Isolation And Analysis Of Novel Dehydroabietylamine, Abietic Acid And Oleanolic Acid Derivatives With Special Focus Of Cytotoxic Effects On Hepatocellular Carcinoma

Muhammed, Ayaz Mustufa (2013) Isolation And Analysis Of Novel Dehydroabietylamine, Abietic Acid And Oleanolic Acid Derivatives With Special Focus Of Cytotoxic Effects On Hepatocellular Carcinoma. Doctoral thesis, Baqai Medical University, Karachi.

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Abstract

Hepatocellular carcinoma (HCC) is one of the major concern due to its life threatening and fetal effects. Reported data suggest that it is the fifth most frequent neoplasm and third largest cause of mortality among all the prevailing cancers; with the average life of 6 months after diagnosis including surgical treatment options, suggesting poor prognosis of the disease (Pisani 2002, Sala 2004, Bruix 2005 ).Alarmingly, around 600,000 individuals loss their life every year due to HCC and almost same number of new cases registered worldwide per year (Fallopi 2011, Jemal 2005). Because of high prevalence rate of hepatitis B, C and aflatoxin B food contaminated products, especially Asia and subshahran African countries contributing major chunk of the disease (Bosch 2004, Tanaka 2002). So far available therapies are not very successful in terms of both quality and survival; sorafenib, multikinase inhibitor is only FDA approved drug against HCC (Lachenmayer 2009, Keating 2009).Keeping in mind that structural manipulation is still noteworthy and essentially one of the focused technique for drug efficacy enhancement and finding new novel drugs with potentially broad bioactive spectra; new derivatives of dehydroabietylamine (DAA), abietic acid (AB) and oleanolic acid (OA) were synthesized, purified and subjected for cytotoxic effects with special focus of hepatocellular carcinoma.Screening of 40 new derivatives using SRB protocol on breast cancer and HCC cell lines was performed. Preliminary screening findings concluded that dehydroabietylamine derivative-2 (DAAD-2) with Nacetyl cysteine in ring A at C-18 is the most potent derivative among all trial drugs. DAAD-2 subjected for cytotoxic effects on ten HCCs and one breast cancer cell line. Hep3B cells were the most sensitive with IC50 of 2.00±0.4 ìM on DAAD-2.Similarly, obvious morphological deviations including detachment of cells, cell rounding and low confluency; and statistically significant time dependent changes in sub-G1(8-9 fold increase) and G2/M phase (2 fold decrease) in Hep3B cells after 48 and 72 hours of DAAD-2 treatment were recorded.Alkaline comet assay was performed to see the single stranded DNA breaks and WHSC1 gene expression experiments were also performed.The present outcomes also exhibit the structural significance of our trial novel drugs, their vital influence and correlation on cytotoxic and cell proliferation studies. Our current findings provide sufficient evidence that DAAD-2 induces growth attenuation of HCC cells by apoptotic mechanism of death. Further microarray and invivo studies on anti carcinogenic properties of different kind of cancers including HCC and its mechanism of action can be opted to rationalize the role of DAAD-2 in future cancer research and therapy.

Item Type: Thesis (Doctoral)
Uncontrolled Keywords: Effects, Isolation, Cytotoxic, Analysis, Focus, Novel, Carcinoma, Dehydroabietylamine, Derivatives, Hepatocellular, Abietic, Oleanolic, Acid
Subjects: Q Science > QD Chemistry
Depositing User: Muhammad Khan Khan
Date Deposited: 07 Oct 2016 06:40
Last Modified: 07 Oct 2016 06:40
URI: http://eprints.hec.gov.pk/id/eprint/2340

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