Programmed cell death (PCD) associated with the stilbene motif of arotinoids: discovery of novel apoptosis inducer agents possessing activity on multidrug resistant tumor cells

Considering that the stereochemistry of the C9–C10 alkenyl portion of natural 9- cis-RA, as the one of the olefinic moiety of the previously described isoxazole retinoid 4, seems of particular importance for their apoptotic activity, we prepared a novel class of TTNPB analogues bearing both the cis...

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Published in:Bioorganic & medicinal chemistry letters 2000-12, Vol.10 (23), p.2669-2673
Main Authors: Simoni, Daniele, Roberti, Marinella, Paolo Invidiata, Francesco, Rondanin, Riccardo, Baruchello, Riccardo, Malagutti, Cinzia, Mazzali, Angelica, Rossi, Marcello, Grimaudo, Stefania, Dusonchet, Luisa, Meli, Maria, Raimondi, Maria Valeria, D'Alessandro, Natale, Tolomeo, Manlio
Format: Article
Language:English
Subjects:
Antineoplastic agents
Antineoplastic Agents - chemistry
Antineoplastic Agents - pharmacology
Apoptosis - drug effects
Biological and medical sciences
Drug Resistance, Multiple
General aspects
HL-60 Cells
Humans
K562 Cells
Medical sciences
Pharmacology. Drug treatments
Retinoids - chemistry
Retinoids - pharmacology
Stilbenes - pharmacology
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Summary:Considering that the stereochemistry of the C9–C10 alkenyl portion of natural 9- cis-RA, as the one of the olefinic moiety of the previously described isoxazole retinoid 4, seems of particular importance for their apoptotic activity, we prepared a novel class of TTNPB analogues bearing both the cis or trans configuration of the alkenyl portion. The compounds were evaluated in vitro for their cytotoxic and apoptotic activities. We discovered that the cis-TTNPB 9c possesses apoptotic activity comparable with that of the retinoid 4. Moreover, the amino arotinoid 16c showed potent apoptotic activity in HL60 promyelocytic leukemia cells. Interestingly, 16c proved to be a particularly potent apoptosis-inducing agent active in multidrug resistant (MDR) cell lines. Therefore, to the best of our knowledge, 16c may represent the first known aminoarotinoid endowed with potent apoptotic activity in MDR cells. Taken together, these results seem to point out that the cis-stilbene motif of arotinoids may be at least an important feature in conferring cytotoxic and apoptotic activity to this class of compounds.
ISSN:0960-894X
1464-3405
DOI:10.1016/S0960-894X(00)00547-3