الفهرس 
Neocryptolepine SynthesisOnly 14 pages are availabe for public view
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Abstract
This thesis includes three chapters. The first chapter is the introduction which
comprises an updated literature survey of synthesis, reactions and biological
applications of neocryptolepine and its analogues as well as their regioisomers:
cryptolepine, isocryptolepine an indoloquinoline alkaloids isolated from Cryptolepis
sanguinolenta). This review included the most important methods of total synthesis of
these alkaloids as well as their reactions and biological activities are considered. The
naturally occurring neocryptolepine (5-methylindolo [2,3-b]quinoline) and its
analogues exhibited prominent anticancer and antimalarial activity. However, the
main problem of this class of compounds is their poor aqueous solubility, hampering
their bioavailability and preventing their clinical development. To overcome such
problem of insolubility, and also to improve the physicochemical and the
pharmacological properties. In this context, this work was designed to encapsulate or
nanoformulate such biologically active compounds into mesoporous silica oxide
nanoemulsion with aim to improve their delivery and selectivity toward the diseased
cancer cells with minimum effect on healthy ones.
The second chapter is devoted to results and discussion which included the
preparation of 11-chloroneocryptolepine 5 that was achieved by chlorination of 1Hmethylindole-
3-carboxylate 1 with N-chlorosuccinimide in the presence of 1,4-
dimethylpiperazine, followed by the addition of N-methylaniline 2 as a
trichloroacetate salt. The resulting intermediates 3 were cyclized in boiling diphenyl
ether to give the required tetracyclic indoloquinolinone 4 core structure of the
neocryptolepine nucleus, which upon reaction with phosphorus oxychloride give the
corresponding key intermediate 11-chloroneocryptolepine 5. This three-step approach,
starting from easily accessible intermediates, was employed for the preparation of
new analogues with amines as substitution pattern in good yields, and high degree of
purity. Thus, Synthesis of aminoalkylamino neocryptolepine 7a-e were achieved after
reaction of 5 with an excess of appropriate diamines 6a,b via a nucleophilic aromatic
substitution (SNAr) reaction mechanism, in which the substitution of the amino group
to chlorine atom of 5 at the unsaturated sp2 C-11 position of 5 takes place as depicted
in results and discussion section. This reaction proceeds through the addition of the
amino group (: Nu ) to form a resonance-stabilized anion with a new C N bond
followed by elimination of HCl as triethyl amine hydrochloride salt to afford the end products 7a,b as depicted in the plausible mechanism of this reaction shown in results
and discussion .
Moreover, the structures of of target compounds under study 7a,b have been
established on the basis of IR, 1H NMR, 13C NMR and mass spectral analysis and the
analytical data of all compounds are in agreement with their proposed structure.
The mesoporous silica nanoparticles were prepared by using tetraethyl ortho silicate
and span 60 as precursor and surfactant respectively. In this study, three different
concentrations of aminoneocryptolepine 7b denoted as NPA (0.2, 0.3 and 0.6 g) were
used to evaluate the potential efficiency of the their mesoporous silica oxide
nanoemulsion. The results illustrated that the nanoparticles were formed with
spherical size and exhibited small size (less than 500 nm with the utilization of high
concentration of synthesized amino-neocryptolepine analogue 7b (NPA, 0.6 g) with
good stabilization against agglomeration (more than -30 mv). In addition, the asprepared
nanoemulsions had no phase separation as observed by our naked eyes even
after 30 days. The result depicted also that the fabricated silica oxide nanoemulsion
has the abilit
cell viability of the produced nanoemulsion system loaded with different
concentrations of NPA was greater than silica oxide nanoemulsion without loading
affirming that NPA had positive impact for increasing the safety and cell viability of
the whole nanoemulsion. Moreover, the Cytotoxicity of the prepared nanoemulsions
loaded with NPA (7b) as anticancer drug model in vitro was evaluated and the results
proved the biocompatibility of model with no toxic effect. Based on these obtained
promising data, it can be considered that the prepared NPA loaded silica oxide
nanoemulsion seem to have potential for use as an effective anticancer drug nanosystem.