TR201904869A2 - Benzoxazole derivative compounds with anti-cancer effects. - Google Patents
Benzoxazole derivative compounds with anti-cancer effects. Download PDFInfo
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- TR201904869A2 TR201904869A2 TR2019/04869A TR201904869A TR201904869A2 TR 201904869 A2 TR201904869 A2 TR 201904869A2 TR 2019/04869 A TR2019/04869 A TR 2019/04869A TR 201904869 A TR201904869 A TR 201904869A TR 201904869 A2 TR201904869 A2 TR 201904869A2
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- Prior art keywords
- acetamide
- compound
- dimethylamino
- phenyl
- compound according
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- -1 Benzoxazole derivative compounds Chemical class 0.000 title claims abstract description 57
- 230000001093 anti-cancer Effects 0.000 title claims abstract description 28
- 150000001875 compounds Chemical class 0.000 claims abstract description 261
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 29
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- 238000011282 treatment Methods 0.000 claims abstract description 19
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 claims description 100
- 238000002844 melting Methods 0.000 claims description 33
- 230000008018 melting Effects 0.000 claims description 33
- 229910052799 carbon Inorganic materials 0.000 claims description 32
- 238000000034 method Methods 0.000 claims description 31
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 claims description 28
- BCMCBBGGLRIHSE-UHFFFAOYSA-N 1,3-benzoxazole Chemical compound C1=CC=C2OC=NC2=C1 BCMCBBGGLRIHSE-UHFFFAOYSA-N 0.000 claims description 27
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 24
- 238000005160 1H NMR spectroscopy Methods 0.000 claims description 23
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- METKIMKYRPQLGS-UHFFFAOYSA-N atenolol Chemical compound CC(C)NCC(O)COC1=CC=C(CC(N)=O)C=C1 METKIMKYRPQLGS-UHFFFAOYSA-N 0.000 claims description 19
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 12
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- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 8
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- OOBIBPPDEPYZRV-UHFFFAOYSA-N 2-[4-[2-(dimethylamino)ethyl]piperazin-1-yl]-N-[4-(5-fluoro-1,3-benzoxazol-2-yl)phenyl]acetamide Chemical compound CN(CCN1CCN(CC1)CC(=O)NC1=CC=C(C=C1)C=1OC2=C(N=1)C=C(C=C2)F)C OOBIBPPDEPYZRV-UHFFFAOYSA-N 0.000 claims 3
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Abstract
Buluş; anti-kanser etkili yeni benzoksazol türevi bileşikler ve bu bileşiklerin çeşitli kanser tedavilerinde kullanımı ile ilgilidir. Buluşta, 6-diamino-N-(4-(5-florobenzo[d]tiyazol-2-il)-2- metilfenil)hekzanamit öncül bileşiği kullanılarak antikanserojen bileşikler elde edilmektedir.Meet; new benzoxazole derivative compounds with anti-cancer effects and the use of these compounds in various cancer treatments. In the invention, anticarcinogenic compounds are obtained using the precursor compound 6-diamino-N- (4- (5-fluorobenzo [d] thiazol-2-yl) -2-methylphenyl) hexanamide.
Description
TARIFNAME ANTI-KANSER ETKILI BENZOKSAZOL TÜREVI BILESIKLER Bulusun Ilgili Oldugu Teknik Alan Bulus; anti-kanser etkili yeni benzoksazol türevi bilesikler ve bu bilesiklerin çesitli kanser tedavilerinde kullanimi ile ilgilidir. Bulusta, 6-diamino-N-(4-(5-flor0benzo[d]tiyazoI-2-iI)-2- metilfenil)hekzanamit öncül bilesigi kullanilarak antikanserojen bilesikler elde edilmektedir. DESCRIPTION ANTI-CANCER EFFECTIVE BENZOXAZOL DERIVATIVE COMPOUNDS Technical Field of the Invention Meet; New benzoxazole derivative compounds with anti-cancer effects and their effects on various cancers related to its use in treatment. In the invention, 6-diamino-N-(4-(5-fluorobenzo[d]thiazol-2-yl)-2- Anticarcinogenic compounds are obtained by using methylphenyl)hexanamide precursor. is being done.
Bulusla Ilgili Teknigin Bilinen Durumu (Önceki Teknik) Kanser, kardiyovasküler hastaliklar ile birlikte dünyada ölümcül hastaliklarin basinda yer almakta olup; hücrelerde DNA'nin hasari sonucu hücrelerin kontrolsüz veya anormal bir sekilde büyümesi ve çogalmasidir. Çok çesitli kanser tipleri olmasina ragmen, hepsi anormal hücrelerin kontrol disi çogalmasi ile baslar ve tedavi edilmez ise ciddi rahatsizliklara, hatta ölüme dahi neden olabilir. Hastaligin çok faktörlü olmasi ve çok sayida alt tipe sahip olmasi her geçen gün tedavisi ile ilgili yeni yaklasimlari gündeme getirmektedir. Kanser tedavisi için kullanilan bir yöntem olan kemoterapi; vücutta hizla büyüyen kanser hücrelerini yok etmek için kullanilan agresif bir kimyasal ilaç tedavisidir. State of the Art of the Invention (Prior Art) Cancer is one of the deadliest diseases in the world along with cardiovascular diseases. is receiving; uncontrolled or abnormal growth of cells as a result of damage to DNA in cells growth and proliferation. Although there are many different types of cancer, all It starts with the out-of-control proliferation of abnormal cells and, if left untreated, can become serious. can cause illness or even death. The fact that the disease is multifactorial and The fact that it has a large number of subtypes brings new approaches to treatment every day. brings. Chemotherapy, a method used for cancer treatment; speed in the body It is an aggressive chemical drug therapy used to destroy growing cancer cells.
Kemoterapi; kanser hücrelerinin çogalmasini önleyip, yayilmasini yavaslatarak hastaligin kontrol altina alinmasini saglamak, kisinin yasam kalitesini artirmak, cerrahi veya radyoterapi öncesi yapilacak lokal tedavileri kolaylastirmak veya cerrahi veya radyoterapi sonrasi hastalik nüksünü azaltmak amaciyla uygulanmaktadir. Kemoterapi ilaçlari kan yolu ile vücuda dagilarak kanser hücrelerine ulasarak bu hücreleri öldürür veya kontrolsüz büyümesine engel olur. Kanser hücrelerine zarar veren kanser ilaçlarinin seçicilikleri düsük oldugundan; ayni zamanda saglikli hücrelere de zarar vermekte, buna bagli olarak da çesitli yan etkiler ortaya çikmaktadir. Chemotherapy; disease by preventing the proliferation of cancer cells and slowing their spread. to ensure that it is taken under control, to increase the quality of life of the person, to undergo surgery or facilitating local treatments before radiotherapy or surgery or radiotherapy It is applied in order to reduce the recurrence of the disease after the disease. chemotherapy drugs blood by reaching the cancer cells by dispersing throughout the body, killing these cells or uncontrolled hinders its growth. Selectivities of cancer drugs damaging cancer cells because you are low; it also damages healthy cells, accordingly various side effects occur.
Kanser tedavilerinde kemoterapötik ajanlarin kullanimi; tüm kanser tipleri için vazgeçilmez olsa da bu ilaçlara karsi hücrelerin gelistirmis oldugu direnç, tedavideki basarinin düsüsündeki en önemli faktördür. Günümüzde kanser sebepli ölümler oldukça fazla olup, bu ve benzeri sebeplerden tedavilerin birçogu sonuç vermemektedir. Bu nedenle, günümüzde yeni ve daha etkili ilaçlarin bulunmasina dair çalismalar devam etmektedir. Use of chemotherapeutic agents in cancer treatments; indispensable for all types of cancer Although the resistance developed by the cells against these drugs, the success of the treatment is the most important factor. Today, deaths due to cancer are quite high, For these and similar reasons, most of the treatments do not give results. Because, Today, studies on finding new and more effective drugs continue.
Kanser tedavisinde kullanilmasi amaçlanan ilaçlarda izlenen temel stratejiler, çesitli hücresel mekanizmalarla tümör dokularinda büyümeyi, anjiogenezi, invazyonu ve metastazi önlemeye yöneliktir. Özellikle klasik kemoterapide hizla bölünen tümör hücrelerinin apoptoza gidisini hizlandiran genotoksik ve sitotoksik etkili bilesiklerin kullanilmasi söz konusudur. Bununla birlikte hücrede çesitli yolaklari ve bu yolaklardaki kilit molekülleri hedefleyerek kanser tipine göre degisebilen özgül mekanizmalari etkisiz hale getiren, böylece tümör dokusunun yok edilmesini saglayan yeni nesil ilaç tasarimlari da kanser terapilerinde yerini almistir. Bu kapsamda kanser olusumunda rol oynayan genetik degisikliklerin yaninda epigenetik degisikliklerin de önemli yeri olduguna dair bilgilere dayanarak epigenetik mekanizmalara yönelik çalismalar yapilmistir. Özellikle transkripsiyonun düzenlenmesiyle ilgili olarak DNA metilasyonu ve histon modifikasyonlari önemli hedefler olarak ortaya çikmaktadir. Kemoterapide günümüzde kullanilan bilesiklerin bazilari yan etkilerinin çok fazla olusu, bazilari ise hücrelerin ilaçlara karsi olusturduklari direnç nedeniyle etkinliklerinin azalmasindan dolayi kullanilamamakta; yerine daha etkili, yan etkisi az yeni bilesikler bulunmaya çalisilmaktadir. The main strategies followed in drugs intended for use in cancer treatment, various growth, angiogenesis, invasion, and invasion of tumor tissues by cellular mechanisms. aimed at preventing metastasis. Rapidly dividing tumor, especially in classical chemotherapy genotoxic and cytotoxic compounds that accelerate the apoptosis of cells. is to be used. However, there are various pathways in the cell and By targeting key molecules, specific mechanisms that may vary according to cancer type are neutralized. New generation drug designs that make the tumor tissue It has also taken its place in cancer therapies. In this context, it plays a role in the formation of cancer. that epigenetic changes have an important place in addition to genetic changes. Based on this information, studies on epigenetic mechanisms have been carried out. Especially DNA methylation and histone in relation to regulation of transcription modifications are emerging as important targets. Chemotherapy today Some of the compounds used have too many side effects, and some of them are used by the cells to the drugs. due to the decrease in their effectiveness due to the resistance they form against cannot be used; Instead of finding new compounds that are more effective and have less side effects, is being studied.
Düzlemsel heterosiklik bilesikler, bir biyolojik hedefe yönelik ligand afinitesini ve seçiciligini olusturmak amaci güden farmasötik kimya çalismalarinda önemli bir grubu olustururlar. Planar heterocyclic compounds reduce ligand affinity and selectivity for a biological target. They form an important group in pharmaceutical chemistry studies aiming to create
Benzoksazol halka sistemi ve onun analoglari olan benzimidazol, benzotiyazol ve oksazolopiridin türevleri nükleik asitlerin yapisinda bulunan purin bazlarinin yapisal benzerleridir. Bu nedenle benzoksazol yapilarinin kemoterapötik aktivitelerini, hücrede nükleik asit sentezini inhibe ederek gösterebilecekleri düsünülmektedir. Benzoksazol türevi bilesikler moleküler formülü C7H5NO olan aromatik organik bilesiklerdir. Benzen ve oksazol halka yapisinin birlesmesiyle olusur. Yapilan arastirmalar benzoksazol türevleri ve analoglarinin kemoterapötik aktiviteleri yönünden kayda deger sonuçlar veren bilesikler oldugunu göstermektedir. Teknigin bilinen durumunda yapilan çalismalar benzoksazol türevi bilesiklerin; antifungal, antibakteriyel, antiviral, antitümör ve antitüberküloz aktiviteleri gibi birçok aktiviteye sahip bir kemoterapötik madde oldugunu göstermektedir. Uzun yillardir dogal kaynaklardan elde edilen benzoksazol türevlerinin sitotoksik ve antimikrobiyal etkileri arastirilmis ve bu çalismalar sirasinda elde edilen bilgiler isiginda farkli biyolojik aktiviteye sahip türevler olabilecekleri görülmüstür. The benzoxazole ring system and its analogs benzimidazole, benzothiazole and Oxazolopyridine derivatives are structural components of purine bases found in nucleic acids. are similar. Therefore, the chemotherapeutic activities of benzoxazole structures It is thought that they may show by inhibiting nucleic acid synthesis. benzoxazole derivative compounds are aromatic organic compounds with the molecular formula C7H5NO. Benzene and It is formed by the union of the oxazole ring structure. Studies conducted on benzoxazole derivatives and its analogues have shown remarkable results in terms of chemotherapeutic activities. shows that there are compounds. Studies carried out in the state of the art benzoxazole derivative compounds; antifungal, antibacterial, antiviral, antitumor and It is a chemotherapeutic agent with many activities such as antituberculosis activities. shows. Benzoxazole derivatives obtained from natural sources for many years cytotoxic and antimicrobial effects were investigated and the results obtained during these studies were In the light of the information, it has been seen that they may be derivatives with different biological activities.
