KUNTE, SUNITA S.

English

Open Access Repository of Indian Theses

AbstractCHAPTER ISYNTHESIS AND ANTITUMOR EVALUATION OF NITROVINYL BIPHENYLS: ANTICANCER AGENTS BASED ON ALLOCOLCHICINES               In the present study, considering the structures of colchicine and allocolchicines, a new class of compounds, nitrovinyl biphenyls were designed, synthesized and demonstrated as inhibitors of tubulin polymerisation and cause mitotic arrest in cells. The majority of compounds were found to possess potent anticancer properties with IC50 values in the range of 0.06-7 M and they are equally potent as colchicine against HeLa and MCF7 cells. Compounds 26e and 26f inhibited tubulin assembly greater than 60% and flow cytometry studies indicated growth arrest of cells at the G2/M phase of the cell cycle in a concentration dependent manner.  Treatment of cells with 26f up-regulated Cyclin B1 and Aurora Kinase B mRNA levels suggesting that the mode of action is by virtue of growth arrest at G2/M phase of the cell cycle.Scheme 1. Synthesis of Nitrovinyl Biphenyls using Palladium catalyzed Suzuki cross coupling.A majority of these compounds, except, 26c, g and k demonstrated significant anti-proliferative activity against a majority of cell lines tested.  The compounds 26e and 26f possessed anti-tubulin activity both in vitro as well as within cells as demonstrated by the soluble: polymerized tubulin ratio. Cell cycle arrest at G2/M phase and up-regulation of Cyclin B1 and Aurora Kinase B substantiates the anti-mitotic effects of 26e and 26f.  Overall, the potent anticancer compounds were found to have the ‘oxygen’ substitution at the 4th position of the ring C or the presence of bulky tert-butyl group. Table 1. Invitro Cytotoxic Effects of Compounds 26a-k and Colchicine on HELA, MCF7, HEPG2, A549 and SKNSH Human Cancer cells.Cell lines were treated with different concentration of compounds for 48 h as mentioned in “materials and methods section. Cell viability was measured employing SRB assay. IC50 values are indicated as mean ± SD (standard deviation) of three independent experiments.CHAPTER IICu-CATALYZED AZIDE-ALKYNE 1,3-DIPOLAR CYCLOADDITION: SYNTHESIS OF 1,4-DISUBSTITUTED 1,2,3-TRIAZOLESThis chapter is divided into three sections:Section I deals with the Regioselective synthesis of 1,4-disubstitited 1,2,3-triazoles via three-component coupling of secondary alcohols, TMSN3 and alkynes in the presence of catalytic amount of a Cu(OTf)2 and Cu powder. Section II employs an efficient approach to the one-pot synthesis of -ketotriazoles by the successive treatment of secondary alcohols with [hydroxy(tosyloxy)iodo]benzene (HTIB), NaN3 followed by CuI catalyzed 1,3- dipolar cycloaddition with terminal alkynes.Section III deals with the hydroazidation of homoallyl alcohols to the corresponding allylic azides with migration of the double bond using PdCl2 as a catalyst and TMSN3 as an azide source. The formed allylic azides were converted to 1,4-disubstituted 1,2,3-triazoles using copper iodide. SECTION IREGIOSELECTIVE SYNTHESIS OF 1,4-DISUBSTITITED 1,2,3-TRIAZOLES VIA THREE-COMPONENT COUPLING OF SECONDARY ALCOHOLS , TMSN3 AND ALKYNESIn this section, the reactivity of alcohols in nucleophilic substitution reaction was studied. Whereas, it has been shown that nucleophilic substitution of alcohols with alkali azides generally requires activation of the hydroxyl group of the alcohols by formation of corresponding tosylates. herein, a one-pot two-step reaction between secondary alcohols, TMSN3 and terminal alkynes in the presence of catalytic amount of a Cu(OTf)2 and Cu powder to give 1,4-disubstituted 1,2,3-triazoles was presented (Scheme 2). The products contain various substituents on triazole ring and alkyl side chains on N-1 of the triazole. This three-component coupling reaction proceeds via nucleophilic substitution of the secondary alcohols with TMSN3 to afford the corresponding azides in the presence of Cu(OTf)2 without activation of the hydroxyl group. The in situ generated azide on Cu(I) catalyzed reaction with terminal alkynes gave 1,4-disubstituted 1,2,3-triazoles in excellent yields. The reaction conditions were optimized by varying the catalyst or the solvent.Scheme 2.SECTION IITANDEM OXIDATIVE Α-TOSYLOXYLATION OF ALCOHOLS/NUCLEOPHILIC ADDITION OF AZIDE/COPPER-CATALYZED 1,3-DIPOLAR CYCLOADDITIONan efficient method for the synthesis of 1,4-disubstituted 1,2,3-triazoles from a variety of secondary alcohols, sodium azide and terminal alkynes has been developed via a simple one-pot, three-step procedure involving the oxidative α-tosyloxylation of alcohols, followed by azidation of the formed α-tosyloxyketones and copper catalyzed 1,3-dipolar cycloaddition (Scheme 3).Scheme 3.SECTION IIIEFFICIENT SYNTHESIS OF ALLYLIC AZIDES AND ONE-POT REGIOSELECTIVE SYNTHESIS OF 1, 4-DISUBSTITUTED 1,2,3-TRIAZOLES FROM HOMOALLYL ALCOHOLSIn this section the hydroazidation of homoallyl alcohols  to the corresponding  allylic azides with migration of the double bond using PdCl2 as a catalyst