Synthesis and Biological Evaluation of New Podophyllic Aldehyde Derivatives with Cytotoxic and Apoptosis-Inducing Activities

• Published in: Journal of medicinal chemistry 2010-02, Vol.53 (3), p.983-993
• Main Authors: Castro, M, Miguel del Corral, José M, García, Pablo A, Rojo, M, de la Iglesia-Vicente, Janis, Mollinedo, Faustino, Cuevas, Carmen, San Feliciano, Arturo
• Format: Article
• Language: English
• Subjects: Aldehydes - chemistry; Antineoplastic agents; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Apoptosis - drug effects; Biological and medical sciences; Cell Cycle - drug effects; Cell Proliferation - drug effects; Drug Screening Assays, Antitumor; General aspects; HT29 Cells - drug effects; Humans; Lung Neoplasms - drug therapy; Magnetic Resonance Spectroscopy; Medical sciences; Melanoma - drug therapy; Molecular Structure; Pharmacology. Drug treatments; Podophyllotoxin - analogs & derivatives; Podophyllotoxin - chemistry; Tumor Cells, Cultured
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm901373w

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 μM 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 GI50 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.