Literatürde çesitli hücresel makromolekülü ve yolagi etkiledigi bilinen çok sayida benzoksazol türeviyle ilgili çalismalar mevcuttur. Bunlar arasinda anti-inflamatuvar, analjezik, antiepileptik, antimalaryal, anti-HlV, antikanser ajanlar, topoizomeraz inhibitörleri, çesitli kinaz inhibitörleri, proteaz inhibitörleri, Glutatyon S transferaz inhibitörleri, siklooksijenaz inhibitörleri olarak sentezlenmis çok sayida türev bulunmaktadir. There are numerous cellular macromolecules and pathways known to affect various cellular macromolecules in the literature. There are studies on the benzoxazole derivative. These include anti-inflammatory, analgesic, antiepileptic, antimalarial, anti-HIV, anticancer agents, topoisomerase inhibitors, various kinase inhibitors, protease inhibitors, Glutathione S transferase Numerous derivatives synthesized as inhibitors, cyclooxygenase inhibitors are available.
Hücresel yolaklari etkileyebilen bu türevlerin birer potansiyel antikanser ajan olabilecegi ile ilgili çalismalar da son zamanlarda hiz kazanmistir. Benzoksazollerle yapilan antikanser etki çalismalari 1958 yilinda Clayton'un azoboyar maddelerle yaptigi çalismalar sonucu bunlarin antimümör aktiviteye sahip oldugunu bulmasiyla baslamistir. These derivatives, which can affect cellular pathways, may be potential anticancer agents. Studies on the subject have also gained momentum recently. made with benzoxazoles anticancer effect studies were conducted in 1958 by Clayton with azo dyes. As a result of the studies, it started with the finding that these had anti-immune activity.
Dogal bir ürün olan 2-sübstitüe bis(benzoksazol) UK-1 lösemi ve Ienfomalara karsi genis spektrumda antikanser aktivite gösteren bir türev oldugunun gösterilmesi de 2-sübstitüe benzoksazol türevlerinin antikanser aktivitesi ile ilgili çalismalara kaynak olusturmustur. 2-substituted bis(benzoxazole) UK-1, a natural product, is widely used against leukemia and lymphomas. Demonstrating that it is a derivative with anticancer activity in the spectrum of 2-substituted It has been a source for studies on the anticancer activity of benzoxazole derivatives.
UK-1 bilesiginin mekanizmasiyla ilgili yapilan çalismalar sonucunda M92+ iyonlari ile etkilesimi sonucunda Topo ll enzimini inhibe ettigi bulunmustur. Daha sonrasinda çesitli kanser hücre hatlari üzerinde yapilan çalismalarda antikanser etkisi arastirilan çok sayida yeni türev sentezlenmeye devam etmistir. 6-diamino-N-(4-(5-fl0robenzo[d]tiyazoI-2-iI)-2-metilfenil)hekzanamit (Phortress), aminofenilbenzotiyazol içeren ve mevcut antitümör ajanlardan farkli bir mekanizma ile selektif antikanser aktivite gösteren bir bilesiktir. Phortress, suda çözünürlügü yüksek bir bilesik olup, kimyasal yapisi üzerindeki 2,6-diaminohekzanamit fonksiyonu. bilesigin polaritesini yükseltmekte ve hücre membranlarini kolaylikla asarak hücresine girisini saglamaktadir. Phortress hücre içerisine ulastiktan sonra amit grubu üzerinden hidroliz sonucu biyotransformasyona ugrayarak 5-floro-2-(4-amino-3-metil)fenilbenzotiyazol metabolitine dönüsmektedir. 5-fl0ro-2-(4-amino-3-metil)fenilbenzotiyazol ve bu bilesigin flor atomu içermeyen formu, 2-(4-amino-3-metil)fenilbenzotiyazol, aril hidrokarbon (AhR) ligandina yüksek affinite göstermekte, sitosolik AhR baglanmasi gerçeklestikten sonra AhR çekirdek transportörü ile dimerizasyon gerçeklesmektedir. Bu asamayi, sitokrom P üzerinde bulunan ksenobiyotiklerden sorumlu element ile kompleks olusumu, gen transkripsiyonu ve protein indüksiyonu takip etmektedir. Sonuç olarak; kanserli hücrelerde sitokrom CYP1A1 enziminin selektif overekspresyonu Phortress'in reaktif metabolitine dönüsmesini indüklemektedir. Olusan bu metabolit ise DNA sarmalina eklenmekte ve hücre ölümünü gerçeklestirmektedir. As a result of the studies on the mechanism of the UK-1 compound, M92+ ions As a result of the interaction, it was found that it inhibited the Topo ll enzyme. Various later on In studies on cancer cell lines, a large number of studies have been investigated for anticancer effects. new derivatives continued to be synthesized. 6-diamino-N-(4-(5-fluorobenzo[d]thiazol-2-yl)-2-methylphenyl)hexanamide (Phortress), with a mechanism different from existing antitumor agents containing aminophenylbenzothiazole. It is a compound with selective anticancer activity. Photress is a water-soluble compound, the 2,6-diaminohexanamide function on its chemical structure. your compound It raises its polarity and allows it to enter the cell by easily hanging the cell membranes. it provides. After the phortress reaches the cell, hydrolysis via the amide group biotransformation as a result of 5-fluoro-2-(4-amino-3-methyl)phenylbenzothiazole turns into its metabolite. 5-fluoro-2-(4-amino-3-methyl)phenylbenzothiazole and this compound fluorine-free form, 2-(4-amino-3-methyl)phenylbenzothiazole, aryl hydrocarbon (AhR) shows high affinity for its ligand, after cytosolic AhR binding has taken place. The dimerization takes place with the AhR core transporter. This stage, cytochrome Complex with element responsible for xenobiotics present on P formation is followed by gene transcription and protein induction. As a result; Selective overexpression of the cytochrome CYP1A1 enzyme in cancer cells induces its conversion to its reactive metabolite. If this metabolite is formed, it is attached to the DNA helix. added and cell death occurs.
Söz konusu bulus; B-diamino-N-(4-(5-florobenzo[d]tiyazoI-2-il)-2-metilfenil)hekzanamit öncül bilesiginden yola çikilarak elde edilen anti-kanser etkili yeni benzoksazol türevi bilesikler ile ilgilidir. The invention in question; B-diamino-N-(4-(5-fluorobenzo[d]thiazol-2-yl)-2-methylphenyl)hexanamide New benzoxazole derivative with anti-cancer effect obtained from its precursor compound It's about compounds.
Bulusun Kisa Açiklamasi ve Amaçlari Mevcut bulus, Formül 3 ile gösterilen, kanser tedavisinde endike olan benzoksazol türevi bilesikler ve bu bilesiklerin kanser tedavisi için bir ilaç kompozisyonunda kullanimi ile .(Formül 3) Söz konusu bilesikler 6-diamino-N-(4-(5-florobenzo[d]tiyazol-2-il)-2-metilfenil)hekzanamit anti-kanser ajaninin kimyasal yapisi modifiye edilerek elde edilmektedir. Bulusta, biyoizosterizm kavramindan yararlanarak benzotiyazol yerine onun biyoizosteri olan ve ayni zamanda antikanser ajanlarin yapisinda da yer alan benzoksazol halkasi getirilmektedir. Ayrica bulusta; kanserli hücre içerisine geçisi kolaylastirmak adina, 1-(2- dimetilaminoetil)piperazin ve 1-(3-Dimetilaminopropil)piperazin yan gruplari kullanilarak bilesiklerin polaritelerinin arttirilmasi yoluna gidilmektedir. Piperazin sistemi sadece polariteyi arttirmasi amaci ile degil, ayni zamanda anti-kanser aktiviteye katki saglamasi nedeniyle tercih edilmektedir. Sübstitüent degisikliginin antikanser aktivite üzerine etkisini incelemek amaciyla benzoksazol halkasinin 5. konumu hem non-sübstitüe halde birakilmis hemde flor. klor ve metil gruplari ile türevlendirilmistir. Ayrica, benzoksazol halkasina 2. konumdan bagli fenil yapisi, 3. konumuna metil sübstitüenti getirilerek ya da nonsübstitüe halde birakilarak türevlendirilmistir. .2HCl 6-diamino-N-(4-(5-florobenzo[d]tiyazoI-2-il)-2-metiIfenil)hekzanamit Bulusun bir amaci; kanser tedavisine ve/veya önlenmesine kullanilmak üzere yeni bilesikler gelistirilmesidir. Brief Description and Objectives of the Invention The present invention is a benzoxazole derivative indicated by Formula 3, indicated in the treatment of cancer. compounds and their use in a medicament composition for the treatment of cancer. .(Formula 3) Said compounds are 6-diamino-N-(4-(5-fluorobenzo[d]thiazol-2-yl)-2-methylphenyl)hexanamide It is obtained by modifying the chemical structure of the anti-cancer agent. In the find, utilizing the concept of bioisosterism, which is its bioisostere instead of benzothiazole and benzoxazole ring, which is also involved in the structure of anticancer agents is brought. Also in the invention; In order to facilitate the transition into the cancerous cell, 1-(2- using dimethylaminoethyl)piperazine and 1-(3-Dimethylaminopropyl)piperazine side groups The polarity of the compounds is increased. Piperazine system only not only to increase the polarity, but also to contribute to the anti-cancer activity. because it is preferred. The effect of substituent change on anticancer activity In order to examine the 5th position of the benzoxazole ring, both non-substituted left as well as fluorine. It is derivatized with chlorine and methyl groups. Also, benzoxazole the phenyl structure attached to the ring from the 2nd position, by introducing a methyl substituent to the 3rd position, or It has been derivatized by leaving it in the nonsubstituted state. .2HCl 6-diamino-N-(4-(5-fluorobenzo[d]thiazol-2-yl)-2-methylphenyl)hexanamide An aim of the invention is; new for use in the treatment and/or prevention of cancer compounds are developed.
Bulusun bir amaci kanser tedavisinde kullanima uygun, Formül 3 ile gösterilen bilesikleri içeren bir farmasötik kompozisyon ve bu kompozisyonu içeren bir anti-kanser etkili ilaç üretilmesidir. An object of the invention is compounds designated by Formula 3 suitable for use in cancer therapy. a pharmaceutical composition containing the composition and an anti-cancer drug containing this composition. is to be produced.
Bulusun bir diger amaci; yüksek biyolojik aktiviteye sahip benzoksazol türevi bilesiklerin elde edilmesidir. Another purpose of the invention; benzoxazole derivative compounds with high biological activity is to be obtained.
Bulusun bir diger amaci; doza bagli olarak artis gösteren antiproliferatif etkinlige sahip benzoksazol türevi bilesiklerin elde edilmesidir. Another purpose of the invention; It has antiproliferative activity that increases in a dose-dependent manner. is to obtain benzoxazole derivative compounds.
Bulusun bir diger amaci; zamana bagli olarak artis gösteren %DNA sentez inhibisyonu saglayan benzoksazol türevi bilesiklerin elde edilmesidir. Another purpose of the invention; % inhibition of DNA synthesis increasing with time is to obtain benzoxazole derivative compounds that provide
Bulusun bir diger amaci; yüksek oranda apoptotik hücre ölümünü indükleyici etkiye sahip benzoksazol türevi bilesiklerin elde edilmesidir. Another purpose of the invention; has a high rate of inducing apoptotic cell death is to obtain benzoxazole derivative compounds.
