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Abstract Schiff-bases are compounds containing azo methine group (>C=N) and have the general structure R-N=C-R’ where R and R’ are aryl, alkyl, cycloalkyl or heterocyclic groups which may be variously substituted. Often they are referred to as anils, imines or azomethines. The synthesis and properties of Schiff-bases have been widely reviewed [1,2]. The availability of different types of amines and carbonyl compounds enabled the synthesis of Schiff-bases with diverse structural features. Schiff-bases are typically formed by the condensation of a primary amine and an aldehyde/ketone. The resultant compound, R1R2C=NR3, is called a Schiff-base (named after Hugo Schiff), where R1 is an aryl group, R2 is a hydrogenatom and R3 is either an alkyl or aryl group. However, usually compounds where R3 is an alkyl or aryl group and R2 is an alkyl or aromatic group are also regarded as Schiff-bases. Schiff-bases that contain aryl substituents are substantially more stable and more readily synthesized, while those which contain alkyl substituents are relatively unstable. Schiff-bases of aliphatic aldehydes are relatively unstable and readily polymerizable [3], while those of aromatic aldehydes having effective conjugation are more stable. In general, aldehydes react faster than ketones in condensation reactions, leading to the formation of Schiffbases as the reaction centre of aldehyde are sterically less hindered than that of ketone. Furthermore, the extra carbon of ketone donates electron density to the azomethine carbon and thus makes the ketone less electrophilic compared to aldehyde [4]. Schiff-bases are regarded as one of the most important group of chelators for facile preparations of new metal chelates. Introduction Chapter (I) 3 Hydrazones are important compounds for drug design, as possible ligands for metal complexes, organocatalysis and also for the synthesis of heterocyclic compounds [1]. The ease of preparation, increased hydrolytic stability relative to imines and tendency toward crystallinity are all desirable characteristics of hydrazones. Due to these positive traits, hydrazones had been under study for a long time, but much of their basic chemistry remains chemistry remains unexplored. Hydrazone ligands create an environment similar to the one present in biological systems usually by making coordination through oxygen and nitrogen atoms. Various important properties of carbonic acid hydrazides, along with their applications in medicine and analytical chemistry have led to increase interest in their complexation characteristics with transition metal ions [2,3]. The hydrazone unit offered a number of attractive features such as the degree of rigidity, a conjugated system and a NH unit that readily participates in hydrogen bonding and may be a site of protonatione - deprotonation. It is well established that, the formation of metal complexes plays an important role to enhance the biological activity of free hydrazones [4]. Hydrazone ligands are promising compounds because of their ability towards complexation and wide range of biological and nonbiological properties [5]. The chemistry of transition and non- transition metals with ligands from the hydrazine family has been of interest to coordination as well as bio-inorganic chemists due to their different bonding modes with both electron-rich and electron-poor metals. The structural motif, ‒N=C‒CH=N‒NH‒C=N‒, present in hetero-cyclic hydrazones is a remarkable tool for development of multi- functional Introduction Chapter (I) 4 organic receptors that find applications in chemical, environmental and biological sciences. The American Cancer Society estimates that there will be 248,530 new cases of prostate cancer in 2021 and more than 3.1 million prostate cancer survivors in the United States.1 The American Cancer Society also estimates that prostate cancer will be the second leading cause of cancer-related death in US men after lung cancer in 2021.1 Furthermore, rates of prostate cancer are higher in men of African descent compared with men of European descent [5]. Germline testing (genetic testing for genes linked with hereditary cancer risk) has emerged as integral to prostate cancer precision treatment in the metastatic setting, is increasingly informing screening strategies, and provides hereditary cancer information for men and their families [5]. In recent years, there has been an exponential rise in understanding the role of genetic mutations in prostate cancer predisposition and the development of new precision therapies [6]. Many genes are now incorporated into the guidelines for genetic testing to assess the risk of developing prostate