Highly twisted adamantyl arotinoids: synthesis, antiproliferative effects and RXR transactivation profiles.

Abstract

Retinoid-related molecules with an adamantyl group (adamantyl arotinoids) have been described with selective activities towards the retinoid receptors as agonists for NR1B2 and NR1B3 (RARbeta,gamma) (CD437, MX3350-1) or RAR antagonists (MX781) that induce growth arrest and apoptosis in cancer cells. Since these molecules induce apoptosis independently of RAR transactivation, we set up to synthesize novel analogs with impaired RAR binding. Here we describe adamantyl arotinoids with 2,2'-disubstituted biaryl rings prepared using the Suzuki coupling of the corresponding fragments. Those with cinnamic and naphthoic acid end groups showed significant antiproliferative activity in several cancer cell lines, and this effect correlated with the induction of apoptosis as measured by caspase activity. Strikingly, some of these compounds, whereas devoid of RAR binding capacity, were able to activate RXR.

• Authors: Santiago Pérez-Rodríguez, Maria A Ortiz, Raquel Pereira, Fátima Rodríguez-Barrios, Angel R de Lera, F Javier Piedrafita
• Journal: European journal of medicinal chemistry (Eur J Med Chem) Vol. 44 Issue 6 Pg. 2434-46 (Jun 2009) ISSN: 1768-3254 [Electronic] France
• PMID: 19216008 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Retinoid X Receptors
• Retinoids
• Adamantane

Topics

• Adamantane (chemical synthesis, chemistry, pharmacology)
• Antineoplastic Agents (chemical synthesis, chemistry, pharmacology)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Computer Simulation
• Drug Screening Assays, Antitumor
• Humans
• Models, Chemical
• Molecular Structure
• Retinoid X Receptors (antagonists & inhibitors, genetics, metabolism)
• Retinoids (chemical synthesis, chemistry, pharmacology)
• Stereoisomerism
• Structure-Activity Relationship
• Transcriptional Activation (drug effects)