SYNTHESIS AND ANTICANCER ACTIVITY OF FLAVONE DERIVATIVES AGAINST ESTROGEN DEPENDENT CANCERS BY RATIONAL APPROCH

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About Authors:
Vanraj Thakor1*, Jalpa Kher2, Fenil Bhayani1, Bhavini Atodaria1, Malleshappa Noolvi1
1Shree Dhanvantary college of pharmacy, Kim, Surat, Gujarat, India.
2Ashok & Rita Patel institute of Biotechnology, New Vallabh Vidyanagar, Gujarat, India
vanraj7777@gmail.com, jkher3333@gmail.com

Abstract
Aromatase and 17-ßHSD inhibitors are main target of pharmacological interest for the treatment of estrogen dependent cancers. Chalcones, Coumarins, Flavones, Isoflavones have been reported for such inhibition and are used for treatment of brest tumors. So in this topic, Flavone derivatives containing Imidathiadiazole, Thiadiazole, Triazole and benzimidazole hetrocycles synthesised by using simple laboratory reagents like 2-Hydroxy Acetophenone and 4-Hydroxy Benzaldehyde to convert chalcone leads to formation of Flavones by cyclazation using Microwave and followed by attachment of different hetrocycles to form Flavone derivatives and charactrarized by IR, 1H NMR, 13C NMR spectroscopy and elemantal analysis. These Flavone derivatives found to exhibit moderate to high inhibitory activity against Estrogen dependent cancers.

REFERENCE ID: PHARMATUTOR-ART-2107

PharmaTutor (ISSN: 2347 - 7881)

Volume 2, Issue 2

Received On: 01/012/2014; Accepted On: 12/01/2014; Published On: 10/02/2014

How to cite this article: V Thakor, J Kher, F Bhayani, B Atodaria, M Noolvi, Synthesis and Anticancer activity of Flavone Derivatives against Estrogen Dependent Cancers by rational approach, PharmaTutor, 2014, 2(2), 33-43

INTRODUCTION:
Cancer[1] is a class of diseases characterized by uncontrolled division of cells and the ability of these cells to invade other tissues, either by direct growth into adjacent tissue (invasion) or by implantation into distant sites (metastasis). There are so many types of estrogen [2] dependent cancers in which here more emphasize on Breast cancer and uterine cancer. Breast cancer is one of the most common cancers in women. Due to various reasons, the estrogen receptors are over-expressed in these tumour cells and, hence, estrogenicity is enhanced by many folds leading to excessive proliferation. Estrogens are hormones which mainly act on female reproductive system. Estrogens have some beneficial effects as well as harmful effects. Like in females breast and uterine cell proliferation, milk production, cholesterol balance, increase bone strength. Estrogens can also be harmful in case like brest and uterine cell proliferation. Estrogen enhances breast or uterine cancer risk. Cancer is caused by DNA damage (mutations) in genes that regulate cell growth and division.

Normal cells mutated by heredity, radiation chemicals or DNA error during cell cycle which cause the cancer. In addition in excess of estrogen normal cell divide to causes cancer. Estrogen can cause cell proliferation to normal cell as well as cancerous cells.

Figure 1: Effect of estrogen on cell proliferation

Mechanism of Estrogen, SERMs and SDR class of pharmacophores
Estrogens, Antiestrogens, SERMs, SDR, Aromatase class of drugs having different effect on Estrogen receptors. Estrogen molecules bind to the estrogen receptors then co-activators bind to the site and activate estrogen response element this leads to gene activation and gene expression takes place. This leads in next step transcription and translation to form specific proteins. These specific proteins act on cell system in different way. But in case of Antiestrogens and SERMs they bind to estrogen receptors but co-activators could not bind to the site. SDRs and Aromatase inhibitors act differently they stop estrogen bind to receptor by blocking biosynthetic pathways.

Figure 2: Mechanism of Estrogen and Antiestrogens/SERMs

Many of the currently available anticancer drugs are not able to differentiate between normal and cancerous cells or to overcome primary or secondary resistance mechanisms evolved in the cancer cells[3].

Thus, there is a need for new anticancer agents which is having high potency, less toxicity in neoplastic cells, and unique target of action. Presently, cancer therapy interfering with a single biological molecule or pathway has been successfully utilized.

However, there is general belief that agents modulating more than one target could have superior efficacy compared to single target drugs. Therefore, modulating multiple targets simultaneously can be achieved by the combination of multiple drugs with different mechanisms or by single chemical entity that could modulate several targets of a multi-factorial disease. As a result, there is increasing interest in the discovery of agents that concomitantly address more than one biological target for cancer treatment.

Effects of phytoestrogens on human health have been reported for decades. These include not only beneficial action in cancer prevention but also endocrine disruption in males. Since then many molecular mechanisms underlying these effects have been identified. Targets of phytoestrogens comprise steroid receptors, steroid metabolising enzymes, elements of signal transduction and apoptosis pathways, and even the DNA processing machinery. Understanding the specific versus pleiotropic effects of selected phytoestrogens will be crucial for their biomedical application.

Phytoestrogens include chalcones, flavones and iso-flavones which are non-steroidal compounds possessing estrogenic activity. As earlier mentioned need for molecule which is having effect on several targets can be fulfilled by these flavones. This flavone class of drugs can effect on multiple receptors and may be acts like estrogen receptor activators, SERMs, Aromatase inhibitors, 17-β HSD inhibitors and protein kinase B inhibitors.

As shown in figure chalcone, flavones and estradiol having almost same structural similarities and so such molecules reported to have above mentioned activity on estrogen dependent cancers.

Figure 3: Showing structural similarities between Chalcone, Flavone and Estradiol

Figure 4: Currently available marketed drugs acting on Estrogen dependent Cancers

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