cancer and offer guidance for targeted therapeutics[5-7]. In May 2020, the US Food and Drug Administration (FDA) approved 2 poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibitors for the treatment of men with metastatic, castration-resistant prostate cancer (mCRPC) based on improved clinical responses [7,8]. Several challenges exist in implementing genetic testing and counseling into prostate cancer treatment paradigms. These include lack of awareness among providers regarding the utility of genetic testing for prostate cancer treatment and management, concerns around which mutations are clinically relevant, implications for at-risk family members, medical and legal liability if mutations are detected and the duty to warn, access to certified genetic counselors, financial concerns, and the time involved in obtaining a complete family history [9,10]. Additional practice challenges include a relative shortage of genetic counselors; in 2021, there are 5629 certified genetics counselors Introduction Chapter (I) 5 in the United States, and not all states have licensed genetic counselors [11,12]. Therefore, delivery of genetics care has necessitated that primary care providers (PCPs) have increasing working knowledge of germline testing, build collaborative models with genetic services, and consider alternate delivery of genetic information to patients through videos or telehealth [6,12,13]. Considering that men with prostate cancer, men at increased risk for prostate cancer, or prostate cancer survivors constitute a substantial proportion of patients seen by PCPs, there is a critical need to better integrate primary care with the genetic evaluation process. Metallodrugs offer many features over purely organic compounds due to specific characteristics of coordination compounds. Their bioactivity is affected by the type of central atom, its coordination and oxidation number, type and number of the ligands, coordination geometry and charge of the complex [14]. In recent years, the coordinated Chemistry of diamines have attracted the attention of researchers due to their unique capability of constructing complicated organic molecules using centers of metal as intermediates. For example, N-phenyl-ortho-phenylenediamine coordinated to platinum or nickel atoms transforms into imidazophenazine derivatives [15].The coexistence of hydrolizable ester group (-COO-) and amide group (-NHCO-), which are capable of establishing strong intermolecular hydrogen bond interactions, becomes fundamental to obtaining a suite of materials with tailored properties. Specifically, different polyester amides have been developed for biomedical applications such as drug delivery systems [16]. Literature survey reveals that nitrogen - and sulfur-containing compounds showed very good bioactivity, being potentially active against cancer as well as viral and fungal diseases [17,18]. The amide moiety has attracted further interest because it is widespread in natural and synthetic drugs and shows lower toxicity [19]. Bioactivity of amides can also be achieved by constructing the amide with hydroxypentanedioate [20]. Introduction Chapter (I) 6 I.1. Synthesis of Schiff-bases Solvent based synthesis of Schiff-bases through classical condensation of aldehydes (or ketones) and amines require pH control, however the yield of products is low. pH range for such synthesis should be 5 to 8 i.e. weak acid, neutral or weak alkaline medium depending upon the basicity of amines. Microwave assisted synthesis of Schiff-base is rapid and efficient with no use of solvent. The yield of products is also high andpurification is done by simple recrystallization technique [21].Scheme (1): solvent free synthesis by microwave irradiation The microwave –assisted synthesis of Schiff-base from salicyldehyde and different aryl amines is performed efficiently and get high yield of products in short time [21]. Thisis carried in an oven, Midea PJ21B-A 800W and is subjected to microwave for an optimized time on the ”M-High” setting. The solvent free organic synthesis mediated by microwave irradiation performs several economies such as low risk of hazard, time economy and environmental friendship. Purification by simple recrystallization technique offers less contamination. CHO OH H2N + MW OH Solvent free synthesis by using catalyst solvent free synthesis of Schiff-bases obtained from 4,5-diazafluuoren-9-one with substituted amines is done efficiently at room temperature by using SnCl2 catalyst [22]. N Scheme (1): Solvent free synthesis of Schiff-bases by microwave irradiation from salicyldehyde and aniline Introduction Chapter (I) 7 The reaction mixture is grinded in a mortar with the help of pestle and the