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Pure Appl. Chem., 2001, Vol. 73, No. 9, pp. 1437-1444

Retinoic acid and analogs as potent inducers of differentiation and apoptosis. New promising chemopreventive and chemotherapeutic agents in oncology

Daniele Simoni1, Riccardo Rondanin1, Riccardo Baruchello1, Marinella Roberti2, Marcello Rossi1, Stefania Grimaudo3, Natale D'Alessandro4, Francesco Paolo Invidiata5 and Manlio Tolomeo3

1 Dipartimento di Scienze Farmaceutiche, Via Fossato di Mortara 17-19, Università di Ferrara, 44100 Ferrara, Italy
2 Dipartimento di Scienze Farmaceutiche, Università di Bologna, Italy
3 Divisione di Ematologia e Servizio AIDS, Policlinico di Palermo, Italy
4 Dipartimento di Scienze Farmacologiche, Università di Palermo, Italy
5 Dipartimento Farmacochimico Tossicologico e Biologico, Università di Palermo, Italy

Abstract: In this report we will describe the preparation and the biological activity of a novel class of heterocyclic arotinoids endowed with potent cytotoxic and apoptotic acitivity. Structure­activity relationship studies revealed that the different stereochemistry at the C9 double bond of retinoids seems associated with a different biological activity: potent apoptotic activity for the cis-isomers, whereas differentiating activity for the trans structures. An interesting modified Wittig procedure that allows easily to arotinoids will also be described. The substitution of the alkenyl portion with a more flexible oxymethyl or aminomethyl moiety gave compounds with poor activity, whereas isoxazole-bridged arotinoids allowed compounds active also on multidrug-resistant (MDR) leukemia cell lines.