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Genome mining using standard bioinformatics tools has allowed for the uncovering of hidden biosynthesis gene clusters for specialized metabolites in Streptomyces genomes. In this work, we have used an alternative approach consisting in seeking “Streptomyces Antibiotic Regulatory Proteins” (SARP) encoding genes and analyzing their surrounding DNA region to unearth cryptic gene clusters that cannot be identified using standard bioinformatics tools. This strategy has allowed the unveiling of the new ahb cluster in Streptomyces argillaceus, which had not been retrieved before using antiSMASH. The ahb cluster is highly preserved in other Streptomyces strains, which suggests a role for their encoding compounds in specific environmental conditions. By combining overexpression of three regulatory genes and generation of different mutants, we were able to activate the ahb cluster, and to identify and chemically characterize the encoded compounds that we have named ahbamycins (AHBs). These constitute a new family of metabolites derived from 3-amino-4-hydroxybenzoate (3,4-AHBA) known for having antibiotic and antitumor activity. Additionally, by overexpressing three genes of the cluster (ahbH, ahbI, and ahbL2) for the synthesis and activation of 3,4-AHBA, a new hybrid compound, AHB18, was identified which had been produced from a metabolic crosstalk between the AHB and the argimycin P pathways. The identification of this new BGC opens the possibility to generate new compounds by combinatorial biosynthesis.

The aim of this work was to study the spectroscopic and magnetic properties of copper(II) o-, m-, p-aminobenzoates, o-, m-, p-methoxybenzoates and o-, m- and p-nitrobenzoates. The complexes were synthesized and their compositions were evaluated by elementary analysis. The infrared and Raman spectra for Cu(II) aminobenzoates, methoxybenzoates and nitrobenzoates were recorded and assigned. The obtained data were compared with those previously published for aminobenzoic, methoxybenzoic and nitrobenzoic acids and their sodium salts. The structures of Cu(II) o-, m-, p-aminobenzoates, o-, m-, p-methoxybenzoates and o-, m- and p-nitrobenzoates as well as the change in the electronic charges distribution caused by Cu(II) complex formation were discussed.

The possible stable conformers of free Ethyl 2- and 3-aminobenzoate molecules were searched via subsequent single point energy calculations carried out at semi-empirical PM3 theory level. The final equilibrium geometrical parameters for the obtained stable conformers were defined by performing geometry optimizations with B3LYP hybrid DFT method and basis sets of different size and type. The harmonic vibrational normal modes of the two molecules and their corresponding wavenumbers and IR intensities were calculated at the obtained equilibrium geometries using the same method and basis sets used in the geometry optimizations. In the light of these calculated spectral data, a successful assignment for the fundamental bands in the IR spectra of the two molecules was given. In order to fit the calculated harmonic wavenumbers to the experimentally observed ones, two different scaling procedures, called “scaling wavenumbers in Scaled Quantum Mechanics Force Field (SQM FF) methodology” and “scaling wavenumbers with dual empirical scale factors”, were proceeded independently.