Bulusu Açiklayan Sekillerin Tanimlari Bilesik 3a'ya ait IR spektrumu. Description of Figures Explaining the Invention IR spectrum of Compound 3a.
Bilesik Ba'ya ait 1H-NMR spektrumu. 1H-NMR spectrum of compound Ba.
Bilesik 3a'ya ait 13C-NMR spektrumu. 13C-NMR spectrum of Compound 3a.
Bilesik 3a'ya ait kütle spektrumu. Mass spectrum of compound 3a.
Bilesik 3b'ye ait IR spektrumu. IR spectrum of Compound 3b.
Bilesik 3b'ye ait 1H-NlVIR spektrumu. 1H-NIVIR spectrum of Compound 3b.
Bilesik 3b'ye ait 13C-NMR spektrumu. 13C-NMR spectrum of Compound 3b.
Bilesik 3b'ye ait kütle spektrumu. Mass spectrum of Compound 3b.
Bilesik Sc'ye ait lR spektrumu. IR spectrum of the compound Sc.
Bilesik Sc'ye ait 1H-NMR spektrumu. 1H-NMR spectrum of the compound Sc.
Bilesik 3c'ye ait 13C-NMR spektrumu. 13C-NMR spectrum of Compound 3c.
Bilesik Sc'ye ait kütle spektrumu. Mass spectrum of the compound Sc.
Bilesik 3d'ye ait IR spektrumu. IR spectrum of compound 3d.
Bilesik 3d'ye ait 1H-Nli/IR spektrumu. 1H-Nli/IR spectrum of Compound 3d.
Bilesik 3d'ye ait 13C-NMR spektrumu. 13C-NMR spectrum of Compound 3d.
Bilesik 3d'ye ait kütle spektrumu. Mass spectrum of compound 3d.
Bilesik 3e'ye ait IR spektrumu. IR spectrum of Compound 3e.
Bilesik 3e'ye ait 1H-NMR spektrumu. 1H-NMR spectrum of Compound 3e.
Bilesik 3e'ye ait 13C-NMR spektrumu. 13C-NMR spectrum of Compound 3e.
Bilesik 3e'ye ait kütle spektrumu. Mass spectrum of Compound 3e.
Bilesik 3f'ye ait IR spektrumu. IR spectrum of Compound 3f.
Bilesik 3f”ye ait 1H-NMR spektrumu. 1H-NMR spectrum of Compound 3f.
Bilesik 3f'ye ait 13C-NMR spektrumu. 13C-NMR spectrum of Compound 3f.
Bilesik 3f”ye ait kütle spektrumu. Mass spectrum of compound 3f.
Bilesik Sg'ye ait IR spektrumu. IR spectrum of compound Sg.
Bilesik 3g'ye ait 1H-NlVIR spektrumu. 1H-NIVIR spectrum of compound 3g.
Bilesik Sg'ye ait 13C-NMR spektrumu. 13C-NMR spectrum of compound Sg.
Bilesik Sg'ye ait kütle spektrumu. Mass spectrum of the compound Sg.
Bilesik 3h'ye ait IR spektrumu. IR spectrum of Compound 3h.
Bilesik 3h'ye ait 1H-NMR spektrumu. 1H-NMR spectrum of compound 3h.
Bilesik 3h'ye ait 13C-NMR spektrumu. 13C-NMR spectrum of Compound 3h.
Bilesik 3h'ye ait kütle spektrumu. Mass spectrum of compound 3h.
Bilesik Siiye ait IR spektrumu. IR spectrum of Compound Sii.
Bilesik 3i”ye ait 1H-NMR spektrumu. 1H-NMR spectrum of Compound 3i.
Bilesik 3i”ye ait 13C-NMR spektrumu. 13C-NMR spectrum of Compound 3i.
Bilesik 3i”ye ait kütle spektrumu. Mass spectrum of Compound 3i.
Bilesik 3jiye ait lR spektrumu. IR spectrum of compound 3ji.
Bilesik 3j'ye ait 1H-NlVlR spektrumu. 1H-NlVlR spectrum of Compound 3j.
Bilesik 3j'ye ait 13C-NMR spektrumu. 13C-NMR spectrum of Compound 3j.
Bilesik 3j'ye ait kütle spektrumu. Mass spectrum of compound 3j.
Bilesik 3k'ye ait IR spektrumu. IR spectrum of compound 3k.
Bilesik 3k'ye ait 1H-NMR spektrumu. 1H-NMR spectrum of compound 3k.
Bilesik 3k'ye ait 13C-NMR spektrumu. 13C-NMR spectrum of compound 3k.
Bilesik 3k'ye ait kütle spektrumu. Mass spectrum of compound 3k.
Bilesik 3I'ye ait lR spektrumu. IR spectrum of Compound 3I.
Bilesik 3I'ye ait 1H-NMR spektrumu. 1H-NMR spectrum of Compound 3I.
Bilesik 3I'ye ait 13C-NMR spektrumu. 13C-NMR spectrum of Compound 3I.
Bilesik 3I'ye ait kütle spektrumu. Mass spectrum of Compound 3I.
Bilesik 3m'ye ait IR spektrumu. IR spectrum of compound 3m.
Bilesik 3m'ye ait 1H-NMR spektrumu. 1H-NMR spectrum of compound 3m.
Bilesik 3m'ye ait 13C-NMR spektrumu. 13C-NMR spectrum of compound 3m.
Bilesik 3m'ye ait kütle spektrumu. Mass spectrum of compound 3m.
Sekil 53: Bilesik 3n'ye ait IR spektrumu. Figure 53: IR spectrum of Compound 3n.
Sekil 54: Bilesik 3n'ye ait 1H-NMR spektrumu. Figure 54: 1H-NMR spectrum of Compound 3n.
Sekil 55: Bilesik 3n'ye ait 13C-NMR spektrumu. Figure 55: 13C-NMR spectrum of Compound 3n.
Sekil 56: Bilesik 3n'ye ait kütle spektrumu. Figure 56: Mass spectrum of Compound 3n.
Sekil 57: Bilesik 30'ya ait IR spektrumu. Figure 57: IR spectrum of Compound 30.
Sekil 58: Bilesik 30'ya ait 1H-NMR spektrumu. Figure 58: 1H-NMR spectrum of Compound 30.
Sekil 59: Bilesik 30'ya ait 13'C-NMR spektrumu. Figure 59: 13'C-NMR spectrum of Compound 30.
Sekil 60: Bilesik 30'ya ait kütle spektrumu. Figure 60: Mass spectrum of Compound 30.
Sekil 61: Bilesik Sp'ye ait IR spektrumu. Figure 61: IR spectrum of Compound Sp.
Sekil 62: Bilesik 3p'ye ait 1H-NMR spektrumu. Figure 62: 1H-NMR spectrum of Compound 3p.
Sekil 63: Bilesik 3p'ye ait 13C-NMR spektrumu. Figure 63: 13C-NMR spectrum of Compound 3p.
Sekil 64: Bilesik 3p'ye ait kütle spektrumu. Figure 64: Mass spectrum of Compound 3p.
Sekil 65: Bilesik 3n'ye ait 2D HMBC spektrumu. Figure 65: 2D HMBC spectrum of Compound 3n.
Sekil 66: Bilesik 3n'ye ait 2D NOESY spektrumu. saatlik inkübasyon süresi sonrasinda %DNA sentez inhibisyon aktiviteleri. Figure 66: 2D NOESY spectrum of Compound 3n. %DNA synthesis inhibition activities after an hour incubation period.
Sekil 68: MCP-7 hücre dizilerinde Bilesik 3n ve doksorubisin ile 24 ve 48 saatlik inkübasyon süresi sonrasinda %DNA sentez inhibisyon aktiviteleri. Figure 68: 24 and 48 h with Compound 3n and doxorubicin in MCP-7 cell lines %DNA synthesis inhibition activities after the incubation period.
Sekil 69: HepG2 hücre dizilerinde Bilesik 3d, Bilesik 3m, Bilesik Sn ile doksorubisinin 24 ve 48 saatlik inkübasyon süresi sonrasinda %DNA sentez inhibisyon aktiviteleri. Figure 69: Compound 3d, Compound 3m, Compound Sn and doxorubicin in HepG2 cell lines %DNA synthesis inhibition activities after 24 and 48 hours incubation period.
Sekil 70: CB hücre dizilerinde Bilesik 3e, Bilesik 3f, Bilesik 3i, Bilesik 3m ve Bilesik 3n ile doksorubisinin 24 ve 48 saatlik inkübasyon süresi sonrasinda %DNA sentez inhibisyon aktiviteleri. Figure 70: Compound 3e, Compound 3f, Compound 3i, Compound 3m, and Compound 3n in CB cell lines %DNA synthesis after 24 and 48 hours of incubation period with doxorubicin inhibition activities.
Sekil 71: HT-29 hücre dizisinde bilesikler 3i, ?m ile doksorubisin'e ait akis sitometrik analiz diyagrami (HT-29 hücre dizisinde Anneksin/Pi analizi bilesiklerin IC50 konsantrasyonlari ile 24 saatlik inkübasyon süresi sonrasinda gerçeklestirildi (3i kadran geç apoptotik hücreler (Ql-U R; Anneksin V-pozitif/Pl-pozitif); alt sol kadran canli hücreler (Q1-LL; Anneksin V-negatif/PI-negatif) ve alt sag kadran geç apoptotik hücreler (Ol-LR; Anneksin V-pozitif/Pl-negatif). Test edilen bilesiklerin % 85.5 ve 6.5.). Figure 71: Flow cytometric analysis of compounds 3i, ?m and doxorubicin in cell line HT-29 assay diagram (Annexin/Pi assay in HT-29 cell line IC50 of compounds carried out after a 24-hour incubation period with concentrations (3i quadrant late apoptotic cells (Q1-U R; Annexin V-positive/Pl-positive); lower left quadrant viable cells (Q1-LL; Annexin V-negative/PI-negative) and lower right quadrant late apoptotic cells (O1-LR; Annexin V-positive/Pl-negative). % of tested compounds 85.5 and 6.5.).
