Design, synthesis and evaluation of cytotoxic properties of bisamino glucosylated antitumor ether lipids against cancer cells and cancer stem cells

• Published in: MedChemComm Vol. 7; no. 11; pp. 2100 - 2110
• Main Authors: Ogunsina, Makanjuola, Samadder, Pranati, Idowu, Temilolu, Arthur, Gilbert, Schweizer, Frank
• Format: Journal Article
• Language: English
• Published: CAMBRIDGE Royal Soc Chemistry 01.01.2016
• Subjects: Biochemistry & Molecular Biology; Chemistry, Medicinal; Life Sciences & Biomedicine; Pharmacology & Pharmacy; Science & Technology; BREAST-CANCER; APOPTOSIS; RESISTANCE; LEUKEMIA STEM; THERAPEUTIC STRATEGIES; ERADICATION; COMBINATION; SALINOMYCIN; CHEMOTHERAPY; GLYCEROLIPIDS
• ISSN: 2040-2503; 2040-2511
• DOI: 10.1039/c6md00328a

Glycosylated antitumor ether lipids (GAELs) are a class of amphiphilic antitumor agents that kill cancer cells by a non-apoptotic pathway. Previous studies have shown that 2-amino-2-deoxy-D-gluco-based GAELs such as alpha-GLN and beta-GLN show greatly improved antitumor activity against epithelial cancer cells and stem cells. To further optimize the bioactivity, we prepared a series of diamino-D-gluco-based GAELs and their analogs, and screened them against a panel of human epithelial cancer cell lines and cancer stem cells. Most of the new GAEL analogs are more potent than chlorambucil, cisplatin and salinomycin. The most potent bisamine-based GAEL analogs 1, 2, 4 and 8 showed 2-to 3-fold enhanced cytotoxicity against various cancer cell lines when compared to beta-GLN, indicating that the addition of a second amino group enhances the cytotoxic effect. The effect of the most active dicationic GAELs 1 and 4 on cancer stem cells isolated from breast (BT-474) and prostate (DU-145) cell lines revealed that the two GAELs inhibited the formation of tumor spheres and resulted in >95% loss of viability of the cancer stem cells at 5 mu M. Activity of GAEL 1 against BT-474 cancer stem cells is superior to that of salinomycin.