Bu çalışmada kuvvetli PARP inhibitörü 3-aminobenzamid ile enerji kaynaklarının tüketimi engellenerek ve güçlü stimulus baskılanarak siklosporin A ile kombinasyonunun miyokardiyal reperfüzyon hasarının tek başına PARP inhibisyonunun ya da tek başına MPTP baskılanmasının sağladığı korumayı potansiyelize edip etmeyeceğinin araştırılması amaçlandı. Bu amaçla kalpte İR ile indükte oksidatif kardiyak hasar üzerine PARP inhibitörü 3-aminobenzamid(3-AB) + Siklosporin A’(CsA)nın etkilerinin araştırılması planlandı. Çalışmada 350–400 g ağırlığında 40 adet erkek Wistar-albino sıçan kullanıldı. Langendorff sisteminin kullanıldığı çalışmamızda kalpler 18 ml/dk hızla %95 CO2+%5 O2 karışımı ile havalandırılan 37 C sıcaklıktaki modifiye Tyrode solüsyonu ile perfüze edildi. İlaç uygulaması Tyrode solüsyonu içerisine litrede 3 mM 3-Aminobenzamid ve/veya 0,2 M Siklosporin A katılarak yapıldı. Deney gruplarında 10 dakikalık stabilizasyon periyodunun ardından 30 dakika iskemi ve 60 dakika reperfüzyon uygulandı. Gruplar şu şekilde oluşturuldu (n=8); Grup 1: Sham opere grubu, Grup 2: Kontrol grubu, Grup 3: 3-AB grubu, Grup 4: CsA grubu, Grup 5: 3-AB+CsA grup. Tüm gruplarda hemodinamik parametreler [kalp hızı, koroner perfüzyon basıncı, sol ventrikül geliştirilen basıncı (LVDP), maksimum kasılma (dP/dtmax) ve gevşeme hızı (dP/dtmin)] kayıt altına alındı. Reperfüzyonun 0 ve 30. dakikalarında alınan örneklerde laktat dehidrojenaz (LDH) ölçümü yapıldı ve deney sonrasında kalplerde hacim ve ağırlık olarak nekroz alanı yüzdesi tayin edildi. Madde uygulanan gruplarda (Grup 3, 4 ve 5) ölçülen parametreler açısından kontrol grubuna göre anlamlı bir değişiklikler saptanmıştır (p>0.05). 3-AB+CsA gruptan elde edilen hemodinamik parametreler ve LDH değerleri ve ağırlık ve hacim metoduyla ölçülen nekroz alanı değerleri açısından grup 3 ve 4’ten elde edilen değerlerle karılaştırıldığında istatistiksel olarak anlamlı bir farklılık saptanmamıştır (p>0.05). Bu verilerden yola çıkarak her iki mekanizmanın eş zamanlı olarak inhibisyonunun hem hemodinamik parametreler açısından hemde nekroz alanı azaltmada anlamlı bir fark yaratmadığını düşünmekteyiz. Anahtar Kelimeler: Langendorff, İskemi Reperfüzyon Hasarı, Siklosporin A,3-Aminobenzamid, Poli(ADP-Riboz) Polimeraz enzimi In this study we tried to determine that if we inhibit strong stimulus and decrease the depletion of energetic pools by potent PARP inhibitor 3-aminobenzamide (3-AB) will the combination of 3-Aminobenzamid (3-AB) and Cyclosporin A (CsA) be more efficient in the protection of myocardial reperfusion damage than their individual usage. With this aim we planned to search the possible protective effects of PARP inhibitor 3-aminobenzamide + Cyclosporin A combination on the IR induced oxidative cardiac damage. Fourty male wistar albino rats weighing 350-400g were used in the study. Rats were divided into five groups (n=8); Group 1: Sham-opereted, Group 2: IR, Group 3: 3-AB, Group 4: CsA and Group 5: 3-AB + CsA. Isolated rat hearts were exposed to 30 minutes of global ischemia followed by 60 minutes of reperfusion using Langendorff’s apparatus. In groups 3, 4 and 5, 3-Aminobenzamid (0,3 nM/L) and Siklosporin A (0,2 M/L) were added into Tyrode Solution after stabilization period. In all groups hemodynamic parameters (heart rate, coronary perfusion pressure, left ventricular developed pressure (LVDP), LV(dP/dt)max and LV(dP/dt)min were recorded. Myocardial injury was assessed in the terms of infarct size and release of lactate dehydrogenase (LDH) enzyme. Except heart rate all parameters were found significantly different in groups 3, 4 and 5 versus IR group (p0.05). When compared to CsA and 3-AB groups, in 3-AB+CsA group there was no significant difference determined in LDH and hemodynamic parameters and myocardial infarct size estimated by volume and weight method .These results show that use of CsA and 3-AB together provides no significant difference in protection against IR injury Key words: Ischemia-Reperfusion Injury ,Langendorff , Cyclosporin A ,3-Aminobenzamide,RatHeart Bu tez, Dicle Üniversitesi Bilimsel Araştırma Projeleri komisyonu tarafından 10 TF- 12 nolu Yüksek Lisans proje numarası ile desteklenmiştir.