Sekil 72: MCF-7 hücre dizisinde bilesik 3n ile doksorubisin'e ait akis sitometrik analiz diyagrami (MCF-7 hücre dizisinde Anneksin/Pi analizi bilesiklerin lC50 konsantrasyonlari ile 24 saatlik inkübasyon süresi sonrasinda gerçeklestirildi (3n için ICSO degeri . Üst sol kadran nekrotik (Q1-UL; Anneksin V-negatif/Pl-pozitif); üst sag kadran geç apoptotik hücreler (Q1-UR; Anneksin V-pozitif/PI-pozitif); alt sol kadran canli hücreler (Q1- LL; Anneksin V-negatif/PI-negatif) ve alt sag kadran geç apoptotik hücreler (Q1- LR; Anneksin V-pozitif/PI-negatif). Test edilen bilesiklerin °/o Q1-UL, Q1-UR, Q1-LL Sekil 73: HepGZ hücre dizisinde bilesikler 3d, 3m, 3n ve doksorubisin'e ait akis sitometrik analiz diyagrami (HepG2 hücre dizisinde Anneksin/Pi analizi bilesiklerin Anneksin V-negatif/PI-pozitif); üst sag kadran geç apoptotik hücreler (Q1-UR; Anneksin V-pozitif/PI-pozitif); alt sol kadran canli hücreler (Q1-LL; Anneksin V- negatif/Pl-negatif) ve alt sag kadran geç apoptotik hücreler (Q1-LR; Anneksin V- pozitif/Pl-negatif). Test edilen bilesiklerin % Q1-UL, Q1-UR, Q1-LL ve Q1-LR ve 8.3.) Sekil 74: 06 hücre dizisinde bilesikler 3e, 3f, 3i, 3m ve 3n ile doksorubisin'e ait akis sitometrik analiz diyagrami (06 hücre dizisinde Anneksin/Pi analizi bilesiklerin IC50 konsantrasyonlari ile 24 saatlik inkübasyon süresi sonrasinda gerçeklestirildi (3e 3m için ICSO degeri 1.03 iJM; 3n için ICSO degeri 1.44 pM; doksorubisin için lCSO degeri 25.64 plVl). Üst sol kadran nekrotik (Q1; Anneksin V-negatif/Pl-pozitif); üst sag kadran geç apoptotik hücreler (Q2; Anneksin V-pozitif/PI-pozitif); alt sol kadran canli hücreler (Q3; Anneksin V-negatif/PI-negatif) ve alt sag kadran geç apoptotik hücreler (Q4; Anneksin V-pozitif/PI-negatif). Test edilen bilesiklerin % Q1, Q2, Q3 Sekil 75: Bilesik 3m için önerilen biyotransformasyon semasi. Figure 72: Flow cytometric analysis of compound 3n and doxorubicin in MCF-7 cell line diagram (Annexin/Pi analysis in MCF-7 cell line lC50 of compounds carried out after a 24-hour incubation period with concentrations (3n ICSO value for . upper left quadrant necrotic (Q1-UL; Annexin V-negative/Pl-positive); upper right quadrant late apoptotic cells (Q1-UR; Annexin V-positive/PI-positive); lower left quadrant viable cells (Q1- LL; Annexin V-negative/PI-negative) and lower right quadrant late apoptotic cells (Q1- LR; Annexin V-positive/PI-negative). Compounds tested °/o Q1-UL, Q1-UR, Q1-LL Figure 73: Flow of compounds 3d, 3m, 3n and doxorubicin in HepGZ cell line cytometric analysis diagram (Annexin/Pi analysis of compounds in HepG2 cell line Annexin V-negative/PI-positive); upper right quadrant late apoptotic cells (Q1-UR; Annexin V-positive/PI-positive); lower left quadrant viable cells (Q1-LL; Annexin V- negative/Pl-negative) and lower right quadrant late apoptotic cells (Q1-LR; Annexin V- positive/Pl-negative). % of tested compounds Q1-UL, Q1-UR, Q1-LL and Q1-LR and 8.3.) Figure 74: Flow of compounds 3e, 3f, 3i, 3m and 3n and doxorubicin in cell line 06 cytometric analysis diagram (IC50 of Annexin/Pi assay compounds in 06 cell line carried out after a 24-hour incubation period with concentrations (3e) ICSO value for 3m is 1.03 iJM; ICSO value for 3n is 1.44 pM; lCSO for doxorubicin value 25.64 plVl). Upper left quadrant necrotic (Q1; Annexin V-negative/Pl-positive); top right quadrant late apoptotic cells (Q2; Annexin V-positive/PI-positive); lower left quadrant viable cells (Q3; Annexin V-negative/PI-negative) and lower right quadrant late apoptotic cells (Q4; Annexin V-positive/PI-negative). % of tested compounds Q1, Q2, Q3 Figure 75: Recommended biotransformation scheme for compound 3m.
Sekil 76: Bilesik 3n için önerilen biyotransformasyon semasi. Figure 76: The proposed biotransformation scheme for Compound 3n.
Sekil 77: Phortress'in CYP1A1 enzimi aktif bölge ile etkilesimin iki boyutlu görünümü. Figure 77: Two-dimensional view of the interaction of Phortress with the CYP1A1 enzyme active site.
Sekil 78: Bilesik 3n'nin CYP1A1 enzimi aktif bölge ile etkilesimin iki boyutlu görünümü. Figure 78: Two-dimensional interaction of compound 3n with the CYP1A1 enzyme active site. view.
Bulusun Ayrintili Açiklamasi Mevcut bulus; selektif anti-kanser aktivite gösteren 6-diamino-N-(4-(5- florobenzo[d]tiyazol-2-iI)-2-metilfenil)hekzanamit bilesiginin kimyasal modifikasyonu ile sentezlenen yeni benzoksazol türevi bilesikler ile ilgilidir. 6-diamin0-N-(4-(5- florobenzo[d]tiyazol-2-iI)-2-metilfenil)hekzanamit bilesiginin, amit grubu üzerinden hidroliz sonucu olusan amin metaboliti (PM1)ve bu metabolitin oksidatif dehalojenasyonu sonucu olusan flor tasimayan sekonder metaboliti (PM2) anti-kanser etkiden sorumludur. Detailed Description of the Invention The present invention; 6-diamino-N-(4-(5-) showing selective anti-cancer activity by chemical modification of the fluorobenzo[d]thiazol-2-yl)-2-methylphenyl)hexanamide compound It relates to the newly synthesized benzoxazole derivative compounds. 6-diamino-N-(4-(5- Hydrolysis of fluorobenzo[d]thiazol-2-yl)-2-methylphenyl)hexanamide through the amide group amine metabolite (PM1) and oxidative dehalogenation of this metabolite The resulting fluorine-free secondary metabolite (PM2) is responsible for the anti-cancer effect.
Phnrtrrst l:`*k:›.if..idif DCILJJU_ ma::. ui'. 2-5übstitüe-4-(5-sübstitüebenzo[d]oksazoI-Z-iI)aniIin sentezi (Yöntem A) çeviren sogutucu altinda 5 saat karistirilarak isitilir. Reaksiyon ortamindan alinan numune amonyak (NHs) ile nötrallestirildikten sonra Ince Tabaka Kromatografisi (ITK) kontrolü yapilir. Reaksiyon bitiminde, karisim etanol (EtOH) ile seyreltilir ve buz banyosunda sogutulduktan sonra amonyak ile nötrallestirilir. Daha sonra reaksiyon içerigi süzülür ve inorganik kalintilardan ayrilir. Süzüntü içerisindeki etanol alçak basinç altinda uçurulur ve ham ürün Su:Etanol (20:80) karisimindan kristallendirilir. Phnrtrrst l:`*k:›.if..idif DCILJJU_ ma::. ui'. Synthesis of 2-5substituted-4-(5-substitutedbenzo[d]oxazoI-Z-yl)aniline (Method A) It is heated by stirring for 5 hours under a rotating cooler. Sample taken from the reaction medium Thin Layer Chromatography (ITK) control after neutralization with ammonia (NHs) makes. At the end of the reaction, the mixture is diluted with ethanol (EtOH) and placed in an ice bath. After cooling, it is neutralized with ammonia. The reaction contents are then filtered and separated from inorganic residues. The ethanol in the filtrate is evaporated under low pressure and The crude product is crystallized from a mixture of Water:Ethanol (20:80).
R1 NH2 110 “30°C R1 N 2-kloro-N-(2-sübstitüe-4-(5-sübstitüebenzo[d]oksazoI-2-il)fenil)asetamit türevlerinin sentezi (Yöntem B) ilavesiyle manyetik karistirici üzerinde hazirlanan buz banyosuna alinir. Bir damlatma klorür ve THF karisimi çok dikkatli bir sekilde damla damla buz banyosu üzerindeki reaksiyon ortamina ilave edilir. Bu esnada reaksiyon içeriginin kuvvetli bir sekilde karistirilmasina özen gösterilmektedir. Damlatma islemi bitirildiginde reaksiyon ortami buz banyosundan alinip oda isisinda bir saat karistirilir. THF rotavapor araciligiyla uçurulur ve elde edilen kalinti su ile yikanir. Ham ürün kuruduktan sonra etanolden kristallendirilir. R1 NH2 110 “30°C R1 N 2-chloro-N-(2-substituted-4-(5-substitutedbenzo[d]oxazoI-2-yl)phenyl)acetamide Synthesis of derivatives (Method B) It is taken into the ice bath prepared on the magnetic stirrer with the addition of a trickle The mixture of chloride and THF was very carefully placed on the ice bath, drop by drop. added to the reaction medium. At this time, the reaction content is strongly Care is taken to avoid mixing. When the dripping process is finished, the reaction medium is ice. It is taken from the bath and stirred for an hour at room temperature. Flies via THF rotavapor and the residue obtained is washed with water. The crude product is crystallized from ethanol after drying.
/ NH3 TEA/THF / NH 0 C1 (Tep.3) 2-(4-(2-sübstitüe)piperazin-1-iI)-N-(2-metiI-4-(5-metiIbenzo[d]oksazoI-2- il)fenil)asetamit türevlerinin sentezi (Yöntem C) sübstitüepiperazin türevi, 0.5-10000 mL aseton içerisinde geri çeviren sogutucu altinda 7- 36 saat kaynatilarak karistirilir. Reaksiyon bitimi ITK kontrolü ile tayin edildikten sonra aseton agzi açik bir kap içerisinde çeker ocak içinde uçurulur. Elde edilen kalinti üzerine 0.2-4000 mL su ilave edildikten sonra eter ile en az 3 kez ekstre edilir. Eterli fazlar birlestirilir, çözücü uçurulduktan sonra kalan ürün kazinarak alinir. / NH3 TEA/THF / NH 0 C1 (Tap.3) 2-(4-(2-substituted)piperazine-1-yl)-N-(2-methyl-4-(5-methylbenzo[d]oxazoI-2-) Synthesis of il)phenyl)acetamide derivatives (Method C) Substituted piperazine derivative in 0.5-10000 mL of acetone under reflux 7- It is stirred by boiling for 36 hours. After the end of the reaction is determined by the ITK control acetone is evaporated in a fume hood in an open container. on the resulting residue After adding 0.2-4000 mL of water, it is extracted with ether at least 3 times. ethereal phases are combined, after the solvent is evaporated, the remaining product is scraped off.
/ NII _›Asewn û / NH R' N h K2C03/A R' N ;1 TEA/ ODC 2a-2h Aseton K2C03 / A Tablo 1. Bulusa konu sentez ürünleri BILESIK R1 R2 R3 2b -H -CHs -CH3 -H Tablo 2. Bulus konusu anti-kanser etkili benzoksazol türevi bilesikler. / NII _›Asewn û / NH R'NhK2CO3/AR'N;1 TEA/ ODC 2a-2h Nail polish remover K2C03/A Table 1. Synthesis products of the invention COMPOUND R1 R2 R3 2b -H -CHs -CH3 -H Table 2. Anti-cancer benzoxazole derivative compounds of the invention.
BILESIK R1 R2 R3 3c -H .CH3 -CHzCH2N(CH3)2 3d -H .CH3 -CH2CH2CH2N(CH3)2 3e -CH3 -H -CHzCH2N(CH3)2 3f -CH3 -H -CH2CH2CH2N(CH3)2 3 g .CH3 .CH3 -CHZCH2N(CH3)2 3h _cm -CH3 _CH2CH2CH2N(CH3)2 31 -F -H -CH2CH2N(CH3)2 3 j -F -H -CHzCHzCH2N(CH3)2 3k -F -CH3 -CHzCH2N(CH3)2 31 -F -CH3 -CH2CH2CH2N(CH3)2 3m -Cl -H -CH2CH2N(CH3)2 3n -Cl -H -CHzCHzCH2N(CH3)2 .C1 _CH3 -CH2CH2N(CH3)2 Sentezi gerçeklestirilen bulusa konu bilesiklerin lR, iHNMR, 13CNMR ve Kütle Spektroskopisi (HRMS) ile karakterizasyon analizleri yapilmistir. COMPOUND R1 R2 R3 3c -H .CH3 -CHzCH2N(CH3)2 3d -H .CH3 -CH2CH2CH2N(CH3)2 3e -CH3 -H -CHzCH2N(CH3)2 3f -CH3 -H -CH2CH2CH2N(CH3)2 3 g .CH3 .CH3 -CHZCH2N(CH3)2 3h _cm -CH3 _CH2CH2CH2N(CH3)2 31 -F -H -CH2CH2N(CH3)2 3 j -F -H -CHzCHzCH2N(CH3)2 3k -F -CH3 -CHzCH2N(CH3)2 31 -F -CH3 -CH2CH2CH2N(CH3)2 3m -Cl -H -CH2CH2N(CH3)2 3n -Cl -H -CHzCHzCH2N(CH3)2 .C1 _CH3 -CH2CH2N(CH3)2 IR, iHNMR, 13CNMR and Mass of the compounds of the invention were synthesized. Characterization analyzes were performed by spectroscopy (HRMS).
Erime Noktalarinin Tespiti Sentezlenen bilesiklerin erime noktalari Mettler T0led0-MP90 Melting Point System kullanilarak tespit edilmistir. Bir ucu kapali kilcal borulara 1/2 cm kadar konulari sentez bilesikleri cihazin haznelerine yerlestirilmis. Islem bittiginde cihazdan alinan videolar izlenerek erime noktasi tayini yapilmistir. Detection of Melting Points Melting points of synthesized compounds Mettler T0led0-MP90 Melting Point System detected using. Synthesize threads up to 1/2 cm into capillary tubes with one end closed compounds are placed in the chambers of the device. Videos retrieved from the device when the process is finished The melting point was determined by monitoring.
