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Significance of Breast cancer research:      

Cancer is one of the chronic
diseases that impose huge pressure on the medical world to tackle the condition
efficiently. Cancer is generally expressed out like a lump of newly growing
tissue, crawling like a crab and penetrating deeper in the host, disturbing the
normal functions of the organs. If a cancer cell dies no cancer can result and
it is deleted from the population and retrieved from reproduction. The problem
arises with the cells that have been damaged to the extent that mechanism
controlling their growth is no longer effective. At some point there is a
switch operating from restrained growth to cancer proliferation favoring the
malignant growth. The etiology for cancer includes wide variety of factors. The
most recent authoritative estimates suggest that up to 80% of cases are due to
causes that are environmental, including diet, lifestyle, specific habits such
as smoking, as well as exposure in the working place. The toxic chemicals
present in out diet, like synthetic or natural chemicals, nature’s pesticides
are carcinogens (Ames, 1989) which have the ability to damage the DNA leading
to cancer.

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Breast cancer (BC) is the most
occurring problem of its form where it still remains as the second largest reason
for cancer-related mortalities in women population (Jamal, 2011; DeSantis, 2011). It is observed that nearly 90% cancer
related death is not merely due to the primary tumor, but by the occurrence of
metastasis at distant locations (DeSantis, 2011). Reports tell that approximately 30% of women
diagnosed with early breast cancer have the metastasis or recurrence started
already (O’Shaughnessy, 2005). On the molecular basis,
understanding the mechanism of metastasis is very important in treating breast cancer.
Though precise mechanisms underlying the breast cancer metastasis is either not
discovered or understood fully, studies suggest epithelial-mesenchymal transition (EMT) could
contribute as a major mechanism involved in breast cancer metastasis (Creighton , 2010). BC is formed when cells in the
breast grow out of control enabling them to invade nearby tissues or even
spread through the body. Any of the types of tissues in the breast can form
cancer cells, but usually cancer comes from either ducts or glands in the
breast. It may take months or years for a tumor to get large enough to get
noticed in the breast, so screening is done using mammograms, to identify the
tumor. 25% to 30% of axillary node positive breast cancer patients get back the
disease within 10 years and proved to be fatal in some cases.

 

Breast cancer in the Kingdom:      

As far as Saudi Arabia is concerned, incidence of BC was 22.4 for every
ten million women as per IARC reports (Alghamdi, 2013). Age standardized mortality rate (ASMR) was 10.4
women out of each 10 million women in the kingdom (Alghamdi, 2013).  According
to the Saudi cancer society (SCR) report, BC is the most common cancer among
Saudi women in 14 year period. The
evocative epidemiology of BC observations in Saudi Arabia drives immediate
attention to tackle this condition both locally and globally.

 

New
Chemical Entities as effective chemotherapeutics:

 

New Chemical Entities (NCEs) are of primary focus in
recent years, where they contribute in specific inhibition of the biological
process targeting the cancer cells with minimal or least effects on normal
cells. Major advantages of NCEs are they target cancer cells at the molecular
level to inhibit or down regulate the biological process to control cancer cell
proliferation. Thanks to the recent advances in cell biology which has provided
variety of immortal cancer cell lines to screen NCEs in particular cancer
models that mimic in vivo cellular growth.  On the other hand, advances in medical
chemistry have added many synthetic organic derivatives to be screened for
biological efficacy in cancer. Novel drug discovery using NCEs, in particular has gained momentum in
the scientific communities across different disciplines like cell biology,
biochemistry, pharmacology, hematology etc. Some of these compounds arise as
potential hits and add value to the novel drug discovery focusing effective,
economical, least toxic chemotherapeutics against cancer. 

 

Arylidene
indanones belong to a class of chemicals which closely resemble chalcones, added
with ?,?-unsaturated ketone to form a cyclic 5 membered ring. These small molecules
originate from 1-indanone and benzaldehydes through an
aldol reaction (Jose C, 2017). Due to their easy synthesis protocol and structural modifications, it
is possible to synthesize cost effective structural analogues of active
compounds. Arylidene indanones have demonstrated potential antitumor properties
by specific action on the inhibition of the various pathways canonically
providing the mechanistic fuel for the tumor or cancer development (Hari and
Pati, 2007). Indanones are shown to reverse the multi-drug resistance (MDR) in
cells caused by standard anticancer drugs and synergistically act with the
drugs to stop cancerous cell proliferation (Kars et al 2006). We have established
2-arylidene-4, 7-dimethyl indan-1-one to be effective against breast
adenocarcinoma cells by G2/M cell cycle arrest (Prasanna and Harish
2010). The same compound was also effective against lung cancer models by
inhibiting AKT enzyme. Our results suggest DNA damage-mediated activation by
this compound in lung cancer cells leading to extensive apoptosis through the
mitochondrial pathway. Many other potential uses of the Arylidene compounds are
reported, including its activity on Alzheimer’s diseases  (Hari and Pati, 2007).   

 

Approach of this study:

In this context, we have
synthesized structural analogues of 2-arylidene-4, 7-dimethyl indan-1-one by
rational drug design. Though we have not used high throughput screening
strategy for the current approach, more economical and reliable cheminformatics
tools were used which gave us few synthetic analogous, which proved active in
docking studies for MET kinase enzymes. As MET kinase is a well-established
target for many forms of BC, our docking studies were more efficient means for
screening the new analogues in a quick and dependable manner. The current
proposal therefore intends to evaluate the anti-cancer activity of these
compounds for activity in different breast cancer models. The project will
focus on the in vitro biological efficacy of the lead compounds in the BC
malignancies and their respective downstream targets. In vivo efficacy
of the compounds in xenograft animal models would also be determined. In short,
the current investigation will focus on in-silico screening, in-vitro
evaluation with different functional assays to confirm the target specific
activity of our NCEs. Additionally in vivo animal studies will be
performed to assess the real time drug action very much necessary taking the
lead molecule to the next phase of the investigations.

 

 

 

 

 

 

 

 

 

 

 

 

 

 

  

 

 

 

 

 

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