Design and Synthesis of Novel Nuclear Receptor Modulator as Pharmaceutical Agents

Abstract

Nuclear receptors are a large family of structurally related ligands-inducible transcription factor, including steroid receptor (SRs), thyroid/retinoid receptors (TR, RARs, RXRs), vitamin D receptor (VDR), LXR, PPARS and orphan receptor (for which no ligand has been yet identified). These receptors play a crucial role in maintaing homeostasis in multicellular organism. Besides this nuclear receptors have shown direct relation with many diseases such as estrogen receptor, is associated with breast cancer, osteoporosis, Alzheimer’s and fertility and fertility regulation and similarly peroxisome proliferators activated receptor is associated with type-2 diabetes and colon cancer. We focused our research work on design and synthesis of novel scaffolds which act as nuclear receptor modulator and used for the prevention and treatment of various high profile human diseases such as breast cancer, endometrial cancer, osteoporosis, diabetes, and fertility regulation. Among the nuclear hormone receptors super gene family, we are most interested in estrogen receptor (ER) and also peroxisome-proliferators-activated receptor for anti-diabetic activity. As estrogen action is also associated with many health problems in women. In order to use estrogen receptor modulator in its full length, we have designed some selective estrogen receptor modulator (SERMs). The aim of the present dissertation work is synthesis and identification of some novel nuclear receptor modulators scaffolds with selective agonistic as well as antagonistic activity in desired tissue profiles and further the biological evaluation of these scaffolds in vitro cell line model and in vivo animal models for predictive clinical utility. The thesis entitled “Design and Synthesis of Novel Nuclear Receptor Modulator as Pharmaceutical Agents” describes our endeavors leading to the accomplishment of newer anti- proliferative, anti-osteoporotic, anti-thrombotic and anti-diabetic agents. The thesis has been organized under seven main chapters as summarized below: The first chapter presents a concise review on “Organic Reactions in Water” for the synthesis of diverse heterocyclic scaffolds. Because of the insolubility of organic substrates in water, it was generally avoided in synthetic chemistry till the end of last century. Nevertheless, chemical transformations in aqueous solvents are not new to organic chemists. On the contrary, they have attracted the attention of scientists for many years: the first use of water for an organic reaction could be dated back to Wöhler’s synthesis of urea from ammonium cyanate. As illustrated in this review, a variety of strategies have been investigated in order to expand the scope of water-based organic synthesis to embrace also highly hydrophobic reactants. The review has been classified according to various organic reactions in aqueous media. The second chapter of the thesis illustrates the “Synthesis of dihydro-1Hnaphtho[ 1,2-e][1,3]oxazines as Anti-proliferative and Anti-osteoporotic Agents”. Encouraged by the results of previous chapter (Chapter 2) and our lab work on the synthesis of the third generation SERMs we synthesized a series of substituted naphthoxazine analogues and evaluated their anti-proliferative, and anti-osteoporosis activity. Double Mannich-type multicomponent reaction for the synthesis of dihydro-1H-naphtho[1,2- e][1,3]oxazine derivatives has been developed in water via SDS promoted microwave assisted methodology. Some derivatives of this series showed less inhibition against MCF- 7 cell line than tamoxifen while some compounds showed considerable activity against PC-3 cell. The compounds 4b, 4c and 4l were significantly enhances the proliferation in osteoblastic cell in comparison to control. The third chapter describes the “Synthesis of 1-(α-aminobenzyl)naphthols as Antiproliferative Agents.” We have developed an efficient non-ionic surfactant Triton X-100 catalyzed multicomponent reaction for the synthesis of 1-(α-aminobenzyl)naphthols. Triton X- 100 forms stable colloidal medium which plays an essential role in acceleration of the reactions in water. The designed and synthesized 1-(α-aminobenzyl)naphthol and Osubstituted 1-(α-aminobenzyl)naphthol derivatives have screened in various cancer cell lines. The observation suggested that some of the compounds have potential to inhibit growth of estrogen responsive human breast MCF-7 carcinoma cells. It is intended that results from these studies will assist to develop a new potent hybrid prototypes for further