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

Simoni, Daniele; Rondanin, Riccardo; Baruchello, Riccardo; Roberti, Marinella; Rossi, Marcello; Grimaudo, Stefania; D'Alessandro, Natale; Invidiata, Francesco Paolo; Tolomeo, Manlio

doi:10.1351/pac200173091437

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

http://dx.doi.org/10.1351/pac200173091437

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.