title: Synthesis and structure-activity relationships of a new series of retinoid-related biphenyl-4-ylacrylic acids endowed with antiproliferative and proapoptotic activity.
abstract: 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.
authors: Dipartimento di Scienze Molecolari Agroalimentari, Università di Milano, Via Celoria 2, 20133 Milano, Italy.
authors: Raffaella
authors: R
authors: Cincinelli
authors: Sabrina
authors: S
authors: Dallavalle
authors: Raffaella
authors: R
authors: Nannei
authors: Serena
authors: S
authors: Carella
authors: Daniele
authors: D
authors: De Zani
authors: Lucio
authors: L
authors: Merlini
authors: Sergio
authors: S
authors: Penco
authors: Enrico
authors: E
authors: Garattini
authors: Giuseppe
authors: G
authors: Giannini
authors: Claudio
authors: C
authors: Pisano
authors: Loredana
authors: L
authors: Vesci
authors: Paolo
authors: P
authors: Carminati
authors: Valentina
authors: V
authors: Zuco
authors: Chiara
authors: C
authors: Zanchi
authors: Franco
authors: F
authors: Zunino
mesh_terms: 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
chemical_list: D000179:Acrylates; D000970:Antineoplastic Agents; D001713:Biphenyl Compounds; D012176:Retinoids; D000218:Adamantane