optimization and development to get new leads for the treatment of cancer. The fourth chapter of the thesis depicts the “Design and Synthesis of Novel Benzylamino Coumarins as Anti-thrombotic and Anti-proliferative Agents.” We have demonstrated an easy, efficient and green protocol for the synthesis of novel benzylamino coumarin derivatives in water. The advantages of this method are the improvement in the synthesis of benzylamino coumarin derivative without formation of any side product as seen with the use of organic solvent. The synthesized compounds show significant activity against human cancer cell line as well as in vivo anti-thrombotic activity. The fifth chapter of the thesis has been divided in two parts, first part (Chapter 5a) describes the synthesis “Design and Synthesis of 3-amino alkylated indoles as Antidiabetic and Anti-proliferative Agents.” A green and efficient organocatalysed multicomponent reaction has been developed for the synthesis of 3-amino alkylated indole derivatives under solvent-free conditions. L-Proline is a very useful organocatalyst and forms imine intermediates through which the reaction proceeded in a more favourable manner. The advantage of our presented methodology is improved conditions for the synthesis of 3-amino alkylated indole derivatives without the formation of bis-indole. The designed and synthesized 3-amino alkylated indole derivatives have screened in various cancer cell lines and showed the significant activity. Unfortunately compounds did not show significant antidiabetic activity in SLM as well as STZ-S model. Second part (Chapter 5b) involves the “Micelle Promoted Multicomponent Synthesis of 3-amino alkylated indoles via Mannich-type Reaction in Water.” A rapid and green method for three component synthesis of 3-amino alkylated indoles via mannich type reaction of aromatic/aliphatic aldehyde, N-alkylanilines and indoles has been described in water. The advantages features of this procedure are high yielding, operational simplicity, eco-friendly and very mild reaction condition for 3-amino alkylated indole derivatives. The designed and synthesized 3-amino alkylated indole derivatives have been submitted for the in vitro screening against five human cancer cell lines and results are awaited. The sixth chapter of the thesis has been divided in two parts, first part (Chapter 6a), involves “Micelle Promoted Supramolecular Carbohydrate Scaffold-Catalyzed Multicomponent Synthesis of 1,2-dihydro-1- aryl-3H-naphth[1,2-e][1,3]oxazin-3-one and amidoalkyl naphthols Derivatives in Aqueous Medium”. We have developed an easy, efficient and eco-friendly procedure for the one-pot synthesis of 1,2-dihydro-1-aryl-3Hnaphth[ 1,2-e][1,3]oxazin-3-one and amidoalkyl naphthols via a multicomponenet reaction of aldehydes, urea/thiourea/amides with 1/2-naphthol using SDS promoted cellulose sulfuric acid, a recyclable solid-supported acid catalyst in water. This novel methodology allows for the first time preparation of 1,2-dihydro-1-aryl-3H-naphth[1,2-e][1,3]oxazin-3-one and amidoalkyl naphthols in water. The synthesized derivatives have been submitted for the in vitro screening against five human cancer cell lines and results are awaited. Second part (Chapter 6b) depicts the “Cellulose Sulfuric Acid-Catalyzed Synthesis of Dihydropyrano[2,3-c:6,5-c']dipyrazole Derivatives via Knoevenagel/Michael Domino Reaction on Water”. An ecofriendly protocol for the synthesis of dihydropyrano[2,3-c:6,5- c']dipyrazole and dihydrospiro[indolinepyrano[2,3-c:6,5- c']dipyrazol]-2-one derivatives via Knoevenagel/Michael domino reaction of aromatic/hetero aromatic aldehyde and isatin with pyrazolone derivatives using cellulose sulfuric acid as a recyclable catalyst in water has been developed. All the derivatives of dihydropyrano[2,3- c:6,5-c']dipyrazole and dihydrospiro[indolinepyrano[2,3-c:6,5- c']dipyrazol]-2-one have been submitted for the in vitro screening against five human cancer cell lines and anti-hyperglycemic activity in sucrose-loaded model (SLM) and streptozotocin (STZ-S) model and results are awaited. The seventh chapter of the thesis involves “Click Chemistry: Sodium Bicarbonate an efficient Inorgano-green Catalyst for the Synthesis of Knoevenagel and Knoevenagel/Michael Domino Reaction in Water”. It describes that Sodium bicarbonate act as an amphoteric catalyst which plays an essential role in acceleration of the reaction by activated to nucleophile and electrophile both in water. The synthesized chromen hydrazinecarbothioamide derivatives have been submitted for anti-cancer and antihyperglycemic activity and results are awaited.