[Show abstract][Hide abstract] ABSTRACT: Twenty analogues of the natural antitumor agent dolastatin 11, including majusculamide C, were synthesized and tested for cytotoxicity against human cancer cells and stimulation of actin polymerization. Only analogues containing the 30-membered ring were active. Molecular modeling and NMR evidence showed the low-energy conformations. The amide bonds are all trans except for the one between the Tyr and Val units, which is cis. Since an analogue restricted to negative 2-3-4-5 angles stimulated actin polymerization but was inactive in cells, the binding conformation (most likely the lowest-energy conformation in water) has a negative 2-3-4-5 angle, whereas a conformation with a positive 2-3-4-5 angle (most likely the lowest energy conformation in chloroform) goes through cell walls. The highly active R alcohol from borohydride reduction of dolastatin 11 is a candidate for conversion to prodrugs.
[Show abstract][Hide abstract] ABSTRACT: The first synthesis of dolastatin 11, a potent antineoplastic agent from the sea hare Dolabella auricularia, confirmed the proposed structure and established the last configuration in this natural product and in dolastatin 12, majusculamide C, and 57-normajusculamide C.
Journal of the American Chemical Society 03/1997; 119(9). DOI:10.1021/ja963857y · 12.11 Impact Factor