Shimadzu-IR Affinity-IS cihazi kullanilarak bilesiklerin lR spektrumlari elde edilmistir. lR spektrofotometresi ATR ataçmanina toz maddeler uygulanarak spektrumlar çekilmistir. 1H NMR Spektrumlarinin Alinmasi Elde edilen orijinal bilesiklerin 1H NMR spekrumlari DMSO-dö içindeki çözeltilerinin, tetrametilsilana (TMS) karsi Bruker 300 MHz'Iik NMR spektrometresine uygulanmasi sonucu alinmistir. 13G NMR Spektrumlarinin Alinmasi Elde edilen orijinal bilesiklerin 13C NMR spekrumlari DMSO-dö içindeki çözeltilerinin, tetrametilsilana (TMS) karsi Bruker 300 MHz'lik NMR spektrometresine uygulanmasi sonucu alinmistir. 2D NMR Spektrumlarinin Alinmasi 2 boyutlu NMR yöntemi tek boyutlu NMR tekniklerinden kesin yapi tayini için gerekli verilerin alinamadigi durumlarda siklikla basvurulan, iki tane tek boyutlu NMR spektrumunun korelasyonu ile ortaya çikan NMR teknigidir. Temel olarak, korelasyonda kullanilan çekirdeklere göre homonükleer ve heteronükleer olarak ikiye ayrilir. COSY (Correlation Spectroscopy) en sik kullanilan homonükleer spektroskopi teknigidir. IR spectra of the compounds were obtained using the Shimadzu-IR Affinity-IS instrument. lR The spectra were taken by applying powder materials to the spectrophotometer ATR attachment. Acquisition of 1H NMR Spectra 1H NMR spectra of the original compounds obtained in DMSO-d application of tetramethylsilane (TMS) against Bruker 300 MHz NMR spectrometer result is obtained. Acquisition of 13G NMR Spectra 13C NMR spectra of the original compounds obtained, their solutions in DMSO-d, application to the Bruker 300 MHz NMR spectrometer against tetramethylsilane (TMS) result is obtained. Acquisition of 2D NMR Spectra 2D NMR method is required for precise structure determination from one-dimensional NMR techniques. Two one-dimensional NMRs, which are frequently used when data cannot be obtained. It is the NMR technique that emerges with the correlation of the spectrum. Basically, in correlation It is divided into two as homonuclear and heteronuclear according to the nuclei used. COSY (Correlation Spectroscopy) is the most commonly used homonuclear spectroscopy technique.
COSY'de her iki eksende de proton NMR spektrasi mevcuttur ve bir protonun hangi diger protonlarla eslestigi (coupling) hakkinda bilgi verir. HSQC (Heteronuclear single-quantum correlation spectroscopy) ve HMBC (Heteronuclear multiple-bond correlation spectroscopy) eksenlerin birinde proton digerinde ise karbon spektrumunun korelasyonundan elde edilen heteronükleer spektroskopi yöntemleridir. HSQC'de protonun dogrudan bagli oldugu karbon arasindaki etkilesimler hakkinda bilgi alinirken. In COSY, proton NMR spectra are available in both axes and it is possible to determine which other proton is It gives information about the coupling with protons. HSQC (Heteronuclear single-quantum correlation spectroscopy) and HMBC (Heteronuclear multiple-bond correlation) spectroscopy) is the proton on one of the axes and the carbon spectrum on the other. are heteronuclear spectroscopy methods obtained from the correlation at HSQC when obtaining information about the interactions between the carbon to which the proton is directly bonded.
HMBC'de ise 2 ila 4 bag mesafesindeki hidrojen ve karbon arasindaki etkilesimler görülür. In HMBC, on the other hand, interactions between hydrogen and carbon at 2 to 4 bond distances are seen.
Bu yöntemler disinda aralarinda bir bag olup olmamasina bakilmaksizin fiziksel olarak birbirine yakin çekirdekler arasinda korelasyonlar kuran NOESY (Nuclear Overhauser effect spectroscopy) ve ROESY (Rotating frame nuclear Overhauser effect spectroscopy). Apart from these methods, regardless of whether there is a connection between them, they are physically NOESY (Nuclear Overhauser), which establishes correlations between nuclei close to each other effect spectroscopy) and ROESY (Rotating frame nuclear Overhauser effect spectroscopy).
Kütle Spektrumlarinin Alinmasi Elde edilen orijinal bilesiklere ait kütle spektrumlari, numunelerin asetonitril içerisindeki çözeltileri LCMS-IT-TOF (Shimadzu, Kyoto, Japonya) cihazina enjekte edilerek ve elektron sprey iyonizasyon (ESI) iyonlastirma teknigi kullanilarak negatif ve pozitif modda alinmistir. Taking Mass Spectra Mass spectra of the original compounds obtained, solutions are injected into the LCMS-IT-TOF (Shimadzu, Kyoto, Japan) instrument and in negative and positive mode using electron spray ionization (ESI) ionization technique has been taken.
N-(4-(benzo[d]oksazoI-Z-il)fenil)-2-(4-(2-(dimetilamino)etil)piperazin-1-il)asetamid Bilesik 3a, yöntem C'ye göre sentezlenmistir. Erime noktasi 162.9-163.7°C ve verim sonuçlari asagida verilmektedir. N-(4-(benzo[d]oxazoI-Z-yl)phenyl)-2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)acetamide Compound 3a was synthesized according to method C. Melting point 162.9-163.7°C and yield results are given below.
C=O gerilim bandi), , 1H-NMR (, 2.36-2.38 (2H, m, -CH2-), , s, piperazin), , 111.24 benzo[d]0ksazol C2), 169.38 (10, s, C=O). C=O tension band), , 1H-NMR (, 2.36-2.38 (2H, m, -CH2-), , p, piperazine), , 111.24 benzo[d]Oxazole C2), 169.38 (10, s, C=O).
N-(4-(benzo[d]oksazoI-Z-iI)feniI)-2-(4-(3-(dimetilamino)propil)piperazin-1-il)asetamid Bilesik 3b, yöntem C'ye göre sentezlenmistir. Erime noktasi 164.4-165.7°C ve verim %79”dur. N-(4-(benzo[d]oxazoI-Z-yl)phenyl)-2-(4-(3-(dimethylamino)propyl)piperazin-1-yl)acetamide Compound 3b was synthesized according to method C. Its melting point is 164.4-165.7°C and efficiency is 79%.
C=O gerilim bandi), , 1H-NMR (, 2.18 y, piperazin), , 7.74-7.79 benzo[d]0ksazol C2), 169.37 (10, s, C=O). C=O tension band), , 1H-NMR (, 2.18 y, piperazine), 7.74-7.79 benzo[d]Oxazole C2), 169.37 (10, s, C=O).
N-(4-(benzo[d]oksazoI-2-il)-2-metilfeniI)-2-(4-(2-(dimetilamino)etil)piperazin-1-il) asetamid (3c) Bilesik 3G, yöntem C'ye göre sentezlenmistir. Erime noktasi 55.4-58.9°C ve verim %78'dir. N-(4-(benzo[d]oxazoI-2-yl)-2-methylphenyl)-2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl) acetamide (3c) Compound 3G was synthesized according to method C. Its melting point is 55.4-58.9°C and the yield is 78%.
C=O gerilim bandi), , 1H-NMR (, 2.35-2.37 N-(4-(benzo[d]oksaz0l-2-il)-2-metiIfeniI)-2-(4-(3-(dimetiIamino)propil)piperazin-1-iI) asetamid (3d) C=O gerilim bandi), , 1H-NMR (, 2.19 N-(4-(benzo[d]oksazoI-2-iI)feniI)-2-(4-(2-(dimetilamino)etil)piperazin-1-il)asetamid Bilesik Se, yöntem C'ye göre sentezlenmistir. Erime noktasi 151.9-156.3°C ve verim %80'dir. C=O tension band), , 1H-NMR (, 2.35-2.37 N-(4-(benzo[d]oxaz01-2-yl)-2-methylphenyl)-2-(4-(3-(dimethylamino)propyl)piperazine-1-yl) acetamide (3d) C=O tension band), , 1H-NMR (, 2.19 N-(4-(benzo[d]oxazoI-2-yl)phenyl)-2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)acetamide Compound Se was synthesized according to method C. Its melting point is 151.9-156.3°C and yield is 80%.
C=O gerilim bandi), , 1H-NMR (, 2.35- 2-(4-(3-(dimetilamino)propiI)piperazin-1-iI)-N-(4-(5-metilbenzo[d]oksazoI-2-iI)fenil) asetamid (3f) verim %7Tdir. C=O tension band), , 1H-NMR (, 2.35- 2-(4-(3-(dimethylamino)propyl)piperazine-1-yl)-N-(4-(5-methylbenzo[d]oxazoI-2-yl)phenyl) acetamide (3f) efficiency is 7%.
C=O gerilim bandi), , 1H-NMR (, 2-(4-(2-(dimetilamino)etil)piperazin-1-il)-N-(2-metil-4- (5-metiIbenzo[d]oksazoI-2-iI) fenil)asetamid (Sg) Bilesik 3g, yöntem C”ye göre sentezlenmistir. Erime noktasi 53.8-56.9°C ve verim %79'dur. C=O tension band), , 1H-NMR (, 2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-N-(2-methyl-4-(5-methylbenzo[d]oxazoI-2-yl) phenyl)acetamide (Sg) Compound 3g was synthesized according to method C. The melting point is 53.8-56.9°C and the yield is 79%.
C=O gerilim bandi), , 1H-NMR (, 2.36 (3H, fenil Hs), 9.65 (1H, s, NH). benz0[d]0ksazol C2), 168.83 (1C, s, C=O). 2-(4-(3-(dimetiIamino)propil)piperazin-1-iI)-N-(2-metiI-4-(5-metiIbenzo[d]oksazoI-2- il)fenil)asetamid (3h) /EN/î.- ::1 U :Sa Bilesik 3h, yöntem C'ye göre sentezlenmistir. Erime noktasi 64.7-66.8°C ve verim %77'dir. C=O tension band), , 1H-NMR (, 2.36 (3H, phenyl Hs), 9.65 (1H, s, NH). benzO[d]Oxazole C2), 168.83 (1C, s, C=O). 2-(4-(3-(dimethylamino)propyl)piperazine-1-yl)-N-(2-methyl-4-(5-methylbenzo[d]oxazoI-2-) yl)phenyl)acetamide (3h) /EN/î.- ::1 U :Sa Compound 3h was synthesized according to method C. Its melting point is 64.7-66.8°C and the yield is 77%.
C=O gerilim bandi), , 1H-NMR (, 2.17 s, - CH2), , 110.59 (1C, s, benzo[d]0ksazol benzo[cl]0ksazol C2), 168.84 (10, s, C=O). 2-(4-(2-(dimetiIamino)etil)piperazin-1-iI)-N-(4-(5-florobenzo[d]oksazoI-2-il)fenil) asetamid (3i) Bilesik 3i, yöntem C'ye göre sentezlenmistir. Erime noktasi 150.7-152.7°C ve verim %81idir. C=O tension band), , 1H-NMR (, 2.17 s, -CH2), , 110.59 (1C, s, benzo[d]Oxazole) benzo[cl]Oxazole C2), 168.84 (10, s, C=O). 2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-N-(4-(5-fluorobenzo[d]oxazoI-2-yl)phenyl) acetamide (3i) Compound 3i was synthesized according to method C. Its melting point is 150.7-152.7°C and efficiency is 81%.
C=O gerilim bandi), , 1H-NMR (, 2.35238 (2H, m, -CH2-), , s, piperazin), , 106.41 benzo[d]0ksazol C7), , 119.97 (20, fenil C1), , 147.13 (1C, s, s, benz0[d]0ksazol C2), 169.44 (1C, s, C=O). 2-(4-(3-(dimetilamino)propil)piperazin-1-iI)-N-(4-(5-florobenzo[d]oksazoI-2-il)fenil) asetamid (3j) 1; 1] `I 7x2/ . C=O tension band), , 1H-NMR (, 2.35238 (2H, m, -CH2-), , p, piperazine), , 106.41 benzo[d]Oxazole C7), 119.97 (20, phenyl C1), 147.13 (1C, s, s, benz0[d]Oxazole C2), 169.44 (1C, s, C=O). 2-(4-(3-(dimethylamino)propyl)piperazin-1-yl)-N-(4-(5-fluorobenzo[d]oxazoI-2-yl)phenyl) acetamide (3j) one; 1] `I 7x2/ .