and TMSN3 as an azide source has been developed. the formed allylic azides were subsequently converted to 1,4-disubstituted 1,2,3-triazoles through CuI catalyzed 1,3-dipolar cycloaddition with terminal alkynes without isolation and purification of azides (Scheme 4).Scheme 4.This conceptually new approach provides a straightforward and efficient access to allylic azides. In addition, the reaction can be coupled to copper catalyzed 1,3-dipolar cycloaddition to generate 1,4-disubstituted 1,2,3-triazoles in one-pot without isolating the azide intermediate and should prove to be useful for generating multivalent structures.CHAPTER IIICATALYST AND BASE FREE WATER PROMOTED SNAR REACTION OF HETEROARYL HALIDES WITH THIOLSHeterocycles make up an exceedingly important class of compounds. In fact more than half of all known organic compounds are heterocycles. Many natural drugs such as quinine, papaverine, emetine, theophylline, atropine, procaine, codeine, morphine and reserpine are heterocycles. Almost all the compounds we know as synthetic drugs such as diazepam, chlorpromazine, isoniazid, metronidazole, azidothymidine, barbiturates, antipyrine, captopril and methotrexate are also heterocycles. Some dyes (e.g. mauveine), luminophores, (e.g. acridine orange), pesticides (e.g. diazinon) and herbicides (e.g. paraquat) are also heterocyclic in nature.A simple and efficient route for the synthesis of biaryl sulfides have been developed in aqueous medium under base and catalyst-free conditions (Scheme 5). A wide variety of heteroaryl halides and thiols underwent SNAr reaction to provide diaryl sulfides in good to excellent yields. The remarkable key features of the reaction include the use of water as an inexpensive and environmentally benign reaction medium, absence of any additional reagent/catalyst and easy isolation of the products.Scheme 5CHAPTER IVAgOTf CATALYZED DIRECT AMINATION OF BENZYL ALCOHOLS WITH SULFONAMIDESCatalytic amination reactions have received significant interest. Substituted amines are of considerable importance in the pharmaceutical, agrochemical and fine chemical industries. Numerous biologically active molecules such as alkaloids, amino acids and nucleotides contain the amine group.Nucleophilic substitution of the hydroxy group in alcohols by amines generally requires preactivation of the alcohols by transformation in to good leaving groups such as halides, carboxylates and carbonates (Scheme 6).Scheme 6. Substitution of benzyl alcohol by (a) preactivation   (b) catalytic hydrogen transfer, and (c) direct catalytic substitution.We have developed an efficient procedure to obtain benzylic amines from the corresponding primary alcohols and sulfonamides in the presence of silver triflate as catalyst. The methodology is straightforward and environmentally benign with the formation of water as the only by-product (Scheme 7).Scheme 7.CHAPTER VTITANIA SUPPORTED PALLADIUM (0) NANOPARTICLES FOR SUZUKI-MIYAURA CROSS-COUPLING OF ARYL AND HETEROARYL HALIDES The foundation of synthetic organic chemistry rests on the ability to form and manipulate carbon-carbon bonds. The increasing demand of coupled products in chemical and pharmaceutical industries has prompted the development of several transition metal catalysts, which aim to exert the highest turnover number and turnover frequency.The biaryl moiety is an important structural motif in a great number of biologically active compounds and functional molecules. Which includes the natural products Biphenomycin, the pharmaceuticals Valsartan, Telmisartan, Felbinac, Losartan, Imatinib, the agrochemical Boscalid, liquid crystals for LCD screens, chiral ligands for catalysis and organic functional materials.In this chapter, nanocrystalline TiO2-Supported Pd(0) Catalyst was prepared as outlined in the scheme 8 and used for the Suzuki cross coupling reaction of various aryl and heteroaryl halides with aryl/heteroaryl boronic acids at room temperature under air (Scheme 9). The conversion and selectivity results obtained for many substrates were excellent and similar to those provided by more active or even homogeneous catalysts. Scheme 8. Preparation of TiO2 supported palladium catalyst.This methodology is similarly effective using 2-bromo, 3,4,5 trimethoxy benzaldehyde as the coupling partner and gave products in good yield. Further it has been shown that it is useful for the synthesis of terphenyl and tetraphenyls. The catalyst is quantitatively recovered from the reaction by simple filtration and reused for a number of cycles without significant loss of activity. The operational simplicity and the mild reaction conditions add to the value of this method as a practical alternative to the Suzuki coupling. Scheme 9. Suzuki coupling of aryl and heteroaryl halides with aryl boronic acids. PAGE  xii

STUDIES IN ANALYSIS OF PESTICIDES

http://eprints.csirexplorations.com/939/1/Abstract.doc

STUDIES IN ANALYSIS OF PESTICIDES

Abstract

Similar works

Full text

Available Versions

Open Access Repository of Indian Theses