Heterocycle-Containing Retinoids. Discovery of a Novel Isoxazole Arotinoid Possessing Potent Apoptotic Activity in Multidrug and Drug-Induced Apoptosis-Resistant Cells

Abstract

In a search for retinoic acid (RA) receptor ligands endowed with potent apoptotic activity, a series of novel arotinoids were prepared. Because the stereochemistry of the C9-alkenyl portion of natural 9-cis-RA and the olefinic moiety of the previously synthesized isoxazole retinoid 4 seems to have particular importance for their apoptotic activity, novel retinoid analogues with a restricted or, vice versa, a larger flexibility in this region were designed and prepared. The new compounds were evaluated in vitro for their ability to activate natural retinoid receptors and for their differentiation-inducing activity. Cytotoxic and apoptotic activities were, in addition, evaluated. In general, these analogues showed low cytotoxicity, with the restricted structures being slightly more active than the more flexible ones. As an exception, however, the isoxazole retinoid 15b proved to be particularly able to induce apoptosis at concentrations <5 microM, showing a higher activity than the classical retinoids such as all-trans-RA, 13-cis-RA, and 9-cis-RA and the previously described synthetic retinoid 4. 15b also exhibited a good affinity for the retinoid receptors. Interestingly, another important property of 15b was its ability to induce apoptosis in the HL60R multidrug-resistant (MDR) cell line, at the same concentration as is effective in HL60. Therefore, 15b represents a new retinoid possessing high apoptotic activity in an MDR cell line. The ability of 15b to act on K562 and HL60R cells suggests that this compound may have important implications in the treatment of different leukemias, and its structure could offer an interesting model for the design of new compounds endowed with apoptotic activity on MDR- and retinoid-resistant malignancies.

Hypermethylation and Silencing of the Putative Tumor SuppressorTazarotene-Induced Gene 1in Human Cancers

“…The induction of apoptosis after combined treatment with 5-Aza-dCyd and ATRA is possibly explained by retinoic acid acting on the demethylated cell population generated after 5-Aza-dCyd treatment. The K562 cell lines was previously reported to be resistant to differentiation induction by ATRA (23,24). Similar results were obtained when we studied other cell lines, such as the breast cancer cell lines CAMA-1 and BT-474, but using 1 M of ATRA after only 0.1 M of 5-Aza-dCyd instead of 1 M as in the cell line K562.…”

Syntheses and evaluation of the antioxidant activity of acitretin analogs with amide bond(s) in the polyene spacer

“…Furthermore, the indole residue may be substituted by either the pyrrole (analog 13) or the 4-amino-9-fluorenone (analogs 14 and 15) moieties, whereas structural characteristics of the two types of ACI analogs may be combined as exemplified with analog 16. Earlier studies have shown that inclusion of aromatic heterocyclic rings in retinoids is associated with reduced toxicity [5]. The involvement of these particular heterocyclic rings in the design of our analogs stemmed from the anticipation that they could be readily incorporated into the spacer by using the commercially available indole-3-carboxylic acid and -carboxaldehyde or the readily synthesized 3-acetylpyrrole, which include the hydrolytically stable N-C]C-CO structural motif.…”

Pyrazine Arotinoids with Inverse Agonist Activities on the Retinoid and Rexinoid Receptors

“…[12] Heteroaromatic rings have been included as central retinoid linkers less frequently. [14,[16][17][18][19] We therefore set out to design, synthesize and assess the ligand binding of a collection of retinoids that have a pyrazine heterocycle as a central connecting unit. To meet the structural requirements for RAR or RXR selectivity, we focused on two series of positional isomers that are derived from 2,3,6-and 2,3,5-trisubstituted pyrazines (Scheme 1).…”