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Plant compounds play an important role in human medicine. They are a source of new drugs or serve as an inspiration for drugs' development. This thesis presents a study about syntheses of derivatives and biological activities of two groups of natural products, quinones and terpenoids. Terpenoids are plant secondary metabolites which are known for their antimicrobial, anti-inflammatory and anti-tumoral activities. We have focused on two representatives, paclitaxel and carvacrol. GnRH-paclitaxel anti-tumor conjugates potentially suitable for targeted delivery to cancer cells were prepared. Their antiproliferative activities in vitro were evaluated on MCF-7 cancer cell line and cytotoxicity in rat hepatocytes. Carvacrol and its derivative were tested for its possible anti- inflammatory effect, which was assessed in vitro as their potential to inhibit prostaglandin E2 biosynthesis via cyclooxygenase pathway. Quinones, other targets of the thesis, are well-known for biological activities similar to terpenoids. Thymoquinone, juglone and their derivatives were tested in vitro as inhibitors of cyclooxygenases and 5-lipoxygenase. Derivatives of juglone were prepared to help us to suggest structure-activity relationship of this compound. Thymoquinone and its derivatives were evaluated for their antioxidant capacity...

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In the Paris Agreement from 2015, nations agreed to limit the effects of global warming to well below 2°C. To be able to reach those goals, cheap, abundant and carbon neutral energy alternatives needs to be developed. The microorganisms that several billion years ago oxygenated the atmosphere; cyanobacteria, might hold the key for creating those energy technologies. Due to their capacity for photosynthesis, metabolic engineering of cyanobacteria can reroute the carbon dioxide they fix from the atmosphere into valuable products, thereby converting them into solar powered cell factories. Of the many products bacteria can be engineered to make, the production of terpenoids has gained increasing attention for their attractive properties as fuels, pharmaceuticals, fragrances and food additives. In this thesis, I detail the work I have done on engineering the unicellular cyanobacterium Synechocystis sp. PCC 6803 for terpenoid production. By deleting an enzyme that converts squalene into hopanoids, we could create a strain that accumulates squalene, a molecule with uses as a fuel or chemical feedstock. In another study, we integrated two terpene synthases from the traditional medical plant Coleus forskohlii, into the genome of Synechocystis. Expression of those genes led to the formation of manoyl oxide, a precursor to the pharmaceutically active compound forskolin. Production of manoyl oxide in Synechocystis was further enhanced by engineering in two additional genes from C. forskohlii that boosted the flux to the product. To learn how to increase the production of squalene, manoyl oxide or any other terpenoid, we conducted a detailed investigation of each step in the MEP biosynthesis pathway, which creates the two common building blocks for all terpenoids. Each enzymatic step in the pathway was overexpressed, and increased flux was assayed by using isoprene as a reporter and several potential targets for overexpression were identified. The final part of this thesis details the characterization of native, inducible promoters and ribosomal binding sites in Synechocystis.

The thesis entitled "SYNTHETIC INVESTIGATIONS ON TERPENOIDS" consists of two chapters. Chapter I deals with the total synthesis of the sesquiterpenes, 2-pupukeanone 1 Norpatchoulenol 2 and patchouli alcohol 3 and is divided into four sections.

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Although the antomicrobial nature of essential oils and their major constituents, the terpenoids, has been widely investigated the mechanism of their antimicrobial action has not been subject to the same scrutiny. In this study the membrane disruptive nature of the terpenoids has been determined by experiments on the effects of terpenes on both microbial membrane and model lipid bilayer systems. These terpenes exhibited a range of membrane damaging effects. Experiments showed that the terpenoids were able to increase disorder in DPPC bilayers, and that antimicrobially active terpenoids cause increased membrane permeability in living cells. The effect of molecular structure on antimicrobial activity and activity differences between each organism were determined for 60 terpenoids. Terpenoids with a low water solubility were found to be inactive. Hydrogen bond donor capacity and hydrogen bond acceptor capacity were found to be the molecular parameters which most strongly discriminated between activities against individual organisms. Activity against Gram negative Escherichia coli and Pseudomonas aeruginosa was associated also with a molecular size parameter. The protective nature of the outer membrane of P. aeruginosa and E. coli was also investigated. The evidence presented in this thesis has enabled the postulation of a two stage process to explain the overall mode of action of these compounds. / Doctor of Philosophy (PhD)

