Synthesis of Sphaeropsidin a Derivatives in a Search for Compounds Active Against Drug-Resistance Cancer

Despite the recent advances in the treatment of cancer, the intrinsic resistive properties of cancer against chemotherapeutic agents require new chemical agents with promising anticancer activity. One such agent is Sphaeropsidin A (SphA), a fungal metabolite extracted from different sources but mainly from Diplodia cupressi. SphA has shown anticancer activity by overcoming multidrug resistance as well as inducing apoptosis (cell programmed death) by causing marked and rapid irreversible cellular shrinkage. However, SphA has only shown, on average, single digit micromolar anticancer activity against NCI panel of 60 cancer cell lines. To increase its anticancer activity, its SAR (Structure-Activity Relationship) study has suggested that the activity can be enhanced by modifying the double bond at C15-C16. This double bond can be modified by crossmetathesis reaction of SphA with an alkene-containing compounds. Previously, a similar study was done by our research group, and such an approach resulted in a significant increase in activity into the submicromolar region. In this work, we further advance the earlier study and synthesize SphA derivatives with different numbers of aromatic rings (lipophilic bulk). After successfully synthesizing derivatives, their biological evaluation has been done through in vitro assays against seven drug-resistant cancer cell lines. Biological evaluation suggested that as lipophilic bulk increased, the activity also improved. And also, through DNA intercalation assay their binding ability was found. Thus, several SphA analogues with activity exceeding that of the natural product were synthesized as the result of this thesis.

Name thesis:degree_name

Master of Science

Level thesis:degree_level

Masters

Discipline thesis:degree_discipline

Chemistry

Grantor

Texas State University

Year dc:date.issued

2022

Author dc:creator

• Majeed, Iram

Advisor dc:contributor.advisor

• Kornienko, Alexander

Committee members dc:contributor.committeemember

• Hudnall, Todd
• Lewis, Lysle Kevin

• sphaeropsadin A
• cancer
• compounds

Language dc:language.iso

en

Handle dc:identifier.uri

https://hdl.handle.net/10877/18686

OAI identifier oai:identifier

oai:digital.library.txst.edu:10877/18686