Pharmacophore Searching of Benzofuran Derivatives

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2009 Bentham Science Publishers Ltd. Pharmacophore Searching of Benzofuran Derivatives for Selective CYP19. Aromatase Inhibition. Shuchi Nagar*. ,1.
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Letters in Drug Design & Discovery, 2009, 6, 38-45

Pharmacophore Searching of Benzofuran Derivatives for Selective CYP19 Aromatase Inhibition Shuchi Nagar*,1, Md Ataul Islam1, Suvadra Das1, Arup Mukherjee1 and Achintya Saha*,1,2 1

Department of Chemical Technology, University of Calcutta, 92, A.P.C.Road, Kolkata 700 009, India

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School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina 27599, USA Received September 09, 2008: Revised October 30, 2008: Accepted October 30, 2008

Abstract: The cytochrome-P450 (CYP) complex aromatase is the rate-limiting step in the production of endogenous estrogen. This synthesis can be controlled with aromatase inhibitor (AI). Different types of AIs are under extensive study for use in the treatment of advanced breast cancer in postmenopausal patients. In view of such significance, the present study explored the pharmacophores of benzofuran derivatives containing pyridine, imidazole and triazole substituents for inhibiting selective aromatase enzyme, CYP19 activity. Implementing classical QSAR (R2=0.858, Q2=0.737, s=0.349, R2test=0.839) and space modeling (R2=0.908, cost=179.138, rmsd=1.235, R2test=0.867) approaches, it has been explored that molecular hydrophobicity, presence of suitable ring substituent and hydrogen bond acceptors are the crucial key features of the benzofuran scaffold for imparting CYP19 inhibitory activity. Moreover steric properties of the molecule have influence on the activity.

Keywords: Pharmacophore mapping, QSAR, Space modeling, Benzofuran derivatives, CYP19 aromatase inhibition. INTRODUCTION Approximately one-third of breast carcinomas require estrogens for their growth. Production of estrogens takes place in many tissues throughout the body [1], including the ovaries, adipose and breast tissues, muscle and liver. The importance of the mutagenic effects of estrogen on breast cancer are well established from clinical and laboratory studies. After menopause and the decline in ovarian estrogen production, estrogen synthesis is increased in extragonadal sites, such as adipose tissue [2], which is the main source of circulating hormone, predominantly estrone. In fact, level of estrogen in the breast tissue has been found to be several times higher than in the plasma of postmenopausal patients [3]. Evidence suggests that estrogens produced by adipose tissue play important role in the pathogenesis of breast cancer [4]. Inhibiting the effects of peripherally formed estrogen can be achieved either by blocking the estrogen receptor with antiestrogens or blocking the synthesis of estrogens with aromatase inhibitors (AIs). Estrogens (estradiol (E2) and estrone (E3)) are synthesized by the aromatase enzyme in the ovaries. Aromatase is a cytochrome P450 (CYP) enzyme and shares features with other enzymes in this class. It is noted that the aromatase activity of breast adipose tissue in the proximal site is higher than the distal site of tumor [5]. Unique aromatization reaction [6] involving loss of the C-19 carbon and conversion of the steroidal A ring to an aromatic ring provides the opportunity [7] to develop inhibitors selective for aromatase enzyme. Aromatase is a particularly good target for inhibition,

*Address correspondence to these authors at the Department of Chemical Technology, University of Calcutta, 92, A.P.C.Road, Kolkata 700 009, India; Tel: + 91-33-2350-8386; Fax: +91-33-2351-9755; E-mail: [email protected] School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina 27599, USA; E-mail: [email protected] 1570-1808/09 $55.00+.00

especially cytochrome P450 19 (CYP19), because it mediates the last step in steroid biosynthesis and is the ratelimiting for estrogen production. Over the past 20 years, inhibitors of the aromatase enzyme have moved from being experimental to established agents for endocrine treatment of advanced breast cancer, and are currently under consideration for large multicentre trials in the adjuvant therapy of primary breast cancer. There are several different AIs [8] that are under investigation, one of which being benzofuran derivatives. These derivatives have emerged as a new class of potent AIs, which showed promising as chemotherapeutic agents for the treatment of estrogen-dependent tumors [9]. These inhibitors bind to the active site of CYP19 through coordination of a heterocyclic nitrogen lone pair of electrons with the Fe3+ of the heme in the active site of the enzyme [9]. In the present study, substituted benzofuran derivatives [10-13] are targeted to derive the structural and molecular properties requirement for inhibiting selective CYP19 aromatase activity, using quantitative structure activity relationship (QSAR) and space modeling studies. QSAR being a mathematical methodology is statistically validated, and mostly used to correlate experimental or predicted properties derived from chemical structures with biological activities. 3D-QSAR approaches on smaller datasets are used to build models [14-18] for inhibition of CYPs. Kriegl et al. [19] (R2