Dolastatin 11 conformations, analogues and pharmacophore.
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.
Ali
Md Ahad
MA
Department of Chemistry, University of Arizona, Tucson, AZ 85721, USA.
Bates
Robert B
RB
Crane
Zackary D
ZD
Dicus
Christopher W
CW
Gramme
Michelle R
MR
Hamel
Ernest
E
Marcischak
Jacob
J
Martinez
David S
DS
McClure
Kelly J
KJ
Nakkiew
Pichaya
P
Pettit
George R
GR
Stessman
Chad C
CC
Sufi
Bilal A
BA
Yarick
Gayle V
GV
D000199:Actins / Q000378:metabolism*; D000818:Animals; D002470:Cell Survival / Q000187:drug effects*; D047630:Depsipeptides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D007941:Leukemia P388 / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D008958:Models, Molecular; D008968:Molecular Conformation; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
D000199:Actins; D047630:Depsipeptides; C422265:dolastatin 11