All ETDs from UAB

Advisory Committee Chair

Sadanandan E Velu

Advisory Committee Members

Subramaniam Ananthan

Wayne J Brouillette

David E Graves

Ruiwen Zhang

Document Type

Dissertation

Date of Award

2011

Degree Name by School

Doctor of Philosophy (PhD) College of Arts and Sciences

Abstract

Cancer is an abnormal and uncontrolled growth of cells and is one of the most common causes of millions of deaths worldwide. Currently used chemotherapeutic drugs have severe side effects. Hence, there is a need to develop new cancer therapeutic drugs that can offer higher survival rates and fewer limitations. About 60 % of the known anticancer drugs are either natural products or are derived from natural products. Development of marine natural products into drugs has received increasing attention as a part of humanity's quest for newer sources of cancer drugs. Marine natural products are isolated only in small quantities from natural sources, precluding their thorough biological evaluations. One of the better ways of producing marine natural products in larger quantities is through chemical synthesis. This dissertation focuses on the synthesis of some of the heterocyclic quinonoid marine natural products, their analogs and their biological evaluation. The dissertation starts with an introduction that details the challenges in cancer therapy, the available chemotherapeutic drugs and the role of natural products, particularly, marine natural products in cancer drug discovery. Described in the Chapter 1 of this dissertation is the synthesis of analogs of a marine natural product, makaluvamines. Several of the final compounds were evaluated against a number of cancer cell lines in vitro. The most active compounds were evaluated in vivo in mouse xenograft models of a number of cancers. Chapter 2 describes the development of a new synthetic methodology for another related class of marine alkaloids containing a bispyrroloquinone ring system. This research focuses on the development of a CAN mediated oxidative cyclization reaction as a facile methodology for the incorporation of a pyrrole ring onto a 6-aminoindole-4,7-quinones. This dissertation culminates with the total synthesis of four marine alkaloids, zyzzyanones A-D in Chapter 3. The synthetic strategy is an extension of the methodology developed in the second chapter. The key step in these syntheses is an oxidative cyclization of 6-aminoindole-4,7-quinones with acetals in the presence of Mn(OAc)3 as the oxidative cyclization reagent.

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