Improved total synthesis and biological evaluation of potent apratoxin S4 based anticancer agents with enhanced activity

• Published in: Planta Medica
• Main Authors: Chen, QY, Liu, Y, Cai, W, Luesch, H
• Format: Conference Proceeding
• Language: English
• Published: 14.07.2014
• ISSN: 0032-0943; 1439-0221
• DOI: 10.1055/s-0034-1382377

Apratoxins are cytotoxic natural products originally isolated from marine cyanobacteria that act by preventing cotranslational translocation early in the secretory pathway to downregulate receptor levels and inhibit growth factor secretion, leading to potent antiproliferative activity. Through rational design and total synthesis of the apratoxin A/E hybrid apratoxin S4 (1a), we have previously improved the antitumor activity and tolerability in vivo. Apratoxin S4 (1a) and newly designed analogues apratoxins S7-S9 (1b-d) were efficiently synthesized utilizing improved procedures. Apratoxin S9 (1 d) exhibited increased activity with sub-nanomolar potency. Apratoxin S8 (1c) lacks the propensity to be deactivated by dehydration and showed efficacy in a human HCT116 xenograft mouse model. Fig. 1 Apratoxin IC50(nM)cell viability IC50(nM)VEGF-Asecretion S4 (30 S , 34-Me) 1.43 0.32 S7 (30 S , 34-H 2 ) 1.25 0.30 S8 (30 S , 34-Me 2 ) 1.99 0.47 S9 (30 R , 34-Me) 0.69 0.12