الفهرس 
Physical and Spectroscopic TechniquesOnly 14 pages are availabe for public view
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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)
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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)
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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)
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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