Bilesik 3j, yöntem C'ye göre sentezlenmistir. Erime noktasi 161.2-163.0°C ve verim %79'dur. Compound 3j was synthesized according to method C. Its melting point is 161.2-163.0°C and yield is 79%.
C=O gerilim bandi), , 1H-NMR (, 2.18 benzo[d]0ksazol C7a), , 164.53 (10, s, benzo[d]0ksazol C2), 169.42 (1C, s, C=O). 2-(4-(2-(dimetiIamino)etiI)piperazin-I-iI)-N-(4-(5-florobenzo[d]oksazoI-Z-iI)-2-metil fenil)asetamid (3k) Bilesik 3k, yöntem Clye göre sentezlenmistir. Erime noktasi 122.8-124.7°C ve verim %787dir. C=O tension band), , 1H-NMR (, 2.18 benzo[d]oxazole C7a), , 164.53 (10, s, benzo[d]Oxazole C2), 169.42 (1C, s, C=O). 2-(4-(2-(dimethylamino)ethyl)piperazine-I-yl)-N-(4-(5-fluorobenzo[d]oxazoI-Z-yl)-2-methyl phenyl)acetamide (3k) Compound 3k was synthesized according to method Cl. Its melting point is 122.8-124.7°C and efficiency is 787%.
C=O gerilim bandi), , 1H-NMR (, 2.37 (3H. 2-(4-(3-(dimetiIamino)propil)piperazin-1-il)-N-(4-(5-florobenzo[d]oksazoI-2-iI)-2- metilfenil)asetamid (3I) Bilesik 3I, yöntem C'ye göre sentezlenmistir. Erime noktasi 131.3-133.1°C ve verim %79'dur. C=O tension band), , 1H-NMR (, 2.37 (3H. 2-(4-(3-(dimethylamino)propyl)piperazin-1-yl)-N-(4-(5-fluorobenzo[d]oxazoI-2-yl)-2- methylphenyl)acetamide (3I) Compound 3I was synthesized according to method C. Its melting point is 131.3-133.1°C and yield is 79%.
C=O gerilim bandi), , 1H-NMR (, 2.18 piperazin), , 7.25 (1H, td, J1=9.30 Hz, N-(4-(5-klorobenzo[d]oksazoI-2-iI)feniI)-2-(4-(2-(dimetiIamino)etil)piperazin-1-iI) asetamid (3m) Bilesik 3m, yöntem C'ye göre sentezlenmistir. Erime noktasi 153.3-155.9°C ve verim %80'dir. C=O tension band), , 1H-NMR (, 2.18 piperazine), , 7.25 (1H, td, J1=9.30 Hz, N-(4-(5-chlorobenzo[d]oxazoI-2-yl)phenyl)-2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl) acetamide (3m) Compound 3m was synthesized according to method C. Its melting point is 153.3-155.9°C and yield is 80%.
C=O gerilim bandi), , 1H-NMR (, 2.35-2.37 (2H, m, -CH2-), , (2C, s, piperazin), , benzo[d]0ksazol C2), 169.47 (10, s, C=O). C=O tension band), , 1H-NMR (, 2.35-2.37 (2H, m, -CH2-), , (2C, s, piperazine), , benzo[d]Oxazole C2), 169.47 (10, s, C=O).
N-(4-(5-klorobenzo[d]oksazoI-2-il) fenil)-2-(4-(3-(dimetiIamino)propil)piperazin-1-il) asetamid (3n) Bilesik 3n, yöntem C'ye göre sentezlenmistir. Erime noktasi 158.7-160.9°C ve verim %77'dir. N-(4-(5-chlorobenzo[d]oxazoI-2-yl)phenyl)-2-(4-(3-(dimethylamino)propyl)piperazin-1-yl) acetamide (3n) Compound 3n was synthesized according to method C. Its melting point is 158.7-160.9°C and yield is 77%.
C=O gerilim bandi), , 1H-NMR (, 2.16 H2,H5), 10.10 (1H, s, NH). benzo[d]0ksazol C2), 169.44 (1C, s, C=O). C=O tension band), , 1H-NMR (, 2.16 H2,H5), 10.10 (1H, s, NH). benzo[d]Oxazole C2), 169.44 (1C, s, C=O).
N-(4-(5-klorobenzo[d]oksazoI-2-iI)-2-metiIfeniI)-2-(4-(2-(dimetiIamino)etil)piperazin- 1-il)asetamid (30) C=O gerilim bandi), , 1H-NMR (, 234-236 H5), 9.68 (1H, s, NH). N-(4-(5-chlorobenzo[d]oxazoI-2-yl)-2-methylphenyl)-2-(4-(2-(dimethylamino)ethyl)piperazine- 1-yl)acetamide (30) C=O tension band), , 1H-NMR (, 234-236 H5), 9.68 (1H, s, NH).
N-(4-(5-klorobenzo[d]oksazoI-2-iI)-2-metilfeniI)-2-(4-(3-(dimetilamino)propiI) piperazin-1-il)asetamid (3p) ..2 ., / Bilesik Sp, yöntem C'ye göre sentezlenmistir. Erime noktasi 131.8-133.0°C ve verim %TT'dir. N-(4-(5-chlorobenzo[d]oxazoI-2-yl)-2-methylphenyl)-2-(4-(3-(dimethylamino)propyl) piperazin-1-yl)acetamide (3p) ..2 ., / Compound Sp was synthesized according to method C. Its melting point is 131.8-133.0°C and yield is %TT.
C=O gerilim bandi), , 1H-NMR (, 2.19 piperazin), , 7.44 (1H, dd, J1=2.13 Hz, benzo[d]oksazol C2), 168.93 (10, s, C=O). C=O tension band), , 1H-NMR (, 2.19 piperazine), , 7.44 (1H, dd, J1=2.13 Hz, benzo[d]oxazole C2), 168.93 (10, s, C=O).
NMR analizleri Bulusta, sentezi gerçeklestirilen bilesikler arasinda en yüksek aktiviteye sahip olan Bilesik 3n alinarak 2 boyutlu ileri NMR çalismalari (HSQC, NOESY, HMBC) gerçeklestirilmistir (Sekil 65,66). HSQC'den elde edilen veriler isiginda protonlari 2.07 ppm'de pik veren dimetil grubu karbonlarinin 45.58 ppm'de, propil grubunun ikinci konumunun protonlari 1.51 ppm, karbonunun 24.94 ppm'de, dmetil amino grubuna komsu CH2 hidrojenlerinin 2.16 ppm, karbonunun 57.75 ppm'de, piperazine ait metilen gruplarinin propil grubuna ppm”de oldugu görülmüstür. Yine HSQC verilerinden yararlanilarak, proton NMR'da eslesme degerlerinde konumlari tespit edilmis olan benzoksazol 4., 6., ve 7. konum ve HSQCverileri dikkate alinarak 1,4-disübstitüefenil halkasi üzerindeki 7.87 ppm ve 119.95 ppm degerlerine sahip CH grubunun amit grubuna yakin oldugu, 8.12 ppm ve 128.84 ppm degerlerine sahip CH grubunun benzoksazol grubuna yakin oldugu tespit edilmistir. HMBC analizi ile karbonil karbonunun 169.44 ppm'de, sirasiyla benzoksazol anlasilmistir. Yine HMBC sonuçlari dikkate alinarak disübstitüe fenil halkasi üzerindeki görülmüstür. NMR analyzes In the invention, the Compound with the highest activity among the synthesized compounds. 2D advanced NMR studies (HSQC, NOESY, HMBC) were performed by taking 3n. (Fig. 65.66). In the light of data from HSQC, protons peak at 2.07 ppm. Protons of the second position of the propyl group at 45.58 ppm of the dimethyl group carbons 1.51 ppm, at 24.94 ppm of carbon, CH2 hydrogens adjacent to the dmethyl amino group 2.16 ppm, at 57.75 ppm of carbon, methylene groups of piperazine to the propyl group It has been seen that it is in ppm. Again, using HSQC data, proton NMR 4th, 6th, and 7th positions of benzoxazole, whose positions were determined in the match values and 7.87 ppm on the 1,4-disubstitutedphenyl ring, taking into account HSQC data, and The CH group with 119.95 ppm values is close to the amide group, 8.12 ppm and It was determined that the CH group with 128.84 ppm values was close to the benzoxazole group. has been made. HMBC analysis of carbonyl carbon at 169.44 ppm, benzoxazole, respectively. it is understood. Again, taking into account the HMBC results, on the disubstituted phenyl ring has been seen.
Antikanser Aktivite Çalismalari Bulusa konu bilesiklerin anti-kanser aktivitesinin arastirilmasinda HT-29 (insan kolorektal adenokarsinoma hücre dizisi), MCF-7 (insan meme adenokarsinoma hücre dizisi), HepG2 (insan karaciger karsinoma hücre dizisi), A549 (insan akciger karsinoma hücre dizisi) ve OS (siçan glioma hücre dizisi) hücre dizileri kullanilmistir. Anti-kanser aktivitenin selektivitesi NIH3T3 (fare embriyo fibroblast hücre dizisi) hücre dizilerinde degerlendirilmistir. Besiyeri olarak fetal calf serum ve 100 IU/mL penisilin ve 100 mg/mL streptomisin ilave edilmis MCF-7, HepG2 ve C6 hücre dizileri için RPMI 1640, HT-29 ve NIH kullanilmistir. Anticancer Activity Studies In the investigation of the anti-cancer activity of the subject compounds, HT-29 (human colorectal adenocarcinoma cell line), MCF-7 (human breast adenocarcinoma cell line), HepG2 (human liver carcinoma cell line), A549 (human lung carcinoma cell line), and OS (rat glioma cell line) cell lines were used. Anti-cancer activity selectivity in NIH3T3 (mouse embryo fibroblast cell line) cell lines has been evaluated. As medium, fetal calf serum and 100 IU/mL penicillin and 100 mg/mL For MCF-7, HepG2 and C6 cell lines supplemented with streptomycin, RPMI 1640, HT-29 and NIH is used.
Sentezlenen bilesiklerin anti-kanser etkinliklerinin kiyaslanabilmesi amaci ile günümüzde kanser tedavisinde rutin olarak kullanilan doksorubisin tüm aktivite çalismalarinda kullanilmistir. Today, in order to compare the anti-cancer activities of the synthesized compounds, In all activity studies of doxorubicin, which is routinely used in cancer treatment, used.