pABA (p-aminobenzoate) is a precursor of folates and, besides esterification to glucose, has no other known metabolic fate in plants. It is synthesized in two steps from chorismate and glutamine, the first step being their conversion into glutamate and ADC (4-aminodeoxychorismate). In Escherichia coli, two proteins forming a heterodimeric complex are required for this reaction, but, in plants and lower eukaryotes, a single protein is involved. The Arabidopsis enzyme was expressed in E. coli and was purified to homogeneity. The monomeric enzyme (95 kDa) catalyses two reactions: release of NH3 from glutamine (glutaminase activity) and substitution of NH3 for the hydroxy group at position 4 of chorismate (ADC synthase activity). The kinetic parameters of the plant enzyme are broadly similar to those of the bacterial complex, with Km values for glutamine and chorismate of 600 and 1.5 μM respectively. As with the bacterial enzyme, externally added NH3 was a very poor substrate for the plant enzyme, suggesting that NH3 released from glutamine is preferentially channelled to chorismate. The glutaminase activity could operate alone, but the presence of chorismate increased the efficiency of the reaction 10-fold, showing the interdependency of the two domains. The plant enzyme was inhibited by dihydrofolate and its analogue methotrexate, a feature never reported for the prokaryotic system. These molecules were inhibitors of the glutaminase reaction, competitive with respect to glutamine (Ki values of 10 and 1 μM for dihydrofolate and methotrexate respectively). These findings support the view that the monomeric ADC synthase is a potential target for antifolate drugs.

ÖZET Doktora Tezi wc-DÎOKSİMLERİN AMÎNO BENZOAT TÜREVLERÎNÎN SENTEZÎ VE METAL KOMPLEKSLERİNİN İNCELENMESİ Ramazan GÜP Selçuk Üniversitesi Fen Bilimleri Enstitüsü Kimya Anabilim Dalı Danışman: Prof Dr. A. Dinçer BEDÜK 2001, Sayfe: 101 Jüri: Prof. Dr. A Dinçer BEDÜK Prof. Dr. Mustafe YILMAZ Prof Dr. İbrahim KARATAŞ Prof Dr. Mustafe PEHLİVAN Yrd. Doç. Dr. Ahmet GÜLCE Bu çalışmada, o- ve p-amino benzoik asidin metil ve etil esterleri ile vic- dioksimlerin reaksiyonundan on iki yeni ligand ve bunların bazı geçiş metalleri ile kompleksleri sentezlendl Bunun için önce an/ı-kloroglioksim, anrî-dMoroglioksim ve anti- klorofenilglioksim literatürlere göre sentezlenmiştir. Sonra bu v/c-dioksimler o- ve p-amino benzoik asidin metil ve etil esterleri ile reaksiyona sokularak, vic- dioksimlerin amino benzoat türevleri elde edilmiştir. Elde edilen bu ligandlarm Ni(II), Cu(II) ve Co(II) asetat tuzlanyla kompleksleri yapılmıştır.Sentezlenen on iki ligand ve otuz altı kompleksin yapılan, elementel analiz, İR, ^-NMR spektroskopisi ve magnetik süsseptibilite teknikleri kullanılarak aydınlatılmıştır. Anahtar Kelimeler: v/c-Dioksim, metil ve etil o- ve p-aminobenzoat, Cu(II), Ni(II), Co(II) metal kompleksleri u ABSTRACT PhD. Thesis THE SYNTHESIS of v/c-DIOXIME DERIVATIVES WITH AMINOBENZO ATES and INVESTIGATION of METAL COMPLEXES Ramazan GUP Selçuk University Graduate School of Natural and Applied Science Department of Chemistry Supervisor: Prof. Dr. A. Dinçer BEDÜK 2001, page: 112 Jury: Prof. Dr. A Dinçer BEDÜK Prof. Dr. Mustafa YILMAZ Prof. Dr. İbrahim KARAT AŞ Prof Dr. Mustafa PEHLİVAN Yrd. Doç. Dr. Ahmet GÜLCE In this study, twelve new ligand were synthesized by the reaction of methyl and ethyl ester of o- and p-amino benzoic acid with vic-dioximes, and some transition metal complexes of these ligands were isoleted. Firstly awft'-chloroglyoxime, awft'-dichloroglyoxime and anti- chlorophenylglyoxime were synthesized according to previously reported literatures. Then the reactions beetween these compounds with methyl and ethyl esters of o- and p-amino benzoic acid furnished novel v/c-dioxime derivatives mwith aminobenzoate. Finally, the complexes of these ligands with Ni(II), Co(II), Cu(II) acetat salts were isolated. The structures of both ligands and complexes were characterized by IR and ^-NMR spectroscopy, elemental analysis and magnetic susceptibility measurements. Key Words: v/'c-Dioxime, methyl and ethyl o- and p-aminobenzoate, Cu(II), Ni(II), Co(H) metal complexes iv 101

