Total synthesis and evaluation of a key series of C5-substituted vinblastine derivatives.
A remarkably concise seven- to eight-step total synthesis of a systematic series of key vinblastine derivatives is detailed and used to characterize the importance and probe the role of the C5 ethyl substituent (R = H, Me, Pr, CH=CH(2), C[triple bond]CH, CH(2)OH, and CHO vs Et). The analogues, which bear deep-seated structural changes accessible only by total synthesis, were prepared using a powerful intramolecular [4 + 2]/[3 + 2] cycloaddition cascade of 1,3,4-oxadiazoles ideally suited for use in the assemblage of the vindoline-derived lower subunit followed by their incorporation into the vinblastine analogues through the use of a single-step biomimetic coupling with catharanthine. The evaluation of the series revealed that the tubulin binding site surrounding this C5 substituent is exquisitely sensitive to the presence (Et > H, 10-fold), size (Me < or = Et > Pr, 10-fold), shape (Et > CH=CH(2) and C[triple bond]CH, > 4-fold), and polarity (Et > CHO > CH(2)OH, >10-20-fold) of this substituent and that on selected occasions only a C5 methyl group may provide analogues that approach the activity observed with the naturally occurring C5 ethyl group.
Va
Porino
P
Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA.
Campbell
Erica L
EL
Robertson
William M
WM
Boger
Dale L
DL
D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D045744:Cell Line, Tumor; D006801:Humans; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D008968:Molecular Conformation; D014404:Tubulin / Q000378:metabolism; D014747:Vinblastine / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology*
D000970:Antineoplastic Agents; D014404:Tubulin; D014747:Vinblastine