Synthesis and structure-activity relationships of a new series of retinoid-related biphenyl-4-ylacrylic acids endowed with antiproliferative and proapoptotic activity.
Atypical retinoids (AR) represent a class of proapoptotic agents with promising potential in the treatment of neoplastic diseases. In the present work 4'-hydroxybiphenyl-4-ylacrylic acids were studied as a novel series of AR. The synthesized compounds were evaluated for their antiproliferative activity in a human promyelocytic 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 a bulky lipophilic group at position 3' (adamantan-1-yl being the best) and the E configuration of the acrylic moiety appear essential for activity below 1 muM. No substitution on the rings or on the double bond improved the activity. A qualitative correlation between the log P and molecular volume of the 3'-substituent and the antiproliferative activity was found. From the study of a few selected compounds, it appears that the presence of the carboxylic group is an essential requirement for apoptogenic properties but not for antiproliferative activity, this being maintained in amide derivatives. On the other hand, compounds able to induce apoptosis produced a detectable level of genotoxic damage. This observation supports the hypothesis that the genotoxic stress is a critical event mediating apoptosis induction by compounds of this class. Among the compounds investigated, E-3-(3'-adamantan-1-yl-4'-hydroxybiphenyl-4-yl)acrylic acid (2) was chosen for further investigation.
Cincinelli
Raffaella
R
Dipartimento di Scienze Molecolari Agroalimentari, Università di Milano, Via Celoria 2, 20133 Milano, Italy.
Dallavalle
Sabrina
S
Nannei
Raffaella
R
Carella
Serena
S
De Zani
Daniele
D
Merlini
Lucio
L
Penco
Sergio
S
Garattini
Enrico
E
Giannini
Giuseppe
G
Pisano
Claudio
C
Vesci
Loredana
L
Carminati
Paolo
P
Zuco
Valentina
V
Zanchi
Chiara
C
Zunino
Franco
F
D000179:Acrylates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000218:Adamantane / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D001713:Biphenyl Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D012176:Retinoids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D000179:Acrylates; D000970:Antineoplastic Agents; D001713:Biphenyl Compounds; D012176:Retinoids; D000218:Adamantane