Date of Award
2026
Document Type
Thesis
Degree Name
MS in Chemistry
Department
Chemistry
First Advisor
Sabesan SY Yoganathan
Second Advisor
Enjoy EW Wang
Third Advisor
Victor VS Cesare
Abstract
Hepatocellular carcinoma (HCC) remains one of the most challenging malignancies to treat, characterized by late-stage diagnosis, poor prognosis, and significant resistance to currently available systemic therapies. Liver cancer continues to represent a major global health burden, and the lack of effective targeted treatments for advanced disease underscores the urgent need for novel therapeutic agents. Dysregulation of the CDK4/6–Cyclin D–Retinoblastoma (Rb) signaling axis is a well-established driver of uncontrolled proliferation in liver cancer, and while selective CDK4/6 inhibitors have demonstrated clinical success in other malignancies, their application is limited by severe hepatotoxicity, highlighting the need for novel chemical scaffolds capable of targeting this pathway with an improved safety profile. This work describes the rational design and synthesis of a library of eight novel phthalimide-based hybrid derivatives (1C–8C) developed through a pharmacophore hybridization strategy incorporating benzimidazole, tetrahydroisoquinoline (THIQ), and hydroxy-tetrahydroisoquinoline pharmacophoric units. The phthalimide scaffold was selected as the central framework based on its established anticancer relevance and synthetic versatility, while the appended heterocyclic units were chosen for their individually validated roles in clinically relevant anticancer agents. Structural diversity within the library was achieved by systematically varying both the heterocyclic pharmacophore and the amide linker length, using β-alanine and glycine derived precursors to generate paired analogues across all three subclasses. All target compounds were synthesized using a unified HBTU/DIPEA-mediated amide coupling strategy in DMF and isolated using a combination of recrystallization, normal-phase silica gel chromatography, and Biotage reverse-phase purification. The identity and purity of all eight compounds were confirmed by ¹H NMR, ¹³C NMR, HPLC, and LC–MS, with all spectroscopic and analytical data fully consistent with the proposed structures. Synthetic attempts toward four additional target compounds (9C–12C) were also undertaken and documented; these were unsuccessful due to regiochemical ambiguity in the case of 9C and 10C, and prohibitive steric hindrance at the amine coupling partner in the case of 11C and 12C. The synthesized library of compounds 1C–8C represents a well-characterized structural platform grounded in rational pharmacophore design and positioned for future biological investigation as novel therapeutic candidates for liver cancer.
Recommended Citation
Strzeszewski, Daniel, "DESIGN AND CHEMICAL SYNTHESIS OF PHTHALIMIDE DERIVATIVES FOR CDK4/6 INHIBITION AND THERAPEUTIC INTERVENTION IN LIVER CANCER" (2026). Theses and Dissertations. 1146.
https://scholar.stjohns.edu/theses_dissertations/1146