الفهرس 
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Abstract
The lung, colorectal and female breast cancers are the top three types
of cancer in incidence and are responsible for one-third of the incidence and
mortality of cancer. Although, the incidence and mortality brain and CNS
cancers are rare but require difficult regimen of treatment.
The mitotic spindle is one of the validated target in cancer chemotherapy.
Well-known anti-proliferative agents, such as taxanes and vinca
alkaloids, which target tubulin are clinically successful anticancer agents for
certain types of cancer. However, these spindle poisons have certain
limitations, such as resistance and toxicities, making it necessary to find other
ways of targeting the mitotic spindle. A crucial family of motor proteins that
has been shown to be vital for mitosis and that is developing as a target for
chemotherapeutic intervention is the kinesin family. Mitotic kinesin Eg5 is a
member of kinesin family that essential for bipolar spindle formation. The
inhibition of Eg5 leads to the activation of the spindle checkpoint, mitotic
arrest at G2/M phase and subsequent cell death in certain tumor cell lines.
A series of thirty nine 3,4-dihydropyrimidine derivatives bearing the
heterocyclic 1,3-benzodioxole moiety at position 4 in addition to different
substituents at positions 1, 2, 3, 5 and 6 were designed, synthesized via
multicomponent reaction of Biginelli type by cyclocondensation of aldehyde,
urea or its derivatives and active methylene compounds and characterized by
elemental analysis and the spectroscopic data (1H NMR, 13C NMR, and mass
spectroscopy) and evaluated as inhibitors of Eg5 kinesin enzyme.
The target compounds were screened for their cytotoxic activity
towards 60 cancer cell lines according to national cancer institute (NCI),
USA protocol at one dose. Out of thirty nine synthesized compounds, there
were five compounds showed the best antitumor activity against most cell
lines in single dose experiment among the synthesized compounds. Only one
compound was selected by NCI (USA) to be subsequently tested in 5-doses mode and displayed high selectivity towards CNS cancer, prostate cancer and
leukemia subpanel with selectivity ratios of 22.30, 15.38 and 12.56,
respectively at GI50 level. Some representative compounds were assayed
against kinesin enzyme with IC50 values ranged from 1.2 to 18.71 μM which
were more potent than monastrol (IC50 = 20 μM). The most active
compounds were evaluated against human embryonic kidney (HEK 293); a
human normal cell line and exhibited lower toxicity towards HEK 293 in
comparison to doxorubicin (DOX) as a reference drug (IC50 = 11.34 μM).
DNA flow cytometric analysis was performed to measure the effect of two
selected compounds on induction of cycle of NCI-522 cancer cell and SNB-
75 cancer cell in the presence of positive and negative controls. Cell cycle
analysis of selected cancer cells showed cell cycle arrest at G2/M phase.
Further, the assay of levels of active caspase-3 and caspase-9 was
investigated to provoke apoptosis in MDA-MB-435 melanoma cell line and
NCI-H522 lung cancer cell line. Treatment of these cell lines with selected
compounds significantly increased the expression levels of active caspases 3
and 9 in comparison to the control.
Molecular docking study was performed for selected target compounds
along with the reference compound (monastrol) into the allosteric site of
kinesin spindle protein 1Q0B to study the comparative differences in the
binding interactions of these synthesized compounds at molecular level,
explore the structure activity relationships and to explain the data obtained
from the cytotoxicity activity.