TY - JOUR
T1 - Synthesis and structure-activity relationships of new antiproliferative and proapoptotic retinoid-related biphenyl-4-yl-acrylic acids
AU - Cincinelli, Raffaella
AU - Dallavalle, Sabrina
AU - Nannei, Raffaella
AU - Merlini, Lucio
AU - Penco, Sergio
AU - Giannini, Giuseppe
AU - Pisano, Claudio
AU - Vesci, Loredana
AU - Ferrara, Fabiana Fosca
AU - Zuco, Valentina
AU - Zanchi, Chiara
AU - Zunino, Franco
PY - 2007/7/15
Y1 - 2007/7/15
N2 - Atypical retinoids, or retinoid-related molecules (RRMs), represent a class of proapoptotic agents with a promising potential in the treatment of neoplastic diseases. In the present work, the synthesis and structure-activity relationship of a series of 3′-adamantan-1-yl-biphenyl-4-yl-acrylic acids substituted in ring A were studied. The synthesized compounds were evaluated for their antiproliferative activity in a human promyelocitic leukemia cell line (NB4), and in an ovarian carcinoma cell system including IGROV-1, carrying a functional wild-type p53, and a cisplatin-resistant subline, IGROV-1/Pt-1. The presence of at least one oxygenated substituent in positions 4′ or 5′ appears determinant for the antiproliferative activity. With two substituents of this kind the activity increases, particularly in the case of alkylenedioxy compounds. The activation of DNA damage response as indicated by phosphorylation of H2AX histone, RPA-2 protein, and p53 at serine 15 by the most apoptotic compounds provides additional support to the hypothesis that the genotoxic stress is a critical event mediating apoptosis induction by compounds of this group.
AB - Atypical retinoids, or retinoid-related molecules (RRMs), represent a class of proapoptotic agents with a promising potential in the treatment of neoplastic diseases. In the present work, the synthesis and structure-activity relationship of a series of 3′-adamantan-1-yl-biphenyl-4-yl-acrylic acids substituted in ring A were studied. The synthesized compounds were evaluated for their antiproliferative activity in a human promyelocitic leukemia cell line (NB4), and in an ovarian carcinoma cell system including IGROV-1, carrying a functional wild-type p53, and a cisplatin-resistant subline, IGROV-1/Pt-1. The presence of at least one oxygenated substituent in positions 4′ or 5′ appears determinant for the antiproliferative activity. With two substituents of this kind the activity increases, particularly in the case of alkylenedioxy compounds. The activation of DNA damage response as indicated by phosphorylation of H2AX histone, RPA-2 protein, and p53 at serine 15 by the most apoptotic compounds provides additional support to the hypothesis that the genotoxic stress is a critical event mediating apoptosis induction by compounds of this group.
KW - Adamantyl
KW - Antiproliferative activity
KW - Apoptosis
KW - Retinoids
KW - Synthesis
UR - http://www.scopus.com/inward/record.url?scp=34249788978&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=34249788978&partnerID=8YFLogxK
U2 - 10.1016/j.bmc.2007.04.057
DO - 10.1016/j.bmc.2007.04.057
M3 - Article
C2 - 17512204
AN - SCOPUS:34249788978
VL - 15
SP - 4863
EP - 4875
JO - Bioorganic and Medicinal Chemistry
JF - Bioorganic and Medicinal Chemistry
SN - 0968-0896
IS - 14
ER -