qog nqaij hlav thiab txhim kho kev kho mob.

5. Lwm yam teebmeem tshuaj

Ntxiv nrog rau cov teebmeem saum toj no, nws kuj muaj qee qhov teebmeem tshuaj. Piv txwv li, nws tuaj yeem cuam tshuam cov txheej txheem ntawm cell adhesion, tsiv teb tsaws, thiab ntxeem tau, yog li inhibiting metastasis thiab kis ntawm cov qog hlwb. Tsis tas li ntawd, nws tseem tuaj yeem cuam tshuam cov metabolism thiab apoptosis ntawm cov hlwb, yog li ua rau muaj ntau yam kev kho mob.

Zuag qhia tag nrho, nws cov tshuaj pharmacological feem ntau yog tshwm sim hauv nws cov txiaj ntsig integrin inhibitory, tiv thaiv-cov nyhuv qog, cuam tshuam rau angiogenesis, cov nyhuv immunomodulatory, thiab lwm yam teebmeem tshuaj. Cov teebmeem no ua rau sildenafil ib qho tshuaj nrog rau daim ntawv thov dav dav. Txawm li cas los xij, kev tshawb fawb thiab kev tshawb fawb ntxiv yog xav tau ntawm nws cov tshuaj pharmacological kom nkag siab tob txog nws cov kev kho mob thiab kev nyab xeeb ntawm cov kab mob sib txawv.

Cilengitideyog ib tug cyclic pentapeptide nrog cov qauv spatial tshwj xeeb thiab kev ua haujlwm lom neeg. Lub chaw soj nstuam synthesis ntawm sildenafil feem ntau muaj ntau cov kauj ruam, suav nrog peptide saw synthesis, cyclization, thiab purification.

1.Synthesis ntawm peptide chains

• Kauj Ruam 1: Tiv thaiv kev ua kom cov amino acids

Ua ntej, nws yog ib qho tsim nyog los xaiv cov pab pawg tiv thaiv tsim nyog los tiv thaiv cov amino acids uas yuav tsum tau ua, txhawm rau tiv thaiv qhov tsis tsim nyog tshwm sim thaum peptide saw synthesis. Tom qab ntawd, cov amino acids tiv thaiv yog reacted nrog ua kom reagents (xws li N-hydroxysuccinimide ester) los tsim cov amino acid activation intermediates.

Piv txwv ntawm chemical equation:

R-AA-OH+NHS → R-AA-O-NSU

Ntawm lawv, R sawv cev rau sab saw ntawm cov amino acids, AA sawv cev rau cov amino acids, thiab NHS yog N-hydroxysuccinimide.

• Kauj Ruam 2: Tsim cov peptide bonds

React lub activated amino acid intermediate nrog cov amino acid tom ntej (los yog nws daim ntawv activated) los tsim ib daim ntawv cog lus peptide. Cov kauj ruam no feem ntau yog ua nyob rau hauv lub xub ntiag ntawm tsim nyog cov kuab tshuaj thiab catalysts (xws li hauv paus).

Piv txwv ntawm chemical equation:

R₁-UA₁-O-NSU+R₂-UA₂-OH → R₁-UA₁-CO-NH-R₂-UA₂-OH

Ntawm lawv, R ₁ thiab R ₂ sawv cev rau cov saw hlau ntawm ob cov amino acids uas nyob ib sab, thaum AA ₁ thiab AA ₂ sawv cev rau ob cov amino acids uas nyob ib sab.

• Kauj Ruam 3: Maj mam txuas cov saw peptide

Rov ua kauj ruam 2 thiab maj mam txuas cov amino acids uas yuav tsum tau mus rau cov saw peptide kom txog rau thaum cov saw hlau peptide ua tiav. Txhua kauj ruam yuav tsum tau ua kom tiav cov tshuaj tiv thaiv thiab tshem tawm unreacted amino acids thiab los ntawm - khoom.

2.Cyclization ntawm peptide chains

• Kauj ruam 4: Xaiv txoj kev tsim nyog cyclization

Silunglutide yog cyclic pentapeptide, yog li nws yuav tsum tau tsim ib lub voj ntawm ob qho kawg ntawm peptide saw. Cov txheej txheem cyclization feem ntau suav nrog intramolecular acylation, thioester txoj kev, thiab lwm yam. Qhov kev xaiv ntawm txoj kev nyob ntawm seb qhov tshwj xeeb ntawm cov saw peptide thiab cov qauv ntawm lub nplhaib xav tau.

