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Structure-Activity Relationship Studies of Novel Heteroretinoids: Induction of Apoptosis in the HL-60 Cell Line by a Novel Isoxazole-Containing Heteroretinoid Daniele Simoni,*,† Francesco Paolo Invidiata,‡ Riccardo Rondanin,† Stefania Grimaudo,‡ Giuliana Cannizzo,§ Eleonora Barbusca,§ Ferdinando Porretto,§ Nicola D’Alessandro,§ and Manlio Tolomeo§ Dipartimento di Scienze Farmaceutiche, Universita di Ferrara, Via Fossato di Mortara 17-19, 44100 Ferrara, Italy, and` Istituto Farmacochimico and Divisione di Ematologia e Servizio A.I.D.S., Policlinico, Universita di Palermo,` 90123 Palermo, Italy Received April 12, 1999 In a search for retinoic acid receptor (RAR and RXR)-selective ligands, a series of isoxazole retinoids was synthesized and evaluated in vitro in transcriptional activation and competition binding assays for RARs and RXRs. In addition, these compounds were evaluated for their differentiating, cytotoxic, and apoptotic activities. In general, these derivatives showed scarcely any binding affinity and were not active in the transcriptional assay. However, among these isoxazole derivatives, the cis-isomer 14b was identified as a potent inducer of apoptosis, and its activity was found to be 6.5 and 4 times superior than that of 13-cis- and 9-cis-retinoic acids, respectively. On the other hand, compound 13b, which has the trans stereochemistry at the double bond, was found not to be active in the apoptotic assay, but it was endowed with appreciable differentiating activity. Therefore, it seems that the different stereochemistry of the double bond may be associated with a different biological activity: potent apoptotic activity for the cis-isomer but differentiating activity for the trans structure. This biological behavior was found, at least in part, for the 9-cis- and 13-cis-retinoic acids with respect to the all-trans- retinoic acid. Thus, structure 14b could offer an interesting model for the design of new compounds endowed with apoptotic activity. Introduction Programmed cell death, or apoptosis, is a genetically encoded process involved in the homeostasis of multi- cellular organisms and in carcinogenesis.1,2 Several cytotoxic drugs employed in the chemotherapy of ma- lignancies cause apoptosis in neoplastic cells,3 but the mechanisms by which these drugs induce apoptosis are not well-understood at the molecular level, although several studies indicate that wild-type p53 oncosup- pressor gene, the Fas/Fas ligand system, and the caspases activation can play a role in drug-induced apoptosis.4-6 Recently, it has been shown that some natural and synthetic retinoids are capable of inducing apoptosis in cancer cell lines, but the mechanism by which retinoids induce apoptosis is still unknown.7-9 The retinoid signal is mediated by two classes of nuclear receptors: the retinoic acid receptors (RARR, -β, and -γ) and the retinoic X receptors (RXRR, -β, and -γ).10 These receptors usually bind as heterodimers to specific DNA sequences and/or interact with other transcriptional regulators, such as AP-1, to regulate gene transcription. The implication of RARs and RXRs in retinoid-induced apoptosis is still unclear; some observations suggest that cell differentiation mediated by retinoic acid is induced by the activation of RAR, whereas activation of RXR seems to be essential for driving cells into apoptosis;11 on the contrary, other authors have demonstrated the involvement of the RAR in apoptosis induced by reti- noids as shown by the inibition of apoptosis after treatment of HL-60 cells with an RARR antagonist.12,13 Moreover, a novel retinoid has been recently described that induces apoptosis with mechanism(s) not involving the nuclear RAR.14 Thus, as a result of the multiplicity of receptors, hormones, and dimerization pathways, it is likely that the many biological effects associated with retinoids are in fact mediated by several distinct pathways. However, the wider use of retinoids in dermatology (principally in the therapy of psoriasis and acne)10,15,16 and in other diseases such as oncology (treatment of carcinomas and for cancer chemoprevention)17,18 has been precluded by unacceptable side effects19 including skin irritation, lipid and bone toxicity, visual effects, and teratogenicity.7,19 To increase the selectivity to the retinoid receptors and to obtain compounds of pharmacological interest, the relationships between structure and retinoid activity have been extensively studied by preparing a large number of geometric isomers as well as conformationally locked and/or restricted analogues, resulting in specific, rigid, three-dimensional configurations.10,19 Taking these considerations into account, we have recently started a study aimed at evaluating the sub- stitution of the benzene ring portion of potent retinoids, such as the so-called “short retinoids” TTNPB and AM580, with a more hydrophilic isosteric heterocycle (i.e. isoxazole or thiophene). This study has identified a new class of interesting isoxazole-containing heter- |
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