progress reaction is monitored by TLC and column chromatography. N O + N H2N H3C SnCl2 OH grind ng OH H3C Scheme (2) Schiff-base Scheme (2): Solvent free synthesis of Schiff-base obtained from 4, 5-diazafluorene-9-one Solvent and catalyst free synthesis a mixture of substituted aromatic amines and substituted aromatic aldehydes is grindedin a mortar with a pestle made of porcelain and the progress of reaction is monitored by TLC. The crude product of Schiff-base is purified by column chromatography. The completion of reaction takes place within 2-3 minutes. However the synthesis of Schiff-bases from ketone requires aceticacid as a catalyst [23]. Scheme (3): Solvent and catalyst free synthesis a mixture of substituted aromatic amines and substituted aromatic aldehydes. Solvent based synthesis solvent based Schiff-base synthesis generally requires appropriate solvent like ethanol or methanol and mixture is refluxed under pressure by applying acidic, basic or neutral medium. The first preparation of Schiff-base was reported in the 19th century by Schiff (1864). Since then a variety of methods for the synthesis of Schiff-base have been described. The classical synthesis reported by Schiff involves the condensation of a carbonyl compound with an amine N N N Introduction Chapter (I) 8 under azeotropic distillation [24]. Molecular sieves are then used to completely remove water formed in the system [25]. In the 1990s an insitu method for water elimination was developed, using dehydrating solvents such as tetramethylorthosilicate or trimethylorthoformate [26, 27].These methods are dependent on the use of highly electrophilic carbonyl compounds and strongly nucleophilic amines [28]. Presence of water may reverse the reaction by hydrolyzing the Schiff-base. Scheme (4): Solvent based Schiff –base synthesis I.2. Synthesis of Schiff-bases metal complexes The metal complexes of Schiff-bases is prepared by stirring the mixture of metal salts with synthesized Schiff-base ligands using suitable solvent generally ethanol and then refluxing the mixture. The complexes obtained are washed with alcohol and dried. The prepared metal complexes of bis(2-aminobenzaldehyde) malonylhydrazone Scheme (5) by refluxing the mixture for 3 hrs. in alcoholic medium [29]. Scheme (5): General methods of preparation of Schiff-base metal complexes Introduction Chapter (I) 9 Generally Schiff-base metal complexes are prepared by producing a reaction between the Schiff-base and available metal salt in ethanolic medium. This approach is clearly simple and suitable. Essentially, five different synthetic routes can be identified for the preparation of Schiff-base metal complexes Scheme (6). Scheme (6): General methods of preparation of Schiff-base complexes I.3. Structure and properties of Schiff-bases Schiff-bases are generally bidentate (1), tridentate (2), tetradentate (3) or polydentate (4) ligands capable of forming very stable complexes with transition metals. They can only act as coordinating ligands if they bear a functional group, usually the hydroxyl, sufficiently near the site of condensation in such a way that a five or six membered ring can be formed when reacting with a metal ion (Fig. 1). Schiff-bases derived from aromatic amines and aromatic aldehydes have a wide variety of applications in many fields, e.g., biological, inorganic and analytical chemistry [30-31]. Introduction Chapter (I) 10 Applications of many new analytical devices require the presence of organic reagents as essential compounds of the measuring system. Fig.(1): Some classes of Schiff-base ligands I.4. Importance of Schiff-base and their metal complexes: Schiff-bases derived from an amino and carbonyl compound are an important class of ligands that coordinate to metal ions via azomethine nitrogen and have been studied extensively [32]. In azomethine derivatives, the C=N linkage is essential for biological activity, several azomethines were reported to possess remarkable antibacterial, antifungal, anticancer and diuretic activities [33]. Schiff-bases have wide applicationsin food industry, dye industry, analytical chemistry, catalysis, fungicidal, agrochemical and biological activities [34].With the increasing incidence of deep mycosis, there has been increasing emphasis on the screening of new and more effective antimicrobial drugs with low toxicity. Schiff-base complexes are considered to be among the most important stereochemical models in main group and transition metal coordination chemistry due to their preparative accessibility and structural variety [35]. Introduction Chapter (I) 11 A considerable number of Schiff-base complexes have potential biological interest, being used as more or less successful