Natural products are an important resource for cancer therapy, with highly potent
and diverse anticancer activities. Natural product biosynthesis is well comprehended,
however the evolutionary principles governing the alteration of enzymatic assembly lines
to yield molecules with activity toward distinct various cellular targets are not
understood. This gap in knowledge hinders efforts to synthetically combinatorialize
assembly lines to yield “unnatural” natural products with important or hybrid activity
toward up-regulated targets in cancer. Furthermore, natural products did not evolve in the
context of mammalian systems and would benefit from a delivery mechanism to
cancerous cells to improve their ability to generate successful clinical outcomes.
Consequently, natural products were linked to antibodies targeted to cell surface proteins
up-regulated on cancer cells, generating antibody-drug conjugates (ADC). The
conjugation methodology is problematic by yielding ADCs with varying numbers of
drugs loaded per antibody. This lack of batch-to-batch standardization limits our ability to
completely evaluate the safety profiles and efficacy of ADCs and determine proper
dosages for patients. In this research, light was shed on biosynthetic evolutionary changes
through the study of the antimycin-type family of depsipeptides, specifically
demonstrating that modular insertions or deletions lead to natural product structural
diversification. Additionally, a novel biosynthetic enzymatic method was established to
site-selectively conjugate natural products to antibodies in order to facilitate the
development of more sophisticated cancer therapies. / Thesis / Master of Science (MSc)
| Identifer | oai:union.ndltd.org:mcmaster.ca/oai:macsphere.mcmaster.ca:11375/15390 |
| Date | January 2014 |
| Creators | Vanner, Stephanie |
| Contributors | Magarvey, Nathan, Chemical Biology |
| Source Sets | McMaster University |
| Language | English |
| Detected Language | English |
| Type | Thesis |
| Rights | An error occurred on the license name., An error occurred getting the license - uri. |
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