The discovery of potent antitumor agent C11-deoxypsymberin/irciniastatin A: total synthesis and biology of advanced psymberin analogs.
Structure-activity relationship (SAR) studies by modification of the unsaturated side chain of potent anticancer marine natural product psymberin/irciniastatin A (1) suggest that substitution at C4 and C5 is important for the cytotoxicity of psymberin, but the terminal double bond is not essential for activity. An aryl group is a good replacement for the olefin. The total synthesis of structurally simplified C11-deoxypsymberin (29) was completed, and its activity is consistently more potent than the natural product which provides a unique opportunity for further SAR studies in the psymberin and pederin family. Preliminary mechanism studies suggest the mode of action of psymberin is through cell apoptosis.
Huang
Xianhai
X
Department of Chemical Research, Schering-Plough Research Institute, Kenilworth, New Jersey 07033, USA. xianhai.huang@spcorp.com
Shao
Ning
N
Huryk
Robert
R
Palani
Anandan
A
Aslanian
Robert
R
Seidel-Dugan
Cynthia
C
D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D020650:Combinatorial Chemistry Techniques; D003374:Coumarins / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D004354:Drug Screening Assays, Antitumor; D008386:Marine Biology; D015394:Molecular Structure; D011753:Pyrones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; C539203:C11-deoxypsymberin; D003374:Coumarins; D011753:Pyrones; C498383:psymberin