In continuation of the Kingston group's work to identify new compounds from natural products as a part of the International Cooperative Biodiversity Group (ICBG) program and in collaboration with the Institute for Hepatitis and Virus Research (IHVR), the two plants Neoharmsia baronii and Lopholaena cneorifolia were studied to identify their chemical components. Structural elucidation and characterization of the compounds were done using mass spectrometry, 1D and 2D NMR spectroscopy techniques. A systematic study of the ethanol extract of the plant Neoharmsia baronii Drake from the Madagascar forest led to the isolation of seven compounds, characterized as isoflavones and pterocarpans. The structures of the compounds were characterized by using 1D NMR and 2D NMR spectra, mass spectroscopy and in one case, x-ray crystallography. The HSQC and HMBC data along with comparison of these data with reported literature values confirmed the structures. The aforementioned isoflavones and pterocarpans showed varying cytotoxicity to ovarian cancer cell lines, with the isoflavone vogelin E being the most active compound. The extract of Lopholaena cneorifolia was studied as a part of a cooperative project with the IHVR to identify its chemical composition. Fractionation of this extract led to the isolation of three compounds which were characterized as stilbenes. Their structures were elucidated by using 1D NMR and 2D NMR spectra and mass spectroscopic data. / Master of Science

Fungal polyketides are a diverse class of natural products that possess many pharmacological properties, including anticancer properties. These properties are evident in the resorcylic acid lactones, a family of polyketides, including zearalenone and radicicol, which shows potent inhibition of tumour cell growth. The key step in the biosynthesis of these lactones is macrocyclization of a linear carboxylic acid into the macrolactone. This reaction is catalyzed by a polyketide synthase (PKS) thioesterase enzyme. Bacterial PKS thioesterases (TEs) have been extensively studied and their substrate specificity has been characterized in vitro. They are highly substrate selective for the macrocyclization reaction. Since Fungal PKS TEs show little sequence homology to bacterial TEs, we have begun investigating their substrate specificity. In particular we are examining the ability of fungal TEs to macrocyclize compounds with varying ring sizes, stereogenic configuration, and nucleophiles. Herein we present the synthesis of a number of diverse TE substrates and the in vitro macrocyclization results for the TEs from zearalenone and radicicol biosynthetic pathway with these substrates.

Fungal polyketides are a diverse class of natural products that possess many pharmacological properties, including anticancer properties. These properties are evident in the resorcylic acid lactones, a family of polyketides, including zearalenone and radicicol, which shows potent inhibition of tumour cell growth. The key step in the biosynthesis of these lactones is macrocyclization of a linear carboxylic acid into the macrolactone. This reaction is catalyzed by a polyketide synthase (PKS) thioesterase enzyme. Bacterial PKS thioesterases (TEs) have been extensively studied and their substrate specificity has been characterized in vitro. They are highly substrate selective for the macrocyclization reaction. Since Fungal PKS TEs show little sequence homology to bacterial TEs, we have begun investigating their substrate specificity. In particular we are examining the ability of fungal TEs to macrocyclize compounds with varying ring sizes, stereogenic configuration, and nucleophiles. Herein we present the synthesis of a number of diverse TE substrates and the in vitro macrocyclization results for the TEs from zearalenone and radicicol biosynthetic pathway with these substrates.

Fungal polyketides are a diverse class of natural products that possess many pharmacological properties, including anticancer properties. These properties are evident in the resorcylic acid lactones, a family of polyketides, including zearalenone and radicicol, which shows potent inhibition of tumour cell growth. The key step in the biosynthesis of these lactones is macrocyclization of a linear carboxylic acid into the macrolactone. This reaction is catalyzed by a polyketide synthase (PKS) thioesterase enzyme. Bacterial PKS thioesterases (TEs) have been extensively studied and their substrate specificity has been characterized in vitro. They are highly substrate selective for the macrocyclization reaction. Since Fungal PKS TEs show little sequence homology to bacterial TEs, we have begun investigating their substrate specificity. In particular we are examining the ability of fungal TEs to macrocyclize compounds with varying ring sizes, stereogenic configuration, and nucleophiles. Herein we present the synthesis of a number of diverse TE substrates and the in vitro macrocyclization results for the TEs from zearalenone and radicicol biosynthetic pathway with these substrates.