models of biological compounds [36]. Not only have they played a seminal role in the development of modern coordination chemistry, but also they can also be found at key points in the development of inorganic biochemistry, catalysis and optical materials [37]. I.4.1. Biological activities I.4.1.1 Antibacterial activities Schiff-base derived from indoline-2, 3-dione and 2-aminobenzoic acid and its Tin complex showed antibacterial activity against Staphylococcus aureus. The results compared with standard drug(Imipinem) have indicated that compounds were active but activity was less than the standard drug. This activity might be due to the presence of ahydroxyl and phenyl group [38]. The increased activity in the organotin complexes may be due to the coordination and polarity of a tin(IV) atom with oxygen of the ligand. The order of increasing activities is ligand <MeSnL<PhSnL< BZ3SnL, the results matched with the previously reported data for the biological activity of organotin complexes [39]. Complexes of Co(II), Cu(II), Ni (II), Mn(II) and Cr(III) with Schiff-bases derived from 2,6-diacetylpyridine and 2-pyridine carboxaldehyde with 4-amino-2,3-dimethyl-1-phenyl-3-pyrozolin-5-one show antibacterial and antifungal activities against Escherichia coli, Staphylococcus aureus, Klebsiella pneumoniae, Mycobacterium smegmatis, Pseudomonas aeruginosa, Enterococcus cloacae, Bacillus megaterium and Micrococcus leteus. The results showed that L1 ligand has a greater effect against E. coli than the other bacteria while it has no activity Introduction Chapter (I) 12 against S. aureus. Metal complexes have a greater effect than L2 against almost all bacteria [40]. The Schiff-base 4-chloro-2-(2-morphiolinoethylimino) methyl phenolatomethanolchloro and its Zn(II) complex was screened for antibacterial activity against two Gram positivebacterial strains (B. subtilis and S. aureus) and two Gram-negative bacterial strains(E. coli and P. fluorescence) by the MTT method. The Schiff-base showed significant activity against two Gram-negative bacterial strains with MIC of 12.5μgmL-1but was inactive against two Gram negativebacterial strains. The Zn(II) complex showed a wide range of bactericidal activities against the Gram positive and Gram negative bacteria, were potent than, or similar with commercial antibiotics (Kanamycin and penicillin) [41]. Bidentate complexes of Co(II), Ni(II), Cu(II), Zn(II), Cd(II) and Hg(II) with benzofuran-2-carbohydrazide and benzaldehyde [BPMC] or 3,4-dimethoxybenzaldehyde [BDMePMC] showed biological activities. Co(II) and Cd(II) complexes of [BPMC] are moderately active toward E.coli whereas copper(II), zinc(II) and nickel (II) complexes of [BPMC] and Cu(II) and Zn(II) complexes of [BDMeOPMC] are more active against S.aurious as compared to free ligands. None of the complexes are active against A.niger, but in the case of A.fumigatus,Cu(II), cobalt(II), Ni(II) and cadmium(II) complexes of [BDMeOPMC] are more active than the parent ligands [41]. Amino acid Schiff-base derived from 2-hydroxy-5- methylacetophenone and glycine and its transition metal complexes showed bacterial activities. The ligand was bacteriostatic against bacterial strains except Proteus vulgaris, Shigella flexneri, and Bacillus coagulans. All complexes are either resistant or less sensitive against P.vulgaris. However compared to the antibacterial activity of the standard antibiotic Streptomycin, the activity exhibited by the ligand and its metal Introduction Chapter (I) 13 complexes was lower. The metal complexes showed to exhibited higher activity than the free ligand against the same organism under identical experimental conditions, such increased activity of the metal complexes can be explained on the basis of chelation theory [42]. Mixed ligand complexes with 2,6-pyridine carboxaldehyde bis (phydroxy phenylamine(L1), 2,6- pyridinecarbox –aldehyde bis(o-hydroxy phenyl amine(L2) showed anti - bacterial activities. The data obtained reflect that the two Schiff-base ligands L1 and L2 have moderate activity in comparison with Staphylococcus aureus, Escherichia coli and less active in comparison withPseudomonas aeruginosa. L1 ligand showed a moderate activity towards Bacillus subtilis while L2 ligand was less active. The remarkable activity of the two Schiff-base ligands may be arise from the pyridyl-N and the hydroxyl groups which may play an important role in the antibacterial activity [43] as well as the presence of two imine groups which imports inelucidating the mechanism of transformation reaction in biological system[44]. Tetra and hexacoordinate metal complexes of phosphate Schiff-base ligands were found to be possess remarkable bacterial properties, it is however