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Studies on syntheses, reactions, and biomedical applications of functionalized alkynes

Authors Lai, Kwong Wah
Issue Date 2004
Summary Acetylenes are a very important class of building blocks in organic synthesis. Besides, applications of functionalized alkynes in material sciences, biomedical research, and treatment of diseases are the driving force for research in the chemistry of alkynes. This thesis research deals with the syntheses, reactions, and biomedical applications of functionalized alkynes associated with drug design and discovery. A brief introduction is given in the first chapter with an emphasis on the background information closely related to the topics covered in this thesis. Chapter 2 accounts for the development of a microwave-assisted coupling reaction of aryl chlorides with terminal alkynes. The existing synthetic methods for the preparation of functionalized acetylenes from aryl halides under palladium-catalyzed conditions are first mentioned. It is followed by a brief account of microwave heating in organic synthesis. The details of our findings on the Negishi-type alkynylation of unreactive aryl chlorides with terminal alkynes under microwave irradiation are presented, including optimization of the reaction conditions, and scope and limitation of the new protocol. Chapter 3 describes the synthesis of functionalized benzo[b]furans via the Pd-catalyzed coupling-heteroannulation approach. Inexpensive 2-aminophenols are selected as the starting materials, aiming for diversity-oriented synthesis. The Pd-catalyzed chemistry is first extended to synthesis of nitrobenzo[b]furans via both stepwise and 'one pot' manner. The key reaction steps involve the Sonogashira cross-coupling reaction and the KOt-Bu-promoted 5-endo-dig cyclization. Diversification on the nitrobenzo[b]furans is demonstrated by conversion of the nitro group into sulfonamides. In order to increase the structural diversity on the benzo[b]furan scaffold, various C5 substituted 2,3-diarylbenzo[b]furans have been prepared via the same coupling-heteroannulation sequence. Enediyne anticancer antibiotics are naturally occurring compounds and have generated tremendous interest over the past two decades. In Chapter 4, efforts are dedicated to understanding on the mechanism of action of a novel class of cyclic 1,5-diynes designed by our group. LC-MS analysis is used to determine the structures of reaction intermediates in the incubation mixture and the results support formation of 10-membered ring enediynes from the 1,5-diynes via an allylic rearrangement. Moreover, careful experimentation is carried out to assess the role of possible quinones proposed recently by others for the action of enediynes. Our negative results on DNA cleavage and cytotoxicity by the quinone suggest that quinone is not likely the reactive species responsible for the observed biological activity of enediynes. The last Chapter presents the results on design, synthesis, and biological studies on novel enediyne prodrugs featuring the (E)-3-acyloxy-4-(arylmethylidene)cyclo-deca-1,5-diyne scaffold. On the basis of the mechanism of action given in Chapter 4, two types of 1,5-diynes are designed. One series of 1,5-diynes possess an internal nucleophilic hydroxyl group attached to the ortho position of the benzene ring to facilitate a regiospecific allylic rearrangement. The other series of 1,5-diynes are capable of being activated at basic pH by saponification of the para acyloxy group, leading to formation of the reactive quinone methide and the cyclic enediyne skeleton. DNA cleavage and cytotoxicity data support the base activation and LC-MS analysis confirms formation of enediyne in the incubation mixture. The outcome of this thesis research on functionalized alkynes is of originality and contributes to the advancement of modern acetylene chemistry and biology. Moreover, the developed synthetic methodologies are applicable to general organic synthesis. The bioactivity observed with cyclic 1,5-diynes encourages further research in this direction.
Note Thesis (Ph.D.)--Hong Kong University of Science and Technology, 2004
Language English
Format Thesis
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