Synthesis and Biological Evaluation of Some Hydrazide-Hydrazone Derivatives as Anticancer Agents

In this study, a series of hydrazide-hydrazone derivatives (3a-3u) were synthesized and evaluated for their anticancer activities against prostate cancer cell line (PC-3), breast cancer cell line (MCF-7), colon cancer cell line (HT-29) and human umbilical vein endothelial cells (HUVEC) using MTT assay. In particular, compound 3h having a pyrrole ring was found to be the most potent derivative with IC50 = 1.32, 2.99, 1.71 µM against PC-3, MCF-7, HT-29 cancer cell lines respectively using paclitaxel as a standard compound. Furthermore, compound 3h was subjected to further biological studies such as caspase-3 activity and Annexin-V assay to evaluate their inhibitory potentials. The activity results displayed that compound 3h increased caspase-3 activation and the number of cells to early apoptosis. The additional studies like pharmacokinetics, bioavailability scores and drug-likeness properties were also evaluated. The in silico pharmacokinetics predictions displayed that the bioavailability of these compounds may be high

5-(4-Aminofenil)-2-Sübstitüeamino-1,3,4-Tiyadiazol bileşiklerinden türeyen Sübstitüe ürelerin sentezi ve yapılarının aydınlatılması

1. Bu araştırmada, antimikrobiyal ve sitotoksik etkilerinin taranması amacı ile N-5-(4-aminofenil)-2-alkil/arilamino-1-3,4-tiyadiazol-N'-alkil/aril)üre türevi bi-leşikler sentezlenmiştir. Araştırmanın birinci kısmında, benzokainin hidrazin hidrat ile reaksiyona sokularak 4-(benzoilamino)benzoilhidrazin kazanılmış, bu bileşiğin etil, siklohekzil, fenil, fenetil ve 4-klorofenil isotiyosiyanatlara katımı ile 1-[4-(benzoilamino)benzoil]-4-alkil/ariltiyosemikarbazidler (3a-e) sentezlenmiştir. 3a-e’den hareketle, 2-(4-aminofenil)-5-alkil/arilamino-1,3,4-tiyadiazoller (4a-e) anabilim dalımız tarafından modifiye edilen yeni bir yöntem ile elde edilmişlerdir. Araştırmanın ikinci bölümünde, aromatik primer aminler diklorometanlı ortamda butil, t-butil, 4-klorofenil, 2-kloro-6-metilfenil ve 4-triflorometilfenil isosiyanatlara katımları ile onüç adet orijinal üre bileşiği (5a-e) kazanılmıştır. Sentez edilen bileşiklerin saflıkları ince tabaka kromatografisi ile kontrol edildikten sonra yapıları, elementel analiz (C, H, N ve S), UV, IR, 1H-NMR ve kütle spektroskopik yöntemleri kullanılarak aydınlatılmıştır. Bileşiklerin antimikrobiyal etkileri belirlenmiş bazı suşlara karşı Minimum İnhibitör Konsantrasyon (MİK) değerleri mikrodilüsyon yöntemiyle saptanmıştır. Bileşiklerimiz kullanılan standartlar ile kıyaslandıklarında kayda değer antimikrobiyal etki göstermedikleri tespit edilmiştir. Bileşiklerin sitotoksik etlileri HeLa (ATCC CCL-2) hücre hattı kullanılarak MTT [3-(4,5-dimetiltiyazol-2-il)-2,5-difeniltetrazolyum bromür] yöntemine [Cell proliferation Kit I (MTT) Roche-Germany] göre test edilmiştir. Bileşikler içerisinde en yüksek sitotoksik etki N-[4-(2-siklohegzilamino-1,3,4-tiyadiazol-5-il)fenil]-N'-(4-kloro-fenil)üre (5b-III ) için % 82 olarak tespit edilmiştir. Anahtar Sözcükler: Üre, 1,3,4-tiyadiazol, sentez, antimikrobiyal etki, sitotoksik etki 2. SUMMARY SYNTHESIS OF UREAS DERIVED FROM 5-(4-AMİNOPHENYL)-2-SUBSTITUEAMINO-1,3,4-THIADIAZOLE AND CHARACTERİZED STRUCTURES In this research, in order to screen antimicrobial and cyctotoxic activities, substituted N-[4-(2-aryl/alkylamino–1,3,4-thiadiazole–5-yl)phenyl]-N'-(aryl/alkyl)-ureas were synhesized. In the first part of research, benzocaine was reacted with hydrazine hydrate to prepare 4-(benzoylamino)benzoylhydrazine. 1-[4-(Benzoylamino)benzoyl]-4-alkyl/arylthiosemikarbazides were then synthesized by the addition of ethyl, cyclohexyl, phenyl, phenethyl and 4-chlorophenyl isothiocyanates to added 4-(benzoylamino)benzoylhydrazine. From (3a-e), 2-(4-aminophenyl-5-alkyl/arylamino-1,3,4-thiadiazoles (4a-e) were synthesized by using a new method which was modified by our department. In the second part, N-aryl/alkyl-N-[4-(5-alkyl/arylamino-1,3,4-thiadiazole-2-yl)phenyl]ureas were ob-tained from the addition of aromatic primary amine to butyl, t-butyl,4-chlorophenyl, 2-chloro-6-methyl, 4-trifloromethylphenyl isocyanates in dry dichloromethane. Purity of the synthesized compounds were controlled with thin layer chromatographic methods. The structures of the compounds synthesized were confirmed by elementel analysis (C, H, N, S), UV, IR, 1H-NMR methods. Antimycobacterial activites of the compounds synthesized were tested by some strains were determined and the Minium Inhibitor Concetrarion ( MIC) was defined as the lowest concentration of compound giving complete inhibition of visible growth. Compared with the standard compounds used were found not show significant antimicrobial effects.Cyctoxicity of these compounds were evaluated by using HeLa (ATCC CCL-2) cell line according to procedures of MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] Assay [Cell proliferation Kit I (MTT) Roche-Germany]. The highest inhibition was confirmed as 82% for the compound N-[4-(2-cyclohegzylamino-1,3,4-thiadiazole-5-yl)phenyl]-N'-(4-chloro-phenyl)urea [5b-III]. Key words: Urea, 1,3,4-thiadiazole, synthesis, antimicrobial, cytotoxic activity

