Chiral resolution of a caged xanthone and evaluation across a broad spectrum of breast cancer subtypes

• Published in: Bioorganic chemistry Vol. 93; p. 103303
• Main Authors: Chantarasriwong, Oraphin, Dorwart, Tanis J., Morales, Theodore Habarth, Maggio, Stephanie F., Settle, Aspen L., Milcarek, Andrew T., Alpaugh, Mary L., Theodoraki, Maria A., Theodorakis, Emmanuel A.
• Format: Journal Article
• Language: English
• Published: SAN DIEGO Elsevier Inc 01.12.2019; Elsevier
• Subjects: Biochemistry & Molecular Biology; Breast cancer; Chemistry; Chemistry, Organic; Gambogic acid; Garcinia; Life Sciences & Biomedicine; Natural product; Physical Sciences; Science & Technology; Synthetic methods; Natural product; Synthetic methods; Breast cancer; Gambogic acid; Garcinia; INDUCED APOPTOSIS; STEM BARK; TOXICITY; KAPPA-B; BCL-2; IN-VITRO; CHEMISTRY; TETRAPRENYLATED XANTHONES; EXPRESSION
• ISSN: 0045-2068; 1090-2120
• DOI: 10.1016/j.bioorg.2019.103303

Enantiomerically pure or racemic mixtures of (+/−)-MAD28 show increased cytotoxicity against triple negative, metastatic and chemorefractant breast cancer subtypes. [Display omitted] •Racemic resolution of a caged xanthone was performed with a resolving agent.•(+)-,(−)-, and (+/−)- MAD28 are equipotent in a panel of breast cancer cell lines.•(+/−)- MAD28 exhibits higher cytotoxicity against triple negative breast cancer cell lines.•Caged xanthones are promising leads as breast cancer-targeting therapeutics. Racemic resolution of (+/−)-MAD28, a representative caged xanthone, was accomplished using (1S, 4R)-(−)-camphanic chloride as the chiral agent. Selective crystallization of the resulting diastereomers in acetonitrile produced, after hydrolysis, the pure enantiomers. Screening of racemic MAD28 and both enantiomers across a broad spectrum of breast cancer cell lines revealed that they: (a) are equipotent in each of the breast cancer subtypes examined; and (b) exhibit a higher degree of cytotoxicity against breast cancer cell lines of basal-like subtype and triple negative receptor status. The results support the notion that MAD28 and related caged xanthones are promising drug leads against chemoresistant and metastatic cancers.