interesting that the biological activity gets enhanced on undergoing complexation with the metal ions [45]. Neutral tetradentate complexes of transition metals with Schiff-bases derived from 2- aminophenol/2-aminothiophenol and 1-phenyl-2,3-dimethyl-4(4- iminopentan-2-one)-pyrazol-5-one showed antimicrobial activity against Staphylococcus aureus, Bacillus subtilis, Klebsiella imeumoniae, Salmonella typhi, Pseudomonous aeruginosa, Shigella flexneri, Aspergillus niger and Trichoderma viridi. Most of the complexes have higher activity than the free ligand [46]. Complexes of transition metal with Schiff-base derived from 2,3-dihrdrazinoquinoxaline(DHQ) showed antimicrobial acyivity. Preliminary testing of the ligand and its metal Introduction Chapter (I) 14 complexes for antimicrobial activity on the Gram positive S.aureus and Gram negative E.coli showed that the ligand was active only against S.aureusand the activity is enhanced by complexation. I.4.1.2 Antifungal activities The microbial activity of the N-(2-hydroxy-1-naphthalidene) phenylglycine and its transition metal complexes was investigated. From the antifungal screening data it is concluded that the activity of the ligand has increased upon complexation. Cu(II), Ni (II) and Co(II) complexes have shown better antifungal activity compared to the ligand and the corresponding metal salts [47]. Two bidentate Schiff-base ligands 2-(2- hydroxy -3,5- dichloro / dibromo ) benzaldehyde-[4-(3-methyl-3- mesitylcyclobutyl)-1, 3-thiazol-2-yl]hydrazone, L1H, L2H and their metal complexes were tested against a yeast-like fungus C.albicans [48]. The fungicidal effect of salicylaldimine containing formaldehyde and piperazinemoity and its metal polychelates were determind against two yeast Candida albicans and Aspergillus. The Cu(II)-polychelate exhibited high activity against Candida albicans and the other show mild activity. The presence of N and O donor groups in the ligand and its metal polychelates inhibited enzyme production because enzymes that require free hydroxyl group for their activity appear to be especially susceptible to deactivation by the metal ion of polychelates. All the metal polychelates are more toxic than the ligand [49]. Neutral complexes of Co(II), Ni(II), Cu(II) and Zn(II) with Schiff-bases derived from 3-nitrobenzylidene-4- aminoanttipyrine and aniline (L1)/p-nitroaniline(L2) /p-methoxyaniline (L3) showed antifungal activity. A comparative study of the MIC values for the ligands and their complexes indicated that the complexes exhibit higher antimicrobial activity. Such increased activity of the complexes can be explained on the basis of overtone’s concept and Tweedy’s chelation theory [50]. Introduction Chapter (I) 15 Inhibition is enhanced with the introduction of an electron withdrawing nitro group in the phenyl ring [39]. Semicarbazones and thiosemicarbazones complexes of Ni(II) metal showed antifungal activities against 11 pathogenic fungi. The complexes were moderate active against all pathogenic fungi and much lower than those of standard fungicide Nistatin [51]. Co(II), Ni(II) and Cu(II) complexes with Schiff-base 3,3’- thiodipropionic acid bis(4-amino-5-ethylimino-2,3-dimethyl-1-phenyl-3- pyrazoline showed antifungal activity against Alternaria brassicae, Aspergillus niger and Fusarium oxysprum and results indicated that the complexes showed the enhanced activity in comparison to free ligand [52]. I.4.1.3. Antitumor and cytotoxic activities Metal complexes of Schiff-base derived from 2- thiophenecarboxaldehyde and 2-aminobenzoic acid (HL) have been recommended and/ or established a new line for search to new antitumor particularly when one knows that many workers studied the possible antitumor action of many synthetic and semi synthetic compounds e.g. Hodnett et al. and Hickman [53]. Such compounds may have a possible antitumor effect since Gram-negative bacteria are considered a quantitative microbiological method testing beneficial and important drugs in both clinical and experimental tumor chemotherapy [54]. A tridentate Schiff-base derived from the condensation of S-benzyl dithiocarbazate with salicyldehyde and its Zn(II), Sb(II), Cu(II) complexes showed cytotoxic properties [55]. Cu(II) complexes containing Schiffbases derived from S- benzylthiocarbazate and saccharinate showed anticancer properties. The complexes were highly active against the leukemic cell line (HL-60) but only [Cu(NNS)(sac)] was found to exhibit strongcytotoxicity against the ovarian cancer cell line (Caov-3). The activities being higher than the standard anticancer drug Doxorubicin [45]. Introduction Chapter (I) 16 Complexes of Cr(III) were much less cytotoxic than Cr(VI) to cultured human cells [56]. Cr(III) is an essential nutrient that was involved in the glucose tolerance factor(GTF) in maintenance of normal carbohydrate and lipid metabolism [57]. Knoevenagel condensate Schiff-base ligands [L = 3-cinnamalidene acetylacetone-thiosemicarbazone (CAT)/3-cinnamalidene acetyl acetone ethyl thiosemicarbazone(CAET)/3-cinnamalidene acetyl acetonephenyl thiosemicarbazone (CAPT)] and their copper/zinc complexes were synthesized. Theywere characterized by analytical and spectral techniques. from these data, it was found that the ligands adopt square-planar geometry on metalation with Cu(II) and Zn(II). To evaluate the antitumor and cytotoxic activity of the synthesized complexes in mice and human cancer cell lines, the antitumor activity of the complexes was evaluated against an Ehrlich ascites carcinoma (EAC) tumor model. The activity was assessed using survival time and short-term in vitro cytotoxic activity. Oral administration of complexes (100 mg/kg) increased the survival time. The cytotoxic activity of complexes was evaluated using human breast cancer (MDA-MB-231), colon cancer (HCT-116) and nonsmall lung cancer (NCI-H-23) cell lines. Both the complexes possessed significant antitumor and cytotoxic activity on EAC and human cancer cell lines. The invitro antimicrobial screening effect of the investigated compounds was also tested against the various organisms by well diffusion method [58]. Two oxovanadium(IV) complexes of [VO(msatsc)(phen)], (1) (msatsc = methoxyl salicylaldehyde thiosemicarbazone, phen = phenanthroline) and its novel derivative [VO (4-chlorosatsc)(phen)], (2) (4-chlorosatsc = 4-chlorosalicylaldehyde thiosemicarbazone), had been synthesized and characterized by elemental analysis, IR, ES-MS, 1H NMR, and magnetic susceptibility measurements. Their antitumor effects Introduction Chapter (I) 17 on BEL-7402, HUH-7, and HepG2 cells were studied by MTT assay. The antitumor biological mechanism of these two complexes was studied in BEL-7402 cells by cell cycle analysis, Hoechst 33342 staining, AnnexinVFITC/PI assay, and detection of mitochondrial membrane potential (ΔΨm).The results showed that the growth of cancer cells was inhibited significantly, and complexes 1 and 2 mainly caused in BEL-7402 cells G0/G1 cell cycle arrest and induced apoptosis. Both 1 and 2 decreased significantly the ΔΨm, causing the depolarization of the mitochondrial membrane. Complex 2 showed greater antitumor efficiency than that of complex 1 [59]. Eighteen symmetrical bis-Schiff-base derivatives of isatin were synthesized by condensation of the natural or synthetic isatins with hydrazine and were evaluated for their in vitro and in vivo antitumor activities. More than half of the obtained compounds showed potent cytotoxicity according to the MTT assay on five different human cancer cell lines (i.e. HeLa, SGC-7901, HepG2, U251, and A549), with compound 3b 3,3’-(hydrazine-1,2-diylidene) bis(5-methylindolin-2-one) being the most potent compound on HepG2 (IC50" ~ "4.23 μM). 3b was also found to be able to inhibit substantially the tumor growth on the HepS-bearing mice at a dose of 40 mg/kg. The real-time live cell imaging and tracking in the H2B-labeled HeLa cells revealed that 3b could induce mitosis interference and apoptosis-associated cell death. In mechanism study, 3b arrested the cell cycle at the G2/M phase in HepG2 cells by down-regulating the expression of cyclin B1 and cdc 2 [60]. A new cytotoxic copper(II) complex with Schiff-base ligand [CuII(5-Cl-pap) (OAc) (H2O)]·2H2O (1) (5-Clpap= N- 2-pyridiyl methylidene-2-hydroxy-5-chloro-phenylamine), was synthesized and structurally characterized by X-ray diffraction. Single-crystal analysis revealed that the copper atom showed a 4+1 pyramidal coordination, a Introduction Chapter (I) 18 water oxygen appears in the apical position, and three of the basal positions are occupied by the NNO tridentate ligand and the fourth by an acetate oxygen.The interaction of Schiff-base Cu(II) complex with DNA was investigated by UV–visible spectra, fluorescence spectra and agarose gel electrophoresis. The apparent binding constant (Kapp) value of 6.40×105 M −1 for 1 with DNA suggests moderate intercalative binding mode. This copper(II) complex displayed efficient oxidative cleavage of supercoiled DNA, which might indicate that the underlying mechanism involve hydroxyl radical, singlet oxygen-like species, and hydrogen peroxide as reactive oxygen species. In addition, our present work showed the antitumor effect of 1 on cell cycle and apoptosis. Flow cytometric analysisrevealed that HeLa cells were arrested in the S phase after treatment with 1-Fluorescence microscopic observation indicated that complex 1can induce apoptosis