Among Nature's creation, terpenoids are more versatile and exciting natural products. In a remarkable display of synthetic ingenuity and creativity, nature has endowed terpenes with a bewildering array of carbocyclic frameworks with unusual assemblage of rings and functionalities. This phenomenal structural diversity of terpenes makes them ideal targets for developing and testing new synthetic strategies for efficient articulation of carbocyclic frameworks. The thesis entitled “Total Synthesis of Sesquiterpenes Seychellene, Trachyopsanes and Bisepoxysecocalamenenes” describes the studies directed towards the total synthesis of the sesquiterpenes mentioned in the title. For convenience, the results are presented in three chapters; viz (1) First Enantiospecific Total Synthesis of Seychellene; (2) Enantiospecific First Total Synthesis of Trachyopsanes; and (3) Total Synthesis of Bisepoxysecocalamenenes. In each chapter of the thesis, the compounds are sequentially numbered (bold) and references are marked sequentially as superscripts and listed at the end of the chapter. All the spectra included in the thesis were obtained by xeroxing the original NMR spectra. The tricyclic sesquiterpene (−)-seychellene, containing an interesting tricyclo[5.3.1.03,8]undecane carbon framework, was isolated in 1967 by the research group of Hirose from the leaves of Pogostemon cablin Benth. An enantiospecific total synthesis of seychellene has been described in the first chapter of the thesis. To begin with, (R)-carvone has been transformed into 10-(1-methylethylidene)-3,8-dimethyl-tricyclo[5.3.1.03,8]undecan-2-one employing a tandem intermolecular Michael addition followed by intramolecular Michael addition reaction and intramolecular alkylation reactions. Degradation of the isopropylidene group followed by methylenation transformed 10-(1-methylethylidene)-3,8-dimethyltricyclo[5.3.1.03,8]-undecan-2-one into norseychellene. This methodology has been extended to the first enantioselective total synthesis of (+)-seychellene and (−)-seychellene via (S)-3-methylcarvone and (R)-3-methylcarvone, respectively. The marine sesquiterpene 2-isocyanotrachyopsane was isolated in 1996 by Fusetani and co-workers from the nudibranch Phyllidia varicosa. 2Isocyanotrachyopsane shows potent antifouling activity. During a search for DNA damaging agents, in 1997, Patil and co-workers reported the bioassay guided isolation of two new sesquiterpenes 2-formylaminotrachyopsane and N-phenethyl-N'-2-trachyopsanylurea from a sponge collected in Palau, Axinyssa aplysinoides Dendy 1922. In the second chapter of the thesis enantioselective first total synthesis of 2formylaminotrachyopsane and 2-isocyanotrachyopsane, establishing the absolute configuration of the natural products, has been described. To begin with, (R)-carvone has been transformed into a neopupukeandione employing a tandem double Michael reaction and intramolecular rhodium carbenoid CH insertion reactions. Neopupukea-nan-4-ol was transformed into 2-formylaminotrachyopsane by an acid catalyzed biomimetic rearrangement followed by Ritter reaction. Dehydration of formamide group in 2-formylaminotrachyopsane led to 2-isocyanotrachyopsane. In 1998, the research group of Weyerstahl reported the isolation of two new sesquiterpenes 1,10;7,10-bisepoxy-1,10-seco-calamenene and 6,7;7,10-bisepoxy-6,7-seco-calamenene from the essential oil Hedychium gardnerianum Roscoe. Presence of an interesting benzofused dioxabicyclo[3.2.1]octane framework coupled with the fact that the structures of the natural products were assigned on the basis of the spectral data of a mixture of two compounds prompted us to investigate the total synthesis to confirm their structures. The third chapter of the thesis describes the first total synthesis of these two compounds using an intramolecular ketalisation reaction. p-Cresol was converted into 2-(methoxymethoxy)-5-methylisobutyrophenone, which was further transformed in three steps into 1,10;7,10-bisepoxy-1,10-seco-calame-nene. Catalytic hydrogenation of 1,10;7,10-bisepoxy-1,10-seco-calamenene led to litseachromolaevane A, a new sesquiterpene isolated from an anti-HIV fraction of the leaves and twigs of Litsea verticillata Hance by Fong and co-workers in 2003. For the synthesis of 6,7;7,10-bisepoxy-6,7-seco-calamenene, m-cresol was converted into the 6-(methoxymethoxy)-6-[2-(methoxymethoxy)-4-methylphenyl]-2-methylheptan-3-one, which was transformed into 6,7;7,10-bisepoxy-6,7-seco-calamenene by an intramolecular ketalisation reaction.

This thesis describes the synthetic preparation of somecompounds, which can serve as chemical signals for use in thedevelopment of control methods for pest insects. The compoundssynthesised are of the isoprenoid type and of two kinds:carvone derivatives and germacranes. The derivatives of carvoneare based on modifications of this compound, by reactions ofeither its endocyclic or its exocyclic double bond. One type ofmodifications was accomplished by chemoselective additions ofthiophenol. The latter ones imply additions to the exocyclicdouble bond and seem to constitute general, previously rarelystudied reactions. In other modifications of its exocyclic side chain, carvoneafforded some sesqui- and diterpeniod natural products. Thefollowing compounds were synthesised in an enantioselectiveway: (-)-epi-delobanone, (-)-delobanone,(-)-7-hydroxy-3,10-prenylbisaboladien- 2-one (an insecticidalconstituent of Croton linearis) as well as its diastereomer andsome other compounds with similar structures. All of thesecompounds weretested for their antifeedant/feeding deterrentcapability against gnawing of the pine weevil, Hylobiusabietis. The germacranes prepared by means of enantioselective totalsyntheses are: (–)- 1(10),5-germacradien-4-ol and(–)-germacrene D. The former is a constituent of thedefence secretion (an allomone) from the larvae of the pinesawfly, and the needles of Scots pine. (–)-Germacrene D isa ubiquitous compound in nature. For example, it occurs in thepeels of apples and acts as one component of a lure (akairomone) to the apples, which attracts the codling moth,Cydia pomonella. The main problem in the total syntheses of the germacraneswas the formation of the unsaturated monocyclic 10-memberedring. This was achieved by intramolecular alkylation with asuitably functionalised/protected cyanohydrin derivative,which, after further elaboration, afforded a monocyclic10-membered enone, that was used in the syntheses of the twogermacranes mentioned above. In the initial steps in thesynthetic sequence the stereochemistry was established byalkylation of an amide enolate attached to a chiral auxiliary.This approach could most likely also readily furnish the(+)-enantiomers of these germacrenes (of the germacraneterpenoid class) using the opposite enantiomer of the chiralauxiliary in the initial steps. <b>Keywords</b>: isoprenoids, natural product synthesis,allelochemicals, kairomones, allomones, bisabolane terpenoids,Hylobius abietis, germacrane terpenoids, Neodiprion sertifer,stereoselective synthesis.