Total synthesis and biological evaluation of cortistatins A and J and analogues thereof.
Total syntheses of the highly selective antiproliferative natural products cortistatins A (1) and J (5) in their naturally occurring enantiomeric forms are described. The modular and convergent strategy employed relies on an intramolecular oxa-Michael addition/aldol/dehydration cascade reaction to cast the ABCD ring framework of the molecule and both Sonogashira and Suzuki-Miyaura coupling reactions to assemble the necessary building blocks into the required heptacyclic skeleton. A divergent approach from a late-stage epoxy ketone leads to both target molecules in a stereoselective manner. The developed synthetic technologies were applied to the construction of several analogues of the cortistatins which were biologically evaluated and compared to the natural products with regards to their antiproliferative activities against a variety of cancer cells. Analogues 8 and 81, lacking both the dimethylamino and hydroxyl groups of cortistatin A, were found to exhibit comparable biological activity as the parent compound, leading to the conclusion that such functionalities are not essential for biological activity.
Nicolaou
K C
KC
Chemical Synthesis Laboratory@Biopolis, Institute of Chemical and Engineering Sciences (ICES), Agency for Science, Technology and Research (ASTAR), 11 Biopolis Way, The Helios Block, #03-08, Singapore 138667. kcn@scripps.edu
Peng
Xiao-Shui
XS
Sun
Ya-Ping
YP
Polet
Damien
D
Zou
Bin
B
Lim
Chek Shik
CS
Chen
David Y-K
DY
D001688:Biological Products / Q000138:chemical synthesis / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D006576:Heterocyclic Compounds, 4 or More Rings / Q000138:chemical synthesis* / Q000494:pharmacology*; D006801:Humans; D020128:Inhibitory Concentration 50; D007546:Isoquinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D011083:Polycyclic Compounds / Q000138:chemical synthesis* / Q000494:pharmacology*
D001688:Biological Products; D006576:Heterocyclic Compounds, 4 or More Rings; D007546:Isoquinolines; D011083:Polycyclic Compounds; C531521:cortistatin A; C545305:cortistatin J; C039109:isoquinoline