• Kauj Ruam 5: Cyclization cov tshuaj tiv thaiv

Muab cov kab peptide linear nyob rau hauv cov xwm txheej tsim nyog (xws li kub, pH, hnyav, thiab lwm yam) kom tau txais cov tshuaj tiv thaiv cyclization. Cov kauj ruam no feem ntau siv sijhawm ntev dua los ua kom tiav kom tiav cyclization.

Piv txwv ntawm kev sib npaug tshuaj (siv intramolecular acylation ua piv txwv):

R₁-UA₁-CO-NH-R₂-UA₂-CO-NH-NH-R₃-UA₃-CO-NH-R₄-R₄-UA₄-CO-NH-R₅-UA₅-OH →

R₁-UA₁-CO-NH-R₂-UA₂-CO-NH-R₃-UA₃-CO-NH-R₄-R₄-UA₄-CO-NH-R₅-UA₅-CO-NH-R₁

3.Purification thiab kev txheeb xyuas

• Kauj Ruam 6: Purification

Cov khoom siv tsis zoo, los ntawm - cov khoom thiab lwm yam impurities raug tshem tawm los ntawm txoj kev ua kom huv huv (xws li kev ua haujlwm siab ua kua chromatography, gel pom, thiab lwm yam) kom tau txais silengitide nrog purity siab.

• Kauj Ruam 7: Kev txheeb xyuas

Siv ntau txoj hau kev (xws li huab hwm coj spectrometry, nuclear magnetic resonance, thiab lwm yam) los txheeb xyuas cov khoom purified thiab xyuas kom meej tias nws cov qauv thiab purity ua tau raws li qhov yuav tsum tau ua.

Cilengitide(EMD 121974) yog ib qho cyclic pentapeptide integrin inhibitor tsim los ntawm Merck KGaA hauv lub teb chaws Yelemees, feem ntau yog siv los inhibit qog angiogenesis thiab kev kho mob qog noj ntshav. Nws qhov kev tshawb pom tshwm sim los ntawm - kev tshawb fawb tob ntawm cov cell adhesion molecule integrin, tshwj xeeb tshaj yog lub luag haujlwm ntawm v 3 thiab v 5 integrins hauv cov qog loj hlob thiab metastasis. Integrins yog ib qho tseem ceeb ntawm cov cell nto receptors uas kho qhov kev sib cuam tshuam ntawm cov hlwb thiab extracellular matrix (ECM), cuam tshuam rau cell migration, proliferation, thiab ciaj sia taus. Xyoo 1986, cov kws tshawb fawb xws li Richard Hynes thiab Erkki Ruoslahti thawj zaug tau piav qhia txog tsev neeg integrin thiab pom tias lawv ua lub luag haujlwm tseem ceeb hauv qog nqaij hlav thiab metastasis. Hauv xyoo 1990, kev tshawb fawb pom tias v 3 thiab v 5 integrins tau nthuav tawm hauv cov hlab ntsha endothelial thiab ua lub luag haujlwm tseem ceeb hauv cov qog angiogenesis. Txoj kev xav ntawm "anti angiogenic therapy" qhia los ntawm Judah Folkman ntxiv txhawb kev txhim kho cov tshuaj tsom rau cov integrins, vim tias inhibiting cov receptors no tuaj yeem thaiv cov ntshav ntawm cov qog, yog li inhibiting lawv txoj kev loj hlob. Integrins khi rau ECM cov proteins xws li fibronectin thiab fibronectin los ntawm kev paub txog arginine glycine aspartate (RGD) ib ntus. Yog li ntawd, cov kws tshawb fawb tau pib tsim cov molecule me me los yog peptide inhibitors uas muaj RGD raws li kev sib tw los thaiv kev ua haujlwm ntawm integrin. Xyoo 1994, cov kws tshawb fawb los ntawm Max Planck lub koom haum hauv lub teb chaws Yelemees koom tes nrog Merck los tsim cov kev sib raug zoo siab integrin inhibitors raws li cyclic RGD peptides. Los ntawm kev ua kom zoo ntawm cov qauv, lawv pom tias kev sib haum xeeb tuaj yeem txhim kho kev ruaj ntseg thiab khi muaj peev xwm ntawm peptides. Ntawm ntau tus neeg sib tw molecules, Cilengitide (thawj lub npe hu ua EMD 121974) sawv tawm vim nws cov kev xaiv siab ntawm v 3 thiab v 5 integrins thiab cov khoom zoo heev pharmacokinetic. Nws cov qauv tshuaj yog ib qho cyclic pentapeptide (c (RGDef (N-Me) V)), uas txhim kho metabolic stability los ntawm kev hloov methylation.

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