Heterocycle-containing retinoids. Discovery of a novel isoxazole arotinoid possessing potent apoptotic activity in multidrug and drug-induced apoptosis-resistant cells.
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.
Simoni
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D
Dipartimento di Scienze Farmaceutiche, Via Fossato di Mortara 17-19, Università di Ferrara, 44100 Ferrara, Italy. smd@dns.unife.it
Roberti
M
M
Invidiata
F P
FP
Rondanin
R
R
Baruchello
R
R
Malagutti
C
C
Mazzali
A
A
Rossi
M
M
Grimaudo
S
S
Capone
F
F
Dusonchet
L
L
Meli
M
M
Raimondi
M V
MV
Landino
M
M
D'Alessandro
N
N
Tolomeo
M
M
Arindam
D
D
Lu
S
S
Benbrook
D M
DM
D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D017209:Apoptosis; D001565:Benzoates / Q000737:chemistry; D002454:Cell Differentiation / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D020128:Inhibitory Concentration 50; D007555:Isoxazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D018168:Receptors, Retinoic Acid / Q000235:genetics / Q000378:metabolism; D012176:Retinoids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013764:Tetrahydronaphthalenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015533:Transcriptional Activation; D014407:Tumor Cells, Cultured
C430899:4-(5-(5,6,7,8-tetrahydro-5,5,8,8--tetramethylnaphthalen-2-yl)isoxazol-3-yl)benzoic acid; D000970:Antineoplastic Agents; D001565:Benzoates; D007555:Isoxazoles; D018168:Receptors, Retinoic Acid; D012176:Retinoids; D013764:Tetrahydronaphthalenes; C038864:4-(2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-1-propenyl)benzoic acid