of HeLa cells, whose process was mediated by intrinsic mitochondrial apoptotic pathway owing to the activation of caspase-9 andcaspase-3 [61]. Three ternary copper (II) complexes containing 1,10- phenanthroline (phen, 1), dipyrido[3,2-d:2′,3′-f] quinoxaline (dpq, 2) and dipyrido[3,2-a:2′,3′-c] phenazine (dppz, 3), with the formulation [Cu2(NCL)2(H4PASP)]·4.5H2O (1–3) (where NCL=the diimine coligand, H4PASP=N,N′-(p-xylylene)di-2-aminosuccinic acid),were isolated and characterized.The binding of these complexes with calf thymus DNA was studied using UV–visible absorption titration, emission, and circular dichroism spectroscopy, among other methods. The changes in physicochemical properties that occurred upon binding of these complexes with DNA indicate that binding occurs primarily through intercalative interactions. Human tumor cell lines HeLa, PC3, and HepG2 were treated with the copper(II) complexes in vitro and cell survival rate was assessed by 3-(4,5-dimethyl thiazol-2yl)-2,5-diphenyl tetrazolium bromide (MTT) Introduction Chapter (I) 19 assay and crystal violet survival assay. Flow cytometry was performed on treated cells labeled with AnnexinV/PropidiumIodide staining to determine rates of apoptosis. Western blot was performed to determine the expression levels of the apoptotic markers p53, Bax, and Bcl-2. The complexes reduced cell viability and induced apoptosis in cells of human tumor cell lines in a dose-dependent manner. In addition, using a nude mouse xeno graft model, It was found that, the three ternary Cu(II) complexes inhibited human tumor cell growth in vivo. In conclusion, these novel synthetic copper complexes have profound antitumor effects on human tumor cells and are promising therapeutic agents for human tumors [62]. I.4.1.4. Synthetic action on insecticides Schiff-base derived from sulfane thiadizole and salicylaldehyde or thiophene-2-aldehydes and their complexes showed toxicities against insects [63]. α-Amino acid acts as intermediate in synthesis of photostablepyrthriod insecticides [64]. Flourination on aldehyde part of Schiff-base enhances insect acracicidal activity [65]. Schiff-bases (thiadiazole derivatives with salicylaldehyde or o-vanillin) and their metal complexes with Mo(II) showed insecticidal activities against bollworm and promote cell survival rate of mung bean sprouts [66]. I.4.1.5. Plant growth regulator N-acetylated compounds show growth inhibitory activity with seedling of wheat, rye and barley [67]. Schiff-bases showed remarkable activities on plant hormone such as the auxins on root growth [68]. Schiff-base of ester and carboxylic acid showed remarkable activity as plant growth hormone [69]. Schiff-bases of thiodiazole had good plant growth regulatoractivity towards auxin and cytokine [70]. Introduction Chapter (I) 20 I.4.1.6. Antiviral Activities Schiff-bases of gossypol showed high antiviral activity [53]. Ag(I) complexes in oxidation state I showed inhibition against Cucumber mosaic virus; glycine salicylaldehyde Schiff-base Ag(I), gave effective results up to 74% towards C.mosaic virus [71]. I.4.1.7.Other therapeutic activities Several Schiff-bases possess anti – inflammatory, allergic inhibitors reducing activity radical scavenging, analgesic and anti-oxidative action [72]. Thiazole derived Schiff-bases [73] showed analgesic and antiinflammatory activity. Schiff-base of chitosan andcarboxymethylchitosan showed an antioxidant activity such as superoxide and hydroxyl scavenging. Furan semicarbzone metal complexes exhibit significant anthelmintic andanalgesic activites [74]. I.4.2.Catalysts Co(II), Fe(III) and Ru(III) complexes of Schiff-bases derived from hydroxybenzaldehyde were used in oxidation of cyclohexane into cyclohexanol and cyclohexanone in presence of hydrogen peroxide. The most efficient catalysts are the Fe(III) complexes which was unusual because, in general, the Co(II) complexes had high activity for alkane oxidation reactions [75]. chromium-salen complexes are well known catalysts both in heterogeneous and homogeneous [76]. Binucleating complexes of Fe(III), Co(II), Ni(II), Zn(II) with Schiff-bases neytralbis(iminopyridyl)benzene and monoanionicbis (iminopyridyl) phenolate acts as catalysts in the oligomerisation of ethylene [68]. New Mn(II) and Mn(III) complexes of substituted N,N’-bis(salicylidine)-1,2- diimino-2-methylene appeared to be efficient models for peroxidase activity[77]. New Cu(II) complexes of indoxyl thiosemicarbazone (ITSC) showed one pair of well-defined reduction peaks at different potential in Introduction Chapter (I) 21 theforward scan, which represented the reduction of Cu(II)to Cu(I) by one electron process and subsequent oxidation of Cu(I). The quasireversible