Design and Synthesis of Novel Artemisinin Analogs for Hematologic Cancer Therapeutics
Poster #: 134
Session/Time: A
Author:
Nile Daniel Ross, BS
Mentor:
Yali Kong, PhD
Research Type: Basic Science
Abstract
INTRODUCTION:
Artemisinin, a sesquiterpene lactone derived from Artemisia annua, has demonstrated broad biological activity beyond its well-established antimalarial use, including promising anticancer effects. However, its clinical translation to hematologic malignancies has been limited due to the poor solubility, rapid metabolic clearance, and unclear mechanisms of resistance. To address these challenges, we pursued a strategy to design and synthesize novel artemisinin analogs with optimized physicochemical properties for the treatment of hematologic cancers.
METHODS:
Our design strategy focused on the modification of Artemisinin, Dihydroartemisinin (DHA), and Artesunate scaffolds on their C10 and O11 positions to enhance their stability, solubility, and potential interactions with resistance-associated pathways. At the same time, hybrid molecules were also explored through chemical covalent conjugation of artemisinin with potent therapeutics used in hematologic malignancies to enhance their potency and to overcome the known resistance mechanisms. The novel Artemisinin analogs were synthesized using linker tethering and coupling reactions. The reactions were monitored by Thin Layer Chromatography (TLC) and purified by flash chromatography. The purified compounds were structurally characterized by Nuclear Magnetic Resonance (NMR) spectroscopy and analyzed by high resolution mass spectroscopy (HRMS). This chemistry approach yielded a diverse library of analogs with favorable drug-like properties to be evaluated in hematologic cancer cell lines.
RESULTS:
Artemisinin, DHA and artesunate were chosen as scaffolds to tether a linker with the function group -COOH, -NH, -Br, -N3 and -OH, followed by coupling reaction with the potent anti-hematologic agents to generate our novel analogs. We confirmed the structure through NMR and HRMS spectroscopy analysis. The calculated physical properties including PSA and cLogP values by Chemdraw software have shown their improved drug-like properties compared to artemisinin.
CONCLUSION:
Future efforts will focus on biological assays to assess cytotoxicity in leukemia and lymphoma cancer cell lines as well as in normal cell lines, investigate mechanisms of resistance, and evaluate potential synergy with current chemotherapeutics. Collectively, this work demonstrates that rational chemical modification and synergistic drug conjugation strategies provide a viable path toward novel therapies for the treatment of hematologic malignancies and to overcome drug resistance.
Artemisinin, a sesquiterpene lactone derived from Artemisia annua, has demonstrated broad biological activity beyond its well-established antimalarial use, including promising anticancer effects. However, its clinical translation to hematologic malignancies has been limited due to the poor solubility, rapid metabolic clearance, and unclear mechanisms of resistance. To address these challenges, we pursued a strategy to design and synthesize novel artemisinin analogs with optimized physicochemical properties for the treatment of hematologic cancers.
METHODS:
Our design strategy focused on the modification of Artemisinin, Dihydroartemisinin (DHA), and Artesunate scaffolds on their C10 and O11 positions to enhance their stability, solubility, and potential interactions with resistance-associated pathways. At the same time, hybrid molecules were also explored through chemical covalent conjugation of artemisinin with potent therapeutics used in hematologic malignancies to enhance their potency and to overcome the known resistance mechanisms. The novel Artemisinin analogs were synthesized using linker tethering and coupling reactions. The reactions were monitored by Thin Layer Chromatography (TLC) and purified by flash chromatography. The purified compounds were structurally characterized by Nuclear Magnetic Resonance (NMR) spectroscopy and analyzed by high resolution mass spectroscopy (HRMS). This chemistry approach yielded a diverse library of analogs with favorable drug-like properties to be evaluated in hematologic cancer cell lines.
RESULTS:
Artemisinin, DHA and artesunate were chosen as scaffolds to tether a linker with the function group -COOH, -NH, -Br, -N3 and -OH, followed by coupling reaction with the potent anti-hematologic agents to generate our novel analogs. We confirmed the structure through NMR and HRMS spectroscopy analysis. The calculated physical properties including PSA and cLogP values by Chemdraw software have shown their improved drug-like properties compared to artemisinin.
CONCLUSION:
Future efforts will focus on biological assays to assess cytotoxicity in leukemia and lymphoma cancer cell lines as well as in normal cell lines, investigate mechanisms of resistance, and evaluate potential synergy with current chemotherapeutics. Collectively, this work demonstrates that rational chemical modification and synergistic drug conjugation strategies provide a viable path toward novel therapies for the treatment of hematologic malignancies and to overcome drug resistance.