Part I Design, synthesis and evaluation of novel peptide based organocatalysts - Part II Studies towards the preparation and biological evaluation of [1,4]-dibenzodiazepinone analogues

Chintakunta, P 2015, Part I Design, synthesis and evaluation of novel peptide based organocatalysts - Part II Studies towards the preparation and biological evaluation of [1,4]-dibenzodiazepinone analogues, Doctor of Philosophy (PhD), Applied Science, RMIT University.

Document type: Thesis
Collection: Theses

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Title Part I Design, synthesis and evaluation of novel peptide based organocatalysts - Part II Studies towards the preparation and biological evaluation of [1,4]-dibenzodiazepinone analogues
Author(s) Chintakunta, P
Year 2015
Abstract Use of small organic molecules in asymmetric organic transformations has been popularly increasing every year since the turn of this century. The disadvantages associated with the use of transition metal-based catalysts in organic synthesis can be overcome by using small organic molecules; organocatalysts. In comparison to other firmly established asymmetric catalysis fields such as enzymatic catalysis and organometallic catalysis, organocatalysis offers some fundamental advantages: In general, organocatalysts can be used in a wider range of solvents and for a broader scope of substrate in comparison to enzymes. In addition, they are naturally less toxic and less sensitive towards oxidation and moisture than most organometallic based reagents.

This work describes the development of two peptide based triazole organocatalysts for the asymmetric Michael addition reactions. These two catalysts were prepared from simple amino acids L-proline and L-asparagine using simple and scalable click and acid-amine coupling reactions. Synthesised catalysts were evaluated for their catalytic activity in asymmetric Michael addition reaction of cyclohexanone to various nitro olefins which produced Michael adducts with high (up to 99%) enantio- and diastereoselectivities. In addition, transition state energies of four possible enamine-nitrostyrene transition states i.e anti-re, anti-syn, syn-re and syn-si were computationally calculated and these computational or modelling studies revealed the possible reaction mechanism which proceed via formation of anti enamine-re nitrostyrene transition state.

Besides developing proline-triazole peptides for organocatalysis, it was of parallel interest to prepare and investigate hybrid triazole derivatives for anti-cancer properties. Cancer chemotherapy- in short can be described as treatment of cancer with drugs or chemical substances which kills cancer cells. Currently, 50% of patients are undergoing chemotherapy, to remove micro metastasis. However, chemotherapy is able to cure about 10-15% of all cancers. Development of drug resistance in cancer cells to the existing anticancer drugs and undesirable effects of the drugs used in cancer treatment stimulates the need of developing new anticancer agents which selectively kills the cancer cells.

Many triazole containing compounds exhibit extensive range of pharmacological activities including potent anticancer properties, for instance, cefatrizine, tazobactam and carboxyamidotriazole. Whereas, 5,10-dihydro-11H-dibenzo[b,e][1,4]diazepin-11-one derivatives have diverse therapeutic applications in medicinal chemistry. Diazepinomicin is an unusual farnesylated-dibenzodiazepinone secondary metabolite isolated from micromonospora also contains the dibenzodiazepinone skeleton, possesses anti-tumor, anti-bacterial, and anti-inflammatory activity, has also demonstrated in vivo activity in mouse models against breast, prostate, glioma tumours and induced cytotoxicity in human hepatocellular carcinoma cell lines. It was anticipated that, the combination of two pharmacophores dibenzodiazepinone and triazole may produce chemical entities with good anti-cancer and/or other biological properties. Work in Chapter IV describes the preparation of a series of dibenzodiazepinone-triazole hybrid derivatives and their cytotoxic activity evaluation in five human cancer cell lines.

Among the tested dizepinone derivatives, compounds without substitution on benzene ring (attached to triazole) exhibited potent tumour growth inhibition in all tested cancer cell lines. The simple synthetic preparation and their biological properties make these dibenzodiazepinone-triazole scaffolds promising new entities for the development of cancer therapeutics.
Degree Doctor of Philosophy (PhD)
Institution RMIT University
School, Department or Centre Applied Science
Keyword(s) Organocatalysis
Peptide catalysis
Asymmetric Michael addition reaction
Enamine mechanism
Anti-cancer agents
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Created: Fri, 29 Jan 2016, 13:28:45 EST by Denise Paciocco
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