Synthesis and cytotoxic evaluation of combretafurazans.
Combretastatin A-4 is an antitumoral and antitubulin agent that is active only in its cis configuration. In the present manuscript, we have synthesized cis-locked combretastatins embodying a furazan ring (combretafurazans). To achieve this, we have developed a new strategy that exploits the dehydration of vicinal dioximes using the Mitsunobu reaction. Among the advantages of following such a strategy are the mild conditions used for the construction of the diarylfurazan derivatives, allowing for the presence of highly functionalized substrates and deactivated aromatic rings. Combretafurazans are more potent in vitro cytotoxic compounds compared to combretastatins in neuroblastoma cells, yet maintaining similar structure-activity relationship and pharmacodynamic profiles.
Tron
Gian Cesare
GC
Dipartimento di Scienze Chimiche, Alimentari, Farmaceutiche e Farmacologiche, Universitá del Piemonte Orientale "A. Avogadro", Via Bovio 6, 28100 Novara, Italy.
Pagliai
Francesca
F
Del Grosso
Erika
E
Genazzani
Armando A
AA
Sorba
Giovanni
G
D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001555:Benzene Derivatives / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001704:Biopolymers; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D005455:Fluorescent Antibody Technique; D006801:Humans; D008968:Molecular Conformation; D010069:Oxadiazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014404:Tubulin / Q000737:chemistry
D000970:Antineoplastic Agents; D001555:Benzene Derivatives; D001704:Biopolymers; D010069:Oxadiazoles; D014404:Tubulin