nature of the Cu(II)/Cu(I) was due to inherent reducing tendency of thiosemicarbazone ligands [78]. Ruthenium and cobalt complexes with Schiff-bases (bis-salicylaldehyde-o-phenylene-diaimine(saloph) and substituted (Cl, Br and NO2) oxidize α-pinene into camphene, 2,7,7- trimethyl sspinene (3-oxatricyclo- 4, 1, 1, o2, 4- octane), 2,3-epoxy, campholene aldehyde and D-verbenone [79]. Ni(II) complexes with bidentate(NN) ligands become an efficient catalyst precursor for olefin oligomerisation in presence of an activator [80]. A wide variety of Co(II) complexes were known to bind dioxygen more or less reversibly and were therefore frequently studied as model compounds for natural oxygen carrier and for their use in O2 storage, as well as in organic syntheses due to their catalytic properties under mild conditions [81]. I.4.3.Antifertility and enzymatic Activity About 20 Zinc enzymes are known in which zinc was generally tetrahedrally four coordinate and bonded to hard donor atoms such as nitrogen or oxygen [82]. The Schiff-base complexes of 2-pyridine carboxaldehyde and its derivatives had been reported to possess high super oxide dismutase activities [83]. The interaction of DNA with complexes [Cr(Schiff-base) (OH2)2]ClO4 was reported [84]. Ternary complexes of Cu(II) containing NSO donor Schiff-base showed DNA cleavage activity. In the presence of 3-mercaptopropionic acid (5mM) as a reducing agent, the complexes (40 μM) showed efficient DNA cleavage activity giving the order NSO-dppz> ONO-dppz> NSO-dpq> ONO dpq [85]. I.4.4.Dyes Chromium azomethine complexes, cobalt complex Schiff-base [86],unsymmetrical complex 1:2 chromium [87] dyes gave fast colours Introduction Chapter (I) 22 to leathers, food packages, wools etc. Azo groups containing metal complexes [89] were used for dying cellulose polyester textiles. Some metalcomplexes are used to mass dye polyfibers [90]. Co(II) complex of a Schiff-base (salicylaldehyde with diamine) had excellent light resistance, storage ability and does not degrade even in acidic gases (CO2) [91]. Novel tetradentate Schiff-base acted as a chromogenic reagent for determination of nickel in some natural food samples [92]. I.4.5. Polymers Photochemical degradation of natural rubber yield amine terminated liquid natural rubber (ATNR) when carried out in solution, in presence of ethylene diamine [82]. ATNR on reaction with glyoxal yield poly Schiff-base [93], which improved aging resistance. Organo-cobalt complexes with tridentate Schiff-base acted as initiator of emulsion polymerization and co-polymerization of dienyl and vinyl monomers [94]. I.4.6. Miscellaneous applications Transition metal complexes with 1, 10-phenanthroline and 2, 2- bipyridine are used in petroleum refining [95]. Popova and Berova reportedthat, copper is good for liver function, its level in blood and urine has influence in pregnancy disorders, nephritis hepatitis, leprosy, anemia and leukemia in children [96]. NLO Metal complexes of Schiff-base derived from tetradentate precursor 1- phenylbutane-1,3-dionemono-S- methylisothiosemicarbazone with ohydroxybenzaldehyde or its phenylazoderivative showed nonlinear optical (NLO) properties. A comparison between complexes of different metals with the same phenylazo-substituted ligand indicated that, the NLO response strongly depends upon the electronic configuration of the metal center [97]. It has been reported that, Zn(II) complexes with Schiff-bases type chelating ligands can be used as an effective emitting layer [98]. In addition, it had also been shown that, Zn(II) complexes with benzothiazoles, which are oxidized Introduction Chapter (I) 23 forms of benzothiazolines are luminescent [99]. Zinc(II) and Cd(II) complexes with N2S2 -Schiff-base ligands are a new class ofluminescent compounds, and the careful derivatization of the substituents on the pendent phenyl rings permits a fine tuning of the emission wavelength [100]. Baker’s yeast contains a benzofuran derivative which actedas an antioxidant preventing haemorrhagine liver necrosis in rats and haemolysis of red cells in vitamin E deficiency [101]. Amino acid Schiff-base complexes derived from 2-hydroxy-1-naphthaldehydes are important due to their use as radiotracers in nuclear medicine [102]. Macrocyclic Schiff-bases of dithiocarbazic acid have many fundamental biological functions, such as photosynthesis and transport of oxygen in mammalianand other respiratory system [103]. Continue to our work, new metal complexes of sulphonyl amino acid derivative ligand have been prepared and spectroscopically characterized and also the cytotoxic activity of the ligands and some of their metal complexes against prostate cancer cell lines (PC-3) were studied |