Bazı yeni hidrazit-hidrazonlar ve bunlardan türetilen sübstitüe 1,3,4-oksadiazol türevlerinin sentezi ve biyolojik aktivitelerinin incelenmesi

ÖZETBazı Yeni Hidrazit-Hidrazonlar ve Bunlardan Türetilen Sübstitüe 1,3,4-Oksadiazol Türevlerinin Sentezi ve Biyolojik Aktivitelerinin İncelenmesiAmaç: Hidrazonlar organik moleküllerin önemli sınıflarından birini oluşturan, CO-NH-N=CH- farmakofor grubu içermekte ve antiinflamatuar, antifungal, antimikrobiyal, antitüberküler ve antikanser aktivite gibi çeşitili aktivite göstermektedirler. Bu tez çalışmasında bir seri hidrazit-hidrazon türevi bileşikler ve bu bileşiklerin siklizasyonu sonucunda elde edilen 1,3,4-oksadiazolin bileşiklerin sentezi ve biyolojik aktivitelerinin incelenmesi amaçlanmıştır.Gereç ve Yöntem: Hidrazon bileşikleri hidrazit ve çeşitli aldehit/ketonların etanollü ortamda reflüks edilmesi sonucunda sentezlenmektedir. Bu çalışmada 4-kloro-2-metiltiyopirimidin-5-karbohidrazitten hareketle bir seri yeni hidrazonlar ve bu hidrazonların asetik anhidritli ortamda siklizasyonu sonucunda 2,3-dihidro-3-asetil-1,3,4-oksadiazol bileşikleri sentezlenmiştir. Hidrazon türevlerinin analjezik etkileri Sıcak Zemin (Hot plate) Testi yöntemiyle, antiinflamatuar etkileri de LOX inhibisyonu testi kullanılarak tayin edilmiştir.Bulgular: Analjezik Aktivitesi test edilen bileşikler içerisinde 2a, 2b, 2c, 2d, 2e, 2f ve 2m’de herhangi bir analjezik etki tespit edilememiştir. 2g, 2h, 2k, 2l, 2n, 2o, 2ö ve 2p, 2r ve 2s’nin kontrol grubu ile kıyaslandığında 20. dakikada başlayan analjezik etkinliği 150. dakikaya kadar devam etmiş ve bu artış istatistiksel olarak anlamlılık göstermiştir. Prototip olarak seçilen bileşiklerin antiinflamatuvar aktiviteleri sonucunda en yüksek inhibisyon % 66.30 ile 2s maddesinde görülmüştür. Bileşik 2a, 2c, 2l ve 2m ‘de ise % 45.11- 15.11 arasında değişen değerlerde inhibisyon göster-mişlerdir. Sonuç: Aktivite çalışmaları göstermiştir ki sentezlenen 2s maddesin hem analjezik hem de antiinflamatuar aktivitesi olduğu tespit edilmiştir.Anahtar kelimeler: Hidrazit, Hidrazon, 1,3,4-oksadiazol, analjezik, antiinflamatuar aktivite.SUMMARYSynthesize of New Hydrazide-Hydrazone and Substituted 1,3,4-Oxadiazole Compunds and Screening Biological ActivitiesAim: Hydrazones, one of the important classes of organic molecules, has –CO-NH-N=CH- farmacofor group which provides antiinflamatuar, antifungal, antimicrobial, antitubercular, anticancer and etc.. In this study, aimed to investigate hydrazide-hydrazone and their corresponding cylization product 1,3,4-oxadiazol.Materials and methods: Hydrazone compounds are obtained by the reflux of hydrazide and various aldehydes/ketones in ethanol medium. using various catalysts. In the present study, new hydrazone and 2,3-dihidro-1,3,4-oxadiazole derivatives are synthesized by reacting the 4-chloro-2-thiomethylpyrimidine-5-carbohydrazide with substituted aromatic aldehydes and then hydrazone compounds are cyclized by using acetic anhydride. Novel compounds are characterized by IR, 1H-NMR, 13C-NMR and MS and elemental analysis. Analgesic effect of hydrazone compounds were investigated on Hot-Plate test and antiinflamatuar effect was measured by LOX inhibition. Results: According to analgesic activity, 2a, 2b, 2c, 2d, 2e, 2f and 2m do not show any analgesic activity. When 2g, 2h, 2l, 2n, 2o, 2ö, 2p, 2r and 2s compounds are compared to control group, their analgesic affect was started on 20 minutes and continued until 150. minutes and the increase was significant as statistically.Some of hydrazone compounds was selected as protype to evaluate antiinflamatuar activity. As result of antiinflamatuar activity, the maximum inhibition was detected 66.30 % for 2s compound. Inhibitions of 2a, 2c, 2l, 2m were observed as % 45.11- 15.11.Discussion: According to activities results, 2s compound shows analgesic activty and antiinflamatuar activity.Keywords: Hydrazide, Hydrazone, 1,3,4-oxadiazole, antiinflamatuar, analgesic activity

