The design, synthesis, and biological evaluation of dimeric β-carbolines based on the structure of neokauluamine and the study of manzamine A dimerization toward neokauluamine / Jaruwan Chatwichien.

Format:

Book

Manuscript

Thesis/Dissertation

Author/Creator:

Chatwichien, Jaruwan, author.

Contributor:

Winkler, Jeffrey D., degree supervisor.

Huryn, Donna M., degree committee member.

Joullié, Madeleine M., degree committee member.

Molander, Gary A., degree committee member.

University of Pennsylvania. Department of Chemistry, degree granting institution.

Language:

English

Subjects (All):

Penn dissertations--Chemistry.

Chemistry--Penn dissertations.

Local Subjects:

Penn dissertations--Chemistry.

Chemistry--Penn dissertations.

Physical Description:

2 volumwa (xv, 373 leaves) : illustrations ; 29 cm

Production:

[Philadelphia, Pennsylvania] : University of Pennsylvania, 2016.

Other Title:

Design, synthesis, and biological evaluation of dimeric [beta]-carbolines

Summary:

Neokauluamine, a naturally occurring dimeric β-carboline alkaloid, was isolated from an Indo-Pacific sponge (family Petrosiidae, order Haplsclerida) by Hamann et.al. in 2001. Neokauluamine exhibited improved antimarial activity in vitro and in vivo relative to currently available drugs artemisinin and chloroquine. Moreover, neokauluamine showed potent cytotoxicity against many types of human cancers including lung, colon and cervical cancers. Bases on the structure of neokauluamine, we designed, synthesized and evaluated simple dimeric β-carbolines as lead structures for the development of biologically active compounds. Interestingly, the synthesized dimeric β-carbolines exhibited antimicrobial activity and cytotoxicity against melanoma and lung cancer cell lines comparable to neokauluamine and its monomer, manzamine A. The cellular mechanism by which the dimeric β-carbolines induce cell death in H1299 lung cancer cells was studied and it was found that the β-carboline dimer accumulated in lysosomes and mediated apoptosis by upregulating a pro-apoptotic protein, PUMA (p53 upregulated modulator of apoptosis). The abundance of manzamine A relative to neokauluamine in Nature makes manzamine A an attractive starting material for the synthesis of neokauluamine. Recently, Tsukamoto et.al. discovered a novel manzamine alkaloid, pre-neokauluamine, as the key intermediate in the conversion of manzamine A to neokauluamine. Thus, we designed and synthesized a pre-neokauluamine-based model system to study optimal reaction conditions and selectivity of the key dimerization step.

Notes:

Ph. D. University of Pennsylvania 2016.

Department: Chemistry.

Supervisor: Jeffrey D. Winkler.

Includes bibliographical references.