The biodegradability of seventeen N-substituted aromatic and six alkylphenol compounds were evaluated under methanogenic conditions. Biodegradation was assessed in batch assays inoculated with unacclimated and predigested anaerobic granular sludge at 30°C under agitated conditions over a 150 day period. The compounds were supplied at sub-toxic concentrations in the assays in order to prevent inhibition to the methanogens. The biodegradability test was performed by the measurement of the methane composition in the headspace of the serum flasks. The methanogenic consortia completely mineralized 2-, 3-aminobenzoate, 2-aminophenol and 4-cresol; whereas, 4-aminobenzoate was only partially degraded. The other N-substituted compounds and the alkylphenols tested were not biodegradable under the experimental conditions employed. An additional biodegradability assay was conducted with sludge from an upward-flow anaerobic sludge bed reactor adapted to the degradation of 2-nitrophenol. This sludge mineralized 2-aminophenol without any lag phase while the unadapted sludge required 110 days of acclimation. The three aminobenzoate isomers were fully mineralized by the adapted sludge after similar lag periods observed in the unadapted sludge. The 2-nitrophenol adapted sludge cross-acclimatized to the mineralization of 5-aminosalicylate and 4-aminophenol. This constitutes the first report demonstrating the anaerobic mineralization of 5-aminosalicylate, which indicates that at least some azo dye cleavage products can be degraded in methanogenic consortia.

Department of Chemistry, Faculty of Science, Banaras Hindu University, Varanasi-221 005 Manuscript received 25 October 1983, accepted 26 May 1984 Some new 2-(N-substituted or N,N-disubstituted aminoacetamido)-4-\(\mathcal{p}\)-nitrophenyl, 4-\(\mathcal{m}\)-nitrophenyl, and 4-(2' ,5'-dimethoxy)phenyl thiazoles have been synthesised. Their hydrochlorides have been screened for local anaesthetic activity by Frog's sciatic plexus method and the activity compared with that of procaine hydrochloride. Among them 2-(N-substituted aminoacetamido)-4-\(\mathcal{m}\)-nitrophenylthiazole hydrochlorides are the most potent, almost twice in terms of onset of anaesthesia in comparison with procaine-HCI.

University Departrhent of Chemistry, Saurashtra University, Bhavnagar Manuscript received 28 January 1976; revised 3 June 1976;accepted 23 July 1976 Studies on Sulphonamides. Part II: Preparation of Ethyl-4-(2-arylsulphonamido-4- phenylsulphonyl-s-triazin-6-yl)-aminobenzoate.