Synthesis and biological evaluation of new podophyllic aldehyde derivatives with cytotoxic and apoptosis-inducing activities.
Several series of nonlactonic podophyllic aldehyde analogues were prepared and evaluated against several human tumor cell lines. They had different combinations of aldehyde, imine, amine, ester, and amide functions at C-9 and C-9' of the cyclolignan skeleton. All the compounds synthesized showed cytotoxicity levels in the microM range and below. Within the new series tested, compounds having an aldehyde or imine at C-9 and an ester at C-9' were the most potent, with GI(50) values in the nM range, some of them being several times more potent against HT-29 and A-549 carcinoma than against MB-231 melanoma cells. Cell cycle studies and analysis of the microtubule-disrupting capacity have demonstrated the existence of two different mechanisms of cell death induction for compounds with closely related structures.
Castro
Ma Angeles
MA
Departamento de Quimica Farmaceutica, Facultad de Farmacia, Campus Miguel de Unamuno, Universidad de Salamanca, E-37007 Salamanca, Spain. macg@usal.es
del Corral
José Ma Miguel
JM
García
Pablo A
PA
Rojo
Ma Victoria
MV
de la Iglesia-Vicente
Janis
J
Mollinedo
Faustino
F
Cuevas
Carmen
C
San Feliciano
Arturo
A
D000447:Aldehydes / Q000737:chemistry*; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects*; D004354:Drug Screening Assays, Antitumor; D019073:HT29 Cells / Q000187:drug effects; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy; D009682:Magnetic Resonance Spectroscopy; D008545:Melanoma / Q000188:drug therapy; D015394:Molecular Structure; D011034:Podophyllotoxin / Q000031:analogs & derivatives* / Q000737:chemistry; D014407:Tumor Cells, Cultured
D000447:Aldehydes; D000970:Antineoplastic Agents; C507546:podophyllic acid; D011034:Podophyllotoxin