Fungal polyketides are a diverse class of natural products that possess many pharmacological properties, including anticancer properties. These properties are evident in the resorcylic acid lactones, a family of polyketides, including zearalenone and radicicol, which shows potent inhibition of tumour cell growth. The key step in the biosynthesis of these lactones is macrocyclization of a linear carboxylic acid into the macrolactone. This reaction is catalyzed by a polyketide synthase (PKS) thioesterase enzyme. Bacterial PKS thioesterases (TEs) have been extensively studied and their substrate specificity has been characterized in vitro. They are highly substrate selective for the macrocyclization reaction. Since Fungal PKS TEs show little sequence homology to bacterial TEs, we have begun investigating their substrate specificity. In particular we are examining the ability of fungal TEs to macrocyclize compounds with varying ring sizes, stereogenic configuration, and nucleophiles. Herein we present the synthesis of a number of diverse TE substrates and the in vitro macrocyclization results for the TEs from zearalenone and radicicol biosynthetic pathway with these substrates.

The terpene and terpenoid family of compounds is considered to be the largest group of natural products. These compounds not only display great diversity in their structural features but are also known to have a multitude of biological activities including but not limited to anti-bacterial, anti-cancer, anti-inflammatory, and anti-HIV properties. Remarkably, all the terpenoids formed in nature come from two molecules viz. isopentenyl pyrophosphate and its isomer, dimethylallyl pyrophosphate both consisting of just five carbons but assembled in many ways. Nature utilizes highly efficient, enzyme-mediated cascade reactions to transform simple linear molecules to more complex cyclic scaffolds. Cascade or domino reactions are organic chemistry’s most powerful tools that, if executed correctly, mimic the extreme complexity of reactions occurring in nature. Our group has successfully utilized cationic cascade cyclization reactions, to prepare a large library of natural products along with their analogues. It was during the synthesis of one such natural product that it was discovered that a methoxymethyl (MOM) “protecting group” had been transferred within the same molecule. The optimization of this process not only allowed the synthesis of the desired tricyclic framework but also resulted in the liberated MOM group doing an EAS reaction which gave a new C-C bond. This transferred MOM group was further elaborated to different functional groups. Use of the tandem reaction sequence in an attempt to prepare radulanin E has been described. Total syntheses of two chalcone-based analogous meroterpenoids have been successfully completed using the aforementioned sequence. An advanced intermediate for an entire new class of acridine-based schweinfurthins has been elaborated. The results will be discussed in detail.

No description available.

This thesis describes the isolation and structure elucidation of ten novel secondary metabolites from one fungus (Pycnoporus cinnabarinus), four lichens (Chrysothrix xanthina, Candelaria concolor, Ramalina glaucescens and Xanthoria parietina), three algae (Plocamium mertensii, Laurencia filiformis and Laurencia elata), two plants (Haemodorum simplex and Dianella callicarpa) and one sponge (Dactylospongia sp). The structures of these isolated compounds were elucidated by a combination of spectroscopic and chemical methods. This thesis also reports two new crystal structures, the identification of two new methylsilylated derivatives as well as the isolation of thirty seven previously reported compounds in which the complete structural assignment by one and two dimensional nuclear magnetic resonance spectroscopy (NMR) has been carried out on known compounds with incomplete or no NMR spectroscopic data. Furthermore, detailed spectroscopic analyses resulted in the re assignment of 1H and 13C chemical shifts for several previously isolated natural products. The biological screening (antimicrobial, antiviral and antitumor assays) of crude extracts and isolated natural products has also been presented. The application of chemical profiling techniques including GCxGC and high pressure liquid chromatography-nuclear magnetic resonance (HPLC-NMR) were utilised to assist with the natural product dereplication process (chemical profiling), monitor chemical degradations in situ and to identify the presence of new natural products and artefacts. In total, fifteen separate terrestrial and marine organisms were investigated.

京都大学 / 0048 / 新制・課程博士 / 博士(薬科学) / 甲第20315号 / 薬科博第84号 / 新制||薬科||9(附属図書館) / 京都大学大学院薬学研究科医薬創成情報科学専攻 / (主査)教授 掛谷 秀昭, 教授 高須 清誠, 教授 大野 浩章 / 学位規則第4条第1項該当 / Doctor of Pharmaceutical Sciences / Kyoto University / DFAM