Efficacy of Capecitabine and Temozolomide Regimen in Neuroendocrine Tumors: Data From the Turkish Oncology Group

INTRODUCTION: This study aims to report the efficacy and safety of capecitabine plus temozolomide (CAPTEM) across different lines of treatment in patients with metastatic neuroendocrine tumors (NETs). METHODS: We conducted a multicenter retrospective study analyzing the data of 308 patients with metastatic NETs treated with CAPTEM between 2010 and 2022 in 34 different hospitals across various regions of Turkey. RESULTS: The median follow-up time was 41.0 months (range: 1.7-212.1), and the median age was 53 years (range: 22-79). Our results across the entire patient cohort showed a median progression-free survival (PFS) of 10.6 months and a median overall survival (OS) of 60.4 months. First-line CAPTEM treatment appeared more effective, with a median PFS of 16.1 months and a median OS of 105.8 months (median PFS 16.1, 7.9, and 9.6 months in first-, second- and ≥third-line respectively, P = .01; with median OS values of 105.8, 47.2, and 24.1 months, respectively, P = .003) In terms of ORR, the first-line treatment again performed better, resulting in an ORR of 54.7% compared to 33.3% and 30.0% in the second and third or higher lines, respectively (P < .001). Grade 3-4 side effects occurred only in 22.5% of the patients, leading to a discontinuation rate of 9.5%. Despite the differences in outcomes based on treatment line, we did not observe a significant difference in terms of side effects between the first and subsequent lines of treatment. CONCLUSIONS AND RELEVANCE: The substantial superior outcomes in patients receiving first-line CAPTEM treatment highlight its potential as an effective treatment strategy for patients with metastatic NET

TÜRKIYE’DE YOĞUN BAKIM ÜNITELERINDE VENTILATÖR ILIŞKILI PNÖMONIYI ÖNLEMEK IÇIN ALINAN GÜNCEL ÖNLEMLER: TÜRK TORAKS DERNEĞI SOLUNUM YETMEZLIĞI VE YOĞUN BAKIM ÇALIŞMA GRUBU NOKTA PREVALANS ÇALIŞMASI

Objectives: The inadequate quality and nature of sleep is a commonly reported problem among hospitalized patients. The purpose of this study is to examine the effects of progressive muscle relaxation training program on sleep quality, sleep state, pain and life quality of patients who underwent pulmonary resection