DESIGN, SYNTHESIS AND ESTROGEN RECEPTOR BINDING STUDY OF FLAVONE AND INDANONE BASED LIGANDS

Abstract

The thesis entitle “Design Synthesis and Estrogen Receptor Binding Study of Flavone and Indanone Based Ligands” is divided into five chapters. The present work is aimed to synthesize the novel flavone and indanone based ligands and their anti-proliferative evaluation against breast and cervical cancers. The novel methods are developed in the deprotection of hydroxyl groups for alcohols and phenols. Also, novel reagents are explored for the McMurray coupling reaction using different metal catalysts. All synthesized compounds are characterized using standard analytical techniques like IR, 1HNMR, 13C-NMR, GC-MS, HRMS, etc. The thesis has been divided into five chapters for further transparency and clarity and elaborated as follows: CHAPTER-1 Introduction The first chapter describes the introduction of flavones, indanone and their biological applications, deprotection methods of hydroxyl groups for alcohols and phenols and reagents in the McMurray coupling reaction. Flavone, a sub-class of flavonoid compounds (polyphenolic phytochemicals), is a secondary metabolite of plants which plays important role in various biological processes. Various natural, semi-synthetic and synthetic derivatives of flavones have been synthesized and evaluated for several therapeutic activities like anti-inflammatory, antiestrogenic, anti-microbial anti-allergic, anti-oxidant, anti-tumour and anti cytotoxic activities. Indanone, indenone and indane skeletons are important moiety present in different natural products and biologically active compounds. For example, indenone (3-(2,3- dihydrobenzofuran-6-yl)-5,6-dimethoxy-2-methyl-2,3-dihydro-1H-inden-1-one) was isolated from the fruits of virola sebifera, indanone (pterosin C) is a cytotoxic and antibacterial natural products, donepezil, a potent acetylcholinessterase inhibitor prescribed for the treatment of Alzheimer’s disease, is a marketed drug (Aricept TM), and indenone (5-(4-chlorophenyl)-3- (methylsulfonyl)-2H-indeno[5,6-d]oxazole-2,7(3H)-dione) is a structural analogue of the selective COX-2 inhibitor nimesulide (Fig.1) O MeO MeO NBn.HCl Me O Me CH3 R HO R = H, Pterosine B R = OH, Pterosine C Donepezil hydrochloride (AriceptR) O O MeO MeO O O N O Cl MeO2S 5-(4-chlorophenyl)-3- (methylsulfonyl) -2H-indeno[5,6-d]oxazole- 2,7(3H)-dione 3-(2,3-dihydrobenzofuran-6-yl)- 5,6-dimethoxy-2-methyl-2,3-dihydro -1H-inden-1-one Fig. 1: Bioactive compounds containing indanone and indenone core. CHAPTER-2 Part-A: Highly efficient deprotection of phenolic tetrahydropyranyl and methoxymethyl ethers and sequel cyclization to indanones using Sn (IV) Cl4 catalyst Naseem Ahmed*a, Gulab Khushalrao Pathe a and B. Venkata Babu a Tetrahedron Letters 2014, 55, 3683 – 3687. In this chapter, we have developed a novel, rapid and efficient deprotection method for the phenolic THP and MOM ethers and sequel intramolecular Friedel-Crafts alkylation reaction of THP and MOM protected chalcone epoxides to indanone by SnCl4 catalyst under mild conditions. The reaction took place in 2-3 min to gave the products 1a-1s in excellent yield (90- 98%) at 0 0C without affecting the other functional groups (Scheme 1). These products were fully characterized on the basis of their spectral analysis 1H-, 13C-NMR and GC-MS. Scheme 1: Detetrahydropyranylation and demethoxymethylation of phenol and sequel cyclization reaction. Part-B: SnCl4 or TiCl4: Highly efficient catalysts for detetrahydropyranylation and demethoxymethylation of phenolic ethers and sequel one-pot asymmetric synthesis of 3- aryl-2-hydroxy-2, 3-dihydroindan-1-ones from chalcone epoxides Naseem Ahmed*a, Gulab Khushalrao Pathea RSC Advances 2015, Accepted. In this section, we have described the role of novel SnCl4 or TiCl4 catalysts for the deprotection of phenolic THP and MOM ethers and sequel one-pot regioselective synthesis of trans-3-aryl- 2-hydroxy-1-indanones (R/S) by intramolecular Friedel-Crafts alkylation of chalcone epoxides with enantiomeric excess up to 99.9% under same conditions. Epoxide ring opening followed by intramolecular Friedel-Crafts alkylation was performed in the presence of TiCl4 to obtain the diastereoisomerically pure trans (2R, 3S) indanone derivatives 6a-e (Scheme 2). Scheme 2: Synthesis of enantioselective 3-aryl-2-hydroxyindan-1-ones. CHAPTER- 3 Part-A: Zn-SnCl4: A novel reductive system for deoxygenative coupling of aliphatic, aromatic, chalcone epoxide and indanone carbonyl compounds to olefins Gulab Khushalrao Pathe and Naseem Ahmed*, Tetrahedron Letters 