Bilesiklerin A549, C6, HepG2, HT29, MCFT ve NIH3T3 hücre dizilerine karsi belirlenen C6, HepG2, HT29, MCF? hücre hatlarina karsi antikanser etki göstermektedir. degerleri (ulVl) BILESIK A549 C6 HepG2 HT29 MCF? N IH3T3 Tablo 4. Bilesiklerin A549, CG, HepG2, HT-29 ve MCF-7 hücre dizilerine ait selektivite indeksleri BILESIK A549 CG HepGZ HT29 MCF7 MTT yöntemi ile bilesiklerin sitotoksik etkilerinin belirlenmesi Tetrazolium tuzlari olan 2,3-bis[2-metoksi-4-nitro-5-sülfofenil]-2H-tetrazolum-5- karboksianilit tuzu (XTT) ve 3-[, canli hücrelerdeki metabolik aktivitenin ölçümünde kullanilmaktadir. Tetrazolium tuzlari, metabolizma ve solunum zinciri intakt hücrelerde mitokondriyal süksinat dehidrogenaz enzimi ile formazana dönüsmektedir. Mitokondriyal süksinat dehidrogenaz sari renkli tetrazolium tuzunu elektron kenetli reaktif varliginda çözünür turuncu renkli formazana dönüstürmektedir [1]. Selektivite indeksi, bilesiklerin kanser hücresine karsi belirlenen Bilesiklerin saglikli hücreye zarar verecegi konsantrasyondan 10 kat daha düsük konsantrasyonda kanser hücresi üzerinde sitotoksik etki göstermesi yari etkilerin görülmemesini saglamaktadir. Dolayisiyla bulusa konu anti-kanser etkili bilesikler, kanser hücrelerine seçici olup saglikli hücrelere en az düzeyde zarar vermektedir. MTT sitotoksisite testi ile bulusa konu anti-kanser etkili bilesiklerin selektivite indeksleri 10'un üzerindedir. Determination of compounds against cell lines A549, C6, HepG2, HT29, MCFT and NIH3T3 C6, HepG2, HT29, MCF? It has an anticancer effect against cell lines. values (ulVl) COMPOUND A549 C6 HepG2 HT29 MCF? N IH3T3 Table 4. Selectivity of compounds for A549, CG, HepG2, HT-29 and MCF-7 cell lines indexes COMPOUND A549 CG HepGZ HT29 MCF7 Determination of cytotoxic effects of compounds by MTT method Tetrazolium salts of 2,3-bis[2-methoxy-4-nitro-5-sulphophenyl]-2H-tetrazolum-5- carboxyanide salt (XTT) and 3-[, It is used to measure metabolic activity in living cells. Tetrazolium salts, metabolism and respiratory chain mitochondrial succinate dehydrogenase in intact cells It is converted to formazan by the enzyme. Mitochondrial succinate dehydrogenase yellow colored Tetrazolium salt dissolves in the presence of electron-chelated reagent to orange colored formazan transforms [1]. The selectivity index of the compounds determined against cancer cell 10 times lower than the concentration at which the compounds will damage the healthy cell half-effects show cytotoxic effects on cancer cells at high concentrations. makes it invisible. Therefore, compounds with anti-cancer effects, which are the subject of the invention, It is selective to cells and causes minimal damage to healthy cells. MTT The selectivity indices of the anti-cancer compounds, which were the subject of the cytotoxicity test, were above 10. is on it.
BrdU proliferasyon yöntemi ile bilesiklerin antiproliferatif etkilerinin belirlenmesi -Bromo-2'-deoksiüridin (BrdU), replike olan hücrelerin DNA*sina girdiginde replikasyon esnasinda timidinin yerini alarak DNA*nin yapisina katilmakta ve sonrasinda kendisi için spesifik monoklonal antikorlarla (anti-BrdU antikoru) tespit edilebilmektedir. Hücre içindeki BrdU miktari, çogalan hücre miktari ile orantilidir ve fikse olan hücrelerde direkt ELISA ile hesaplanabilmektedir [2]. Determination of antiproliferative effects of compounds by BrdU proliferation method Replication occurs when bromo-2'-deoxyuridine (BrdU) enters the DNA of replicating cells It participates in the structure of DNA by taking the place of thymidine during and then for itself. It can be detected with specific monoclonal antibodies (anti-BrdU antibody). inside the cell The amount of BrdU is proportional to the amount of proliferating cells and is determined by direct ELISA in fixed cells. can be calculated [2].
MTT sitotoksisite testi ile selektivite indeksleri 10'un üzerinde hesaplanan bulus konusu anti-kanser etkili bilesiklerin ve pozitif kontrol olarak doksorubisinin HT29, MCF?, HepG2 ve CG hücre dizilerinde BrdU testi ile antiproliferatif etkileri belirlenmistir. The subject of the invention, whose selectivity indexes were calculated over 10 by the MTT cytotoxicity test. anti-cancer compounds and doxorubicin as positive control HT29, MCF?, HepG2 and its antiproliferative effects were determined by BrdU test in CG and CG cell lines.
BrdU proliferasyon testi sonuçlarina göre; HT29 hücre dizilerinde Bilesik 3e ve 3n ile doksorubisinin antiproliferatif etkinlikleri doza bagli olarak artmaktadir. Ayrica Bilesik 3e'nin bu hücre dizilerinde %DNA sentez inhibisyon degerleri zamana bagli olarak da artmaktadir. MCFT hücre dizisinde BrdU proliferasyon testi sonuçlarina göre Bilesik 3n ile doksorubisinin antiproliferatif etkinlikleri doza bagli olarak artmaktadir. BrdU proliferasyon testi sonuçlarina göre HepG2 hücre dizisinde Bilesik 3d, Bilesik 3m, Bilesik 3n ile doksorubisinin antiproliferatif etkinliklerinin doza bagli olarak arttigi görülmektedir. Ayrica Bilesik 3d ve ?m ile doksorubisinin bu hücre dizilerinde %DNA sentez inhibisyon degerleri zamana bagli olarak da arttigi görülmektedir. Bilesik 3m için ise IC50/2, IC50 ve 2*IC50 konsantrasyonlarinda 24 saatlik inkübasyon süresinde doksorubisine kiyasla daha yüksek %DNA sentez inhibisyon degerleri elde edilmektedir. CB hücre dizisinde BrdU proliferasyon testi sonuçlarina göre Bilesik 3e, Bilesik 3f, Bilesik 3i, Bilesik 3m, Bilesik 3n ile doksorubisinin antiproliferatif etkinliklerinin doza bagli olarak arttigi görülmektedir. According to the results of BrdU proliferation test; With Compounds 3e and 3n in HT29 cell lines The antiproliferative activities of doxorubicin increase in a dose-dependent manner. Also Compound %DNA synthesis inhibition values in these cell lines of 3e also depend on time. increasing. Compound 3n based on BrdU proliferation test results in MCFT cell line The antiproliferative activities of doxorubicin increase in a dose-dependent manner. BrdU proliferation with Compound 3d, Compound 3m, Compound 3n in HepG2 cell line It has been observed that the antiproliferative activities of doxorubicin increase in a dose-dependent manner. Moreover % DNA synthesis inhibition values of compound 3d and ?m and doxorubicin in these cell lines It also appears to increase with time. For the compound 3m, IC50/2, IC50 and 2*IC50 concentrations were higher compared to doxorubicin at the 24-hour incubation period. high % DNA synthesis inhibition values are obtained. BrdU in the CB cell line Compound 3e, Compound 3f, Compound 3i, Compound 3m, Compound 3n according to proliferation test results It has been observed that the antiproliferative activities of doxorubicin and doxorubicin increase in a dose-dependent manner.
Ayrica Bilesik Se, Bilesik 3f, Bilesik 3i, Bilesik Sin ve doksorubisinin bu hücre dizilerinde Anneksin VIPI yöntemi ile bilesiklerin apoptotik etkilerinin belirlenmesi Hücre apoptoz uyarisi alirsa hücre zarinin sitoplazmik yüzeyindeki bulunan fosfatidilserin (PS) hücre zarinin dis lipid tabakasina geçmektedir. Bu yer degistirme apoptozun erken döneminde gerçeklesmektedir. Anneksin V, hücrenin dis yüzeyine transloke olan fosfatidilserine baglanabilen bir protein oldugu için floresan bir madde (örn. FITC) ile isaretlenerek apoptotik hücre görünür hale getirilebilir. Bu baglanma orani da akis sitometri cihazi ile ölçülebilmektedir. Nekrotik hücrelerde de anneksin baglanmasi görülebilecegi için ayrica vital bir boya olan propidyum iyodür (Pl) boyamasi da yapilmaktadir. Canli hücrelerin zarlari saglam oldugu için Pl boyasi ile boyanmamaktadir. In addition, Compound Se, Compound 3f, Compound 3i, Compound Sin and doxorubicin were found in these cell lines. Determination of apoptotic effects of compounds by annexin VIPI method If the cell is stimulated by apoptosis, phosphatidylserine on the cytoplasmic surface of the cell membrane (PS) penetrates into the outer lipid layer of the cell membrane. This displacement results in early apoptosis. takes place during the period. Annexin V translocates to the outer surface of the cell. with a fluorescent substance (eg FITC) as it is a protein that can bind to phosphatidylserine. By marking the apoptotic cell can be made visible. This bonding rate also can be measured with a cytometer. Annexin binding in necrotic cells Propidium iodide (Pl) staining, which is a vital dye, can also be seen. is being done. Since the membranes of living cells are intact, they are not stained with Pl dye.
Canli hücreler FlTC Aneksin V (-) / PI (-)i erken apoptotik hücreler FlTC Aneksin V (+) / PI (-) ve geç apoptotik veya nekrotik hücreler FITC (+) / PI (+) olarak ayirt edilmektedir pozitif kontrollerin Anneksin V/Pl yöntemi ile apoptotik etkileri belirlenmistir. HT29 hücre dizisinde Bilesik 3e, Bilesik ?m ile doksorubisine ait akis sitometrik analiz diyagrami Sekil 67'de gösterilmektedir. Buna göre IC50 konsantrasyonlarinda apoptotik hücre yüzdesi konsantrasyonlarinda ve 24 saatlik inkübasyon süresinde Bilesik 3i ve Bilesik 3n'nin HT29 hücre dizisinde doksorubisine oranla daha fazla apoptotik hücre ölümünü indükledigi görülmektedir. MCFT hücre dizisinde Bilesik 3n ile doksorubisine ait akis sitometrik analiz diyagrami Sekil 68ide gösterilmektedir. Buna göre IC50 konsantrasyonlarinda apoptotik hücre yüzdesi doksorubisin için %50.13 ve Bilesik 3n için %701 olarak hesaplanmistir. Viable cells FlTC Anexin V (-) / PI (-)i early apoptotic cells FlTC Anexin V (+) / PI (-) and late apoptotic or necrotic cells are distinguished as FITC (+) / PI (+) Apoptotic effects of positive controls were determined by Annexin V/Pl method. HT29 cell Flow cytometric analysis diagram of Compound 3e, Compound ?m and doxorubicin in the sequence Figure It is shown at 67. Accordingly, the percentage of apoptotic cells at IC50 concentrations HT29 concentrations of Compound 3i and Compound 3n at 24 hour incubation time. It induced more apoptotic cell death than doxorubicin in the cell line. is seen. Flow cytometric analysis of Compound 3n and doxorubicin in MCFT cell line The diagram is shown in Figure 68. Accordingly, at IC50 concentrations, apoptotic cell percentage was calculated as 50.13% for doxorubicin and 701% for Compound 3n.
