TY - JOUR
T1 - Synthesis of short retinoidal amides related to fenretinide
T2 - antioxidant activities and differentiation-inducing ability
AU - Anzaldi, Maria
AU - Viale, Maurizio
AU - Macciò, Chiara
AU - Castagnola, Patrizio
AU - Oliveri, Valentina
AU - Rosano, Camillo
AU - Balbi, Alessandro
PY - 2017/4/1
Y1 - 2017/4/1
N2 - Purpose: By a scaffold shortening strategy, a small series of retinoidal amides fenretinide (4-HPR) analogs have been synthesized from α, β-ionones and tested for their antiproliferative and differentiating activities, and antioxidant effect. Methods: The antiproliferative activity and triggering of apoptosis of our short retinoids were evaluated by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and 4′-6-diamidino-2-phenylindole staining and microscope evaluation after 3- or 6-day exposure, while their differentiating activity was established by the analysis of the expression of the CD11b marker of differentiation in treated HL60 target cells and by the superoxide production assayed colorimetrically by the nitro blue tetrazolium-reducing activity assay. Finally, the antioxidant activity was determined by the 2,2′-azino-bis-(3-ethylbenzthiazoline-6-sulphonic acid) diammonium salt radical cation decolourisation assay utilizing the antioxidant Trolox (6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid) as reference (Trolox equivalent antioxidant capacity, or TEAC). Docking analysis was performed to study the binding features to the Retinoic Acid Receptor alpha (RARα). Results: While no pharmacologically relevant antiproliferative activity was evidenced, some of our short retinoids showed a differentiating and antioxidant activity similar to that of 4-HPR. In particular, compound 2b6 displayed a scavenging activity two times more efficient than 4-HPR itself. Finally, the docking analysis showed that these short retinoids, like 4-HPR, bind to the RARα protein with good fitness scores. Conclusion: Our data could pave the way for the design of new potent and less toxic antioxidant and differentiating compounds related to 4-HPR.
AB - Purpose: By a scaffold shortening strategy, a small series of retinoidal amides fenretinide (4-HPR) analogs have been synthesized from α, β-ionones and tested for their antiproliferative and differentiating activities, and antioxidant effect. Methods: The antiproliferative activity and triggering of apoptosis of our short retinoids were evaluated by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and 4′-6-diamidino-2-phenylindole staining and microscope evaluation after 3- or 6-day exposure, while their differentiating activity was established by the analysis of the expression of the CD11b marker of differentiation in treated HL60 target cells and by the superoxide production assayed colorimetrically by the nitro blue tetrazolium-reducing activity assay. Finally, the antioxidant activity was determined by the 2,2′-azino-bis-(3-ethylbenzthiazoline-6-sulphonic acid) diammonium salt radical cation decolourisation assay utilizing the antioxidant Trolox (6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid) as reference (Trolox equivalent antioxidant capacity, or TEAC). Docking analysis was performed to study the binding features to the Retinoic Acid Receptor alpha (RARα). Results: While no pharmacologically relevant antiproliferative activity was evidenced, some of our short retinoids showed a differentiating and antioxidant activity similar to that of 4-HPR. In particular, compound 2b6 displayed a scavenging activity two times more efficient than 4-HPR itself. Finally, the docking analysis showed that these short retinoids, like 4-HPR, bind to the RARα protein with good fitness scores. Conclusion: Our data could pave the way for the design of new potent and less toxic antioxidant and differentiating compounds related to 4-HPR.
KW - 4-HPR
KW - Antioxidant
KW - Differentiation
KW - Retinoidal amides
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U2 - 10.1007/s00280-017-3265-1
DO - 10.1007/s00280-017-3265-1
M3 - Article
AN - SCOPUS:85014708477
VL - 79
SP - 725
EP - 736
JO - Cancer Chemotherapy and Pharmacology
JF - Cancer Chemotherapy and Pharmacology
SN - 0344-5704
IS - 4
ER -