The design, synthesis, and evaluation of the Azetidin-2-one ring as a scaffold for novel combretastatin A4 analogues
Citation:Thomas F. Greene, 'The design, synthesis, and evaluation of the Azetidin-2-one ring as a scaffold for novel combretastatin A4 analogues', [thesis], Trinity College (Dublin, Ireland). School of Pharmacy & Pharmaceutical Sciences, 2009, pp 472
Greene TCD THESIS 8842 The design.pdf (PDF) 233.2Mb
Combretastatin A-4 (CA4) is a natural product first isolated from the Combretum caffrum South African willow tree by Pettit and co-workers. CA4 has proved to be a potent antimitotic agent, with a mechanism of action subsequently elucidated to be that of a tubulin binding agent at the colchicine site. Currently, a water soluble phosphate ester prodrug (CA4P) has shown promise as a vascular targeting agent (VTA) in clinical trials. Our work describes the use of the four-membered azetidin-2-one (β-lactam) ring as scaffold for CA-4 analogues in an effort to gain access to novel agents that possess the potent anticancer activity of CA4 while minimising the problems traditionally associated with CA4 such as stability and water solubility. Initial efforts focussed on the synthesis of a structurally focussed library of β-lactam/CA4 analogues with the aim of identifying promising substitution patterns at the 4- position of the β-lactam ring which mimics the substituted aryl "B" ring of CA4. This library was screened for activity against the MCF7 breast cancer cell line, with the most potent analogues being selected for further optimisation at the 2 and 3-positions of the β-lactam ring. As a result of this process it was found that the biochemical activity of the analogues could be modulated by the substituents attached at the 3-position. This led to the identification of a number of highly optimised analogues that displayed comparable biochemical activity against the MCF7 cell line to that of CA4. One notable analogue proved more potent than CA4 both against the MCF7 cell line and in tubulin polymerisation assays. A number of analogues were submitted to the NCI for screening against the NCI 60 cell line panel and displayed activity comparable to or exceeding that of CA4.
Author: Greene, Thomas F.
Advisor:Meegan, Mary Jane
Qualification name:Doctor of Philosophy (Ph.D.)
Publisher:Trinity College (Dublin, Ireland). School of Pharmacy & Pharmaceutical Sciences
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Type of material:thesis
Availability:Full text available