Dolayisiyla ICso konsantrasyonunda ve 24 saatlik inkübasyon süresinde Bilesik 3n'nin lVICFT hücre dizisinde doksorubisine oranla daha fazla apoptotik hücre ölümünü indükledigi görülmektedir. HepG2 hücre dizisinde Bilesik 3d, Bilesik ?m ve Bilesik 3n ile doksorubisine ait akis sitometrik analiz diyagrami Sekil 69”da gösterilmektedir. Buna göre dizisinde doksorubisine oranla daha fazla apoptotik hücre ölümünü indükledigi görülmektedir. CG hücre dizisinde Bilesik 3e, Bilesik 3f, Bilesik 3i, Bilesik 3m ve Bilesik 3n ile doksorubisine ait akis sitometrik analiz diyagrami Sekil TO'te gösterilmektedir. Buna göre ICso konsantrasyonlarinda apoptotik hücre yüzdesi doksorubisin için %357, Bilesik için %13.6'dir. Dolayisiyla ICso konsantrasyonlarinda ve 24 saatlik inkübasyon süresinde Bilesik 3i'nin CG hücre dizisinde doksorubisine oranla daha fazla apoptotik hücre ölümünü CYP1A1 enzimi aktif bölge ile etkilesim analizleri Bulus konusu anti-kanser etkili bilesikler arasinda en yüksek anti-kanser aktivite potansiyeline sahip olan Bilesik 3n'nin ve Phortress'in CYP1A1 enzim aktif bölgesindeki baglanma ve etkilesim noktalarini belirlemek amaciyla yapi temelli in silico docking metodu uygulanmis ve CYP1A1 kristal yapisi [5] üzerinde protein-Iigand etkilesim analizi gerçeklestirilmistir. Referans bilesik olarak seçilen Phortress'in CYP1A1 enzimi ile olan docking çalismasi sonucunda elde dilen iki ve üç boyutlu görüntüleri incelendiginde bu bilesigin enzim aktif bölgesine uygun bir sekilde baglandigi görülmektedir. 3n kodlu bilesigin CYP1A1 ile yapilan docking çalismalari incelendiginde Phortress ile çok benzer bir sekilde enzim aktif bölgesine yerlestigi görülmektedir. Phortress, CYP1A1 enzimi ile hidroliz yoluyla biyotransformasyona ugrayarak PM1 ve bu bilesigin flor atomu kaybetmis hali olan PM2 metabolitlerine dönüsmektedir. Olusan bu metabolitler, aril hidrokarbon reseptörü (AHR) baglanarak kompleks olusturmaktadir. Yapilan biyotransformasyon çalismalari sonucunda; Bilesik 3n metabolitleri (3nM1 ve 3niVI2) ile Phortress`in aktif metabolitlerinin yapisal benzerlik gösterdigi görülmektedir. Therefore, at the IC 50 concentration and the 24 hour incubation period, Compound 3n More apoptotic cell death than doxorubicin in lVICFT cell line appears to be induced. With Compound 3d, Compound ?m and Compound 3n in HepG2 cell line The flow cytometric analysis diagram of doxorubicin is shown in Figure 69. According to this induced more apoptotic cell death than doxorubicin is seen. Compound 3e, Compound 3f, Compound 3i, Compound 3m, and Compound 3n in the CG cell line The flow cytometric analysis diagram of and doxorubicin is shown in Figure TO. This Percentage of apoptotic cells at IC50 concentrations compared to 357% for doxorubicin, Compound for 13.6%. Therefore, at IC50 concentrations and a 24-hour incubation period Compound 3i induced more apoptotic cell death than doxorubicin in CG cell line. Interaction analyzes with CYP1A1 enzyme active site The highest anti-cancer activity among the compounds with anti-cancer effect of the invention. Compound 3n and Phortress in the CYP1A1 enzyme active site structure-based in silico docking to determine attachment and interaction points method was applied and protein-Iigand interaction analysis on CYP1A1 crystal structure [5] has been carried out. with the CYP1A1 enzyme of Phortress selected as the reference compound. When the two- and three-dimensional images obtained as a result of the docking work are examined, this The compound appears to bind appropriately to the enzyme active site. 3n coded When the docking studies of the compound with CYP1A1 are examined, it is very similar to Phortress. It is seen that the enzyme is somehow located in the active site. Phortress with the enzyme CYP1A1 PM1 and the fluorine atom of this compound are lost by being biotransformed by hydrolysis. It is converted into PM2 metabolites, These metabolites are aryl hydrocarbon receptor (AHR) binds to form a complex. Biotransformation done as a result of their work; The compound 3n metabolites (3nM1 and 3niVI2) and Phortress active It is seen that the metabolites show structural similarity.
Bulusa konu anti-kanser etkili bilesiklerin yapi-etki iliskileri Bulusta sentezi gerçeklestirilen Bilesik 33-3p'nin kimyasal yapilarindaki farkliliklar üç farkli bölgede toplanmaktadir. Birinci bölge, 5. konumundan metili flor ve klor sübstitüe edilen ya da nonsübstitüe halde olan benzoksazol halkasidir. Ikinci bölge benzoksazol halkasinin 2. konumunda bulunan fenil yapisidir. Fenil yapisi, bulusa konu bazi bilesikler 3. konumunda metil sübstitenti tasirken, bazi bilesiklerde bu konumda sübstitüent bulunmamaktadir. Üçüncü ve son bölge ise piperazin halkasidir. Piperazin halkasi 4. konumunda, 2-dimetilaminoetil veya 3-dimetilaminopr0pil yan Zincirlerini tasimaktadir. Structure-effect relationships of the anti-cancer effective compounds of the invention The differences in the chemical structures of Compound 33-3p synthesized in the invention can be found in three different collected in the region. The first region, the methyl from the 5th position is substituted by fluorine and chlorine or the nonsubstituted benzoxazole ring. second zone benzoxazole It is the phenyl structure in the 2nd position of the ring. Phenyl structure, some compounds of the invention While it carries the methyl substituent in the 3rd position, in some compounds the substituent in this position does not exist. The third and final region is the piperazine ring. Piperazine ring 4. In its position, it carries 2-dimethylaminoethyl or 3-dimethylaminopropyl side Chains.
Ikinci Bölge R3: H1 CH3 Birinci Bölge R1: H, C143, FH Cl ÜÇÜÜCU Bölge R3: C Sentez bilesiklerinin A549 hücre hatti üzerindeki ICso degerleri karsilastirildiginda, birinci bölgede metil sübstitüenti tasiyan 3e (IC50= ile klor sübstitüenti tasiyan 3m (ICso= 3.66 plVl) ve 3n (IC50= 3.66 plVI) bilesikleri sitotoksik aktivite açisindan ön plandadir. Her üç bilesikte ikinci bölgelerinde non sübstitüe haldedir. Üçüncü bölgelerinde ise 3e ve 3m bilesikleri 2-dimetilaminoetil yan zincirine sahipken, 3n bilesigi 3-dimetilaminopropil grubu tasimaktadir. Second Zone R3: H1 CH3 First Zone R1: H, C143, FH Cl THIRD Zone R3: C When the IC 50 values of the synthesis compounds on the A549 cell line are compared, the first 3e with methyl substituent in the region (IC50= with chlorine substituent 3m (IC50= 3.66 plVl) and 3n (IC50= 3.66 plVI) compounds are prominent in terms of cytotoxic activity. Each three compounds are non-substituted in their second region. In the third zones, 3e and 3m compounds have 2-dimethylaminoethyl side chain, while compound 3n has 3-dimethylaminopropyl group carries.
Sentez bilesiklerinin C6 hücre hatti üzerindeki IC50 degerleri karsilastirildiginda, birinci bölgede metil sübstitüenti tasiyan 3e (IC50= ile klor sübstitüenti tasiyan 3m (lC50=1.O3 pM) ve 3n (ICso= bilesikleri sitotoksik aktivite açisindan ön plandadir. Her dört bilesikte ikinci bölgelerinde non sübstitüe haldedir. 3. bölgelerinde ise 3e ve 3m bilesikleri 2-dimetilaminoetil yan zincirine sahipkeni 3f ve 3ri bilesikleri 3-dimetilaminopr0pil grubu tasimaktadir. When the IC50 values of the synthesis compounds on the C6 cell line are compared, the first 3e carrying the methyl substituent in the region (IC50 = with chlorine Cytotoxic activity of 3m (IC50=1.O3 pM) and 3n (IC50= compounds carrying the substituent in the foreground. All four compounds are non-substituted in their second region. 3. In regions 3e and 3m compounds have 2-dimethylaminoethyl side chains, while 3f and 3ri The compounds carry the 3-dimethylaminopropyl group.
Sentez bilesiklerinin HepG2 hücre hatti üzerindeki IC50 degerleri karsilastirildiginda, birinci bölgede metil sübstitüenti tasiyan 3e (ICso= ile klor sübstitüenti tasiyan 3m (IC50= bilesikleri sitotoksik aktivite açisindan ön plandadir. Her üç bilesikte ikinci bölgelerinde non sübstitüe haldedir. Üçüncü bölgelerinde ise Be ve 3m bilesikleri 2-dimetilamin0etil yan zincirine sahipken, 3n bilesigi 3- dimetilaminopropil grubu tasimaktadir. When the IC50 values of the synthesis compounds on the HepG2 cell line are compared, 3e carrying the methyl substituent in the first region (with IC 50 = chlorine substituent 3m (IC50= compounds precursors in terms of cytotoxic activity) is in the background. All three compounds are non-substituted in their second region. In their third district On the other hand, Be and 3m compounds have 2-dimethylaminoethyl side chains, while 3n compounds have 3-dimethylaminoethyl side chains. It carries a dimethylaminopropyl group.
Sentez bilesiklerinin HT29 hücre hatti üzerindeki IC50 degerleri karsilastirildiginda, birinci bölgede metil sübstitüenti tasiyan 3e (le, flor sübstitüenti tasiyan 3j (ICso= ve Sn (ICso=O.91 uM) bilesikleri sitotoksik aktivite açisindan ön plandadir. Her alti bilesikte ikinci bölgelerinde non sübstitüe haldedir. 3. bölgelerinde ise 3e ve 3m bilesikleri 2- dimetilaminoetil yan zincirine sahipken, 3f, Sn ve 3j bilesikleri 3-dimetilaminopropil grubu tasimaktadir. When the IC50 values of the synthesis compounds on the HT29 cell line are compared, the first 3e carrying the methyl substituent in the region (le, fluorine substituent carrying 3j (IC 50 = and Sn (IC 50 = O.91) µM) compounds are at the forefront in terms of cytotoxic activity. Second in every six compounds regions are non-substituted. In regions 3, 3e and 3m compounds 2- Compounds 3f, Sn and 3j have a dimethylaminoethyl side chain, while the 3-dimethylaminopropyl group carries.
Sentez bilesiklerinin MCF? hücre hatti üzerindeki IC50 degerleri karsilastirildiginda, birinci bölgede klor sübstitüenti tasiyan 3m (IC50= bilesikleri sitotoksik aktivite açisindan ön plandadir. 3m ve Sn bilesikleri ikinci bölgelerinde non sübstitüe haldedir. 3. bölgelerinde ise 3m bilesigi 2-dimetilaminoetil yan zincirine sahipken, 3n bilesigi 3-dimetilaminopropil grubu tasimaktadir. MCF of synthesis compounds? When the IC50 values on the cell line are compared, the first 3m containing chlorine substituent in the region (IC50= compounds It is in the foreground in terms of cytotoxic activity. 3m and Sn compounds in their second region is substituted. In their 3rd region, the 3m compound is attached to the 2-dimethylaminoethyl side chain. while the 3n compound carries a 3-dimethylaminopropyl group.
Sentezlenen bilesiklerin A549, C6, HepGZ, HT29 ve MCFT hücre hatlarina karsi |C50 degerleri birlikte degerlendirildiginde 3m ve 3n kodlu türevler ön plana çikmaktadir. Her iki bilesiginde birinci bölgede klor sübstitüenti tasimasi, bu sübstitüentin genel antikanser etki profiline olumlu katki sagladigini göstermektedir. Yine her iki bilesiginde ikinci bölgede metil sübstitüenti tasimamasi bu sübstientin aktivite için elzem olmadigini göstermektedir. Üçüncü bölge açisindan kiyaslandiginda, 3m kodlu bilesik 2-dimetilaminoetil yan zincirine sahipken, 3n bilesigi 3-dimetilaminopr0pil grubu tasimaktadir. Bu durum piperazin halkasinin 4. konumundan dimetilaminoalkil sübstitüsyonunun aktivitede hidroksietil sübstitüsyonuna göre daha fazla artisa neden oldugunu göstermektedir. Iki türev aktiviteleri açisidnan kendi aralarinda kiyaslandiginda alkil grubunun uzamasinin sitotoksik etkiyi arttigi görülmektedir. Against A549, C6, HepGZ, HT29 and MCFT cell lines of synthesized compounds |C50 When their values are evaluated together, 3m and 3n coded derivatives come to the fore. Each chlorine substituent transport in the first region in the two compounds, this substituent's general anticancer shows that it contributes positively to the effect profile. Again, in the second region in both compounds The absence of a methyl substituent indicates that this substituent is not essential for activity. Compared to the third region, the 3m-coded compound has a 2-dimethylaminoethyl side chain. while the 3n compound carries the 3-dimethylaminopropyl group. This is the case of piperazine. The dimethylaminoalkyl substitution from the 4th position of the ring is hydroxyethyl in activity. shows that it causes more increase than its substitution. two derivatives elongation of the alkyl group compared to each other in terms of their activities. appears to increase the cytotoxic effect.
Bulusta sentezlenen benzoksazol türevi bilesikler (Bilesik 3a-3p) kanser tedavisinde kullanima uygundur. Dolayisiyla. bulus konusu bilesiklerden (Bilesik 33-3p) en az birini içeren bir ilaç; meme, kolon, karaciger, akciger ve beyin kanseri tedavilerinde endikedir.The benzoxazole derivative compounds (Compound 3a-3p) synthesized in the invention are used in the treatment of cancer. it is suitable for use. Therefore. at least one of the subject compounds (Compound 33-3p) a drug containing; It is indicated in the treatment of breast, colon, liver, lung and brain cancer.
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