2015, 56, 1555-1561. In this part, SnCl4-Zn complex provided a novel reductive system in the deoxygenative crosscoupling of aliphatic, aromatic, chalcone epoxide and indanone carbonyl compounds to olefins in high yield (55-86%) at reflux temperature in THF. The advantage of this reagent is inexpensive, short reaction time and high yield compare to the reagents used in the McMurry cross-coupling reaction. These products were fully characterized on the basis of their spectral analysis 1H-, 13C-NMR, HRMS and GC-MS. Scheme 3: SnCl4-Zn mediated deoxygenative cross-coupling reaction. Part-B: Design, Synthesis of McMurry cross-coupled indanophen, analogs of Tamoxifen by novel SnCl4-Zn reagent and Anti-Proliferative Evaluation of Flavone-Estradiol adduct and Indanone based Ligands against Breast Cancer Cell Line Gulab Khushalrao Pathe, Naveen Konduru, Iram Parveen and Naseem Ahmed*, European Journal of Medicinal Chemistry 2015, Under Review. In this section, we described the synthesis of McMurry cross-coupled indanophen, analog of tamoxifen using novel SnCl4-Zn reagent and anti-proliferative evaluation of indanone based ligands and flavone-estradiol adduct, against human cervical cancer cell line (HeLa) and human breast cancer cell lines (MCF-7& MDA-MB-231). The compounds 3ac, 3ad, 3ae, 3ao displayed the best activity having IC50 = 2.13 - 3.81μM and rest of the compounds also showed comparable activity to the standard drug doxorubicin having IC50 = <28 μM. The flavonesestradiol adduct 6ab, 6ad showed excellent activity than the standard drug having IC50 values in μM 2.85 ± 0.165 & 2.42 ± 0.226 and 3.64 ± 0.276, 2.93 ± 0.137 against MCF-7& MDAMB- 231 and 2.17 ± 0.183, 2.56 ± 0.322 against HeLa respectively. The structure of all the compounds was confirmed by 1H-, 13C-NMR, HRMS, ESI/MS and IR analysis. Scheme 4: Synthesis of Tamoxifen Analogs. CHAPTER-4 SeO2 in water: A mild and efficient promoter for deprotection of acetyl, methoxymethyl and tetrahydropyranyl ethers and sequel oxidation of carbonyl carbons Gulab Khushalrao Pathea and Naseem Ahmed*a, RSC Advances 2015, 5, 59114-59119. In this chapter, we have reported SeO2-water system provided an efficient and one-pot green deprotection of acetyl, THP and MOM ethers in alcohols and phenols and sequel oxidation of alpha carbonyl carbons to dicarbonyl functional groups at 80 0C in 30-60 min. Using substrate: SeO2 in 1:3 ratio, the reaction gave excellent yield (85-95%) for acetyl and THP deprotections and a moderate yield (30-40%) for MOM deprotection without affecting other functional groups. However, substrate: SeO2 in 1:1 ratio in 1ml H2O, got only deprotection product in 85- 95% yields for Ac and THP and demethoxymethylation gave moderate yields (30-40%) at 80 0C in 30-60 min (Scheme 6). The products were characterized on the basis of their spectral analysis 1H- and 13C-NMR, GC-MS. Scheme 6: Deprotection of acetyl, MOM and tetrahydropyranyl ethers and sequel oxidation of active methylene in SeO2-water promoter. CHAPTER-5 Part-A: Mild and efficient reductive deoxygenation of epoxides to olefins with SnCl2/NaI as a novel reagent Gulab Khushalrao Pathea and Naseem Ahmed*a, Synthesis 2015, Ahead of print. In this chapter, we have developed a novel, highly efficient protocol for deoxygenation of aliphatic and aromatic epoxides, chalcone epoxide, nitro styrene epoxide and nitrochromene epoxide to corresponding olefins using SnCl2/NaI in ethanol as a novel reagent, for this conversion with up to 96% yield. This methodology has more importance than the earlier methods such as inexpensive reagents, high yield, short reaction time, environment friendly (Scheme 7). These compounds were further characterised by NMR, IR and GC-MS. Scheme 7: Deoxygenation of aliphatic and aromatic epoxide by SnCl2/NaI. Part-B: Efficient and green protocol for the eliminative deoxygenation of aliphatic and aromatic epoxides to olefin with polyphosphoric acid as a novel catalyst Gulab Khushalrao Pathea and Naseem Ahmed*a, Helvetica Chemica Acta 2015, Under Review. In this part, we have developed a highly efficient and green catalytic deoxygenation of aliphatic and aromatic epoxides, chalcone epoxide, nitro styrene epoxide and nitrochromene epoxide to olefin using 30 mol% of polyphosphoric acid up to 96 % yields. This methodology have more importance than the earlier methods such as inexpensive reagents, high yield, short reaction time, environment friendly and solvent free. These compounds were further characterised by NMR, IR and GC-MS. Scheme 8: Deoxygenation of nitrostyrene epoxide by polyphosphoric acid catalyst.