New alpha-amino phosphonic acid derivatives of vinblastine: chemistry and antitumor activity.
A series of new amino phosphonic acid derivatives of vinblastine (1, VLB) has been synthesized and tested in vitro and in vivo for antitumor activity. The compounds were obtained from O4-deacetyl-VLB azide. All of the new products studied were capable of inhibiting tubulin polymerization in vitro. The most potent antitumor compounds bore an alkyl substituent on the phosphonate. In these compounds, the anti-tumor activity strongly depended on the stereochemistry of the phosphonate. The phosphonate (1S)-[1-[( O4-deacetyl-3-de(methoxycarbonyl)vincaleukoblastin-3-yl] carbonyl]amino]-2-methylpropyl]phosphonic acid diethyl ester exhibited a remarkable activity against cancer cell lines both in vitro and in vivo.
Lavielle
G
G
Institut de Recherches Servier, Suresnes, France.
Hautefaye
P
P
Schaeffer
C
C
Boutin
J A
JA
Cudennec
C A
CA
Pierré
A
A
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000627:therapeutic use; D002478:Cells, Cultured; D055598:Chemical Phenomena; D002621:Chemistry; D007941:Leukemia P388 / Q000188:drug therapy; D051379:Mice; D008811:Mice, Inbred DBA; D063065:Organophosphonates / Q000138:chemical synthesis*; D013329:Structure-Activity Relationship; D014747:Vinblastine / Q000031:analogs & derivatives*
D000970:Antineoplastic Agents; D063065:Organophosphonates; D014747:Vinblastine