Access Type

Open Access Dissertation

Date of Award

January 2015

Degree Type

Dissertation

Degree Name

Ph.D.

Department

Chemistry

First Advisor

Peter R. Andreana

Second Advisor

Zhongwu Guo

Abstract

ABSTRACT

BIOLOGICAL EVALUATION OF THE VACCINE CANDIDATE TF-PS A1 AND A ONE-POT MULTICOMPONENT COUPLING/CYCLIZATION FOR NATURAL PRODUCT HERBICIDE (±)-THAXTOMIN A

By

JEAN PAUL BOURGAULT

August 2015

Advisor: Prof. Peter R. Andreana

Major: Chemistry (Organic)

Degree: Doctor of Philosophy

The -aminooxy derivative of the Thomsen–Friedenreich tumor associated carbohydrate antigen has been synthesized in 11 steps utilizing a D-GalN3 acceptor carrying a pre-installed -N-hydroxysuccinimidyl moiety. The natural  linkage was prepared in high selectivity employing a suitably protected D-GalN3-thioglycoside donor with N-hydroxysuccinimide. With access to -TF-ONH2, the preparation of the TF-PS A1 vaccine candidate ensued smoothly through oxime bond formation. This construct was then administered to C57/BL6 mice in the presence of titer max gold adjuvant. The induced antibodies were then examined through ELISA, 51Cr cytotoxic assays and a SCID mouse study involving MCF-7 induced tumors. While the induced antibody titers were not substantial these antibodies were shown to have ~30% cytotoxicity in ADCC and CMC based assays against the breast cancer cell line MCF-7. In addition passive transfer of the IgG antibody fraction reduced the tumor of volume (20%) of SCID mice challenged with the MCF-7 cell line when compared to PBS treated controls. These antibodies were also shown to bind the colon cancer cell line HCT-116 and MCF-7 through FACS analysis.

Herbicide (±)-thaxtomin A has been prepared in a one-pot procedure with a 32% isolated yield. The Ugi reaction was utilized with 4-nitroindolylacetaldehyde, methylamine, 3-hydroxyphenylpyruvic acid, and methyl isocyanide to prepare in situ a dipeptide intermediate which then underwent an alkaline mediated keto-amide cyclization to provide TA and it’s anti diastereomer. Modification of diastereoselectivity to favor the syn confirmation (TA) was realized using microwave-induced irradiation in the presence of KOH. In addition a series of electronically modified derivatives have been prepared to study the interesting CH- interaction found in TA. These derivatives when cyclized have provided further evidence for the CH- influence on the formation of the syn DKP due to the increase of the anti product when the nitro and phenol substituents were removed. With this evidence we believe the CH- contact is influencing the diastereomeric ratio creating the observed syn preference of TA under thermodynamic conditions.

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