Design and synthesis of 4-HPR derivatives for rhabdoid tumors.
Rhabdoid tumors (RTs) are aggressive pediatric malignancies with poor prognosis that arise due to loss of the hSNF5/INI1 tumor suppressor. Molecular studies indicate that cyclin D1, a downstream effector of INI1 is up regulated in RT, and is essential for this tumor formation. Previously we demonstrated that 4-HPR, a synthetic retinoid that targets Cyclin D1, is a potential chemotherapeutic agent for RT. To facilitate further chemical development of this retinoid, and to determine its active moiety, we synthesized small chemical libraries of 4-HPR and tested their cytotoxic effect on RT cells. We synthesized 4-HPR (1) and the derivatives (5a-5n) starting from retinoic acid. First, retinoic acid was converted to acid chloride derivatives, then in the presence of DMF, base, and aniline derivatives, we synthesized the corresponding 4-hydroxy phenyl amine derivatives (5a-5n). This procedure gave 70-90% yield. Then, the 4-HPR derivatives were tested for their ability to inhibit RT cells using an in vitro cell survival assay. We found that the 4-hydroxy group at para-position is essential for cytotoxic activity against RT cells. Furthermore, we identified a few derivatives of 4-HPR with higher cytotoxic potencies than 4-HPR. In addition, we demonstrate that either chloro, fluoro or iodo derivatives at meta-position of phenyl ring retain the cytotoxic activity. Interestingly, substitution of iodo-moiety at meta-position (5j) substantially increased the efficacy (IC(50) approximately 3muM, Fig. 1D). These results indicate that chemical modification of 4-HPR may result in derivatives with increased therapeutic potential for RTs and that halogen substituted 4-HPR that retain the activity can be synthesized for further therapeutic and diagnostic use.
Das
Bhaskar C
BC
Department of Nuclear Medicine, Albert Einstein College of Medicine, Bronx, NY 10461, USA. bdas@aecom.yu.edu
Smith
Melissa E
ME
Kalpana
Ganjam V
GV
D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D017209:Apoptosis; D049109:Cell Proliferation; D002470:Cell Survival; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D002712:Chlorides / Q000737:chemistry; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D017313:Fenretinide / Q000138:chemical synthesis / Q000494:pharmacology*; D006801:Humans; D020128:Inhibitory Concentration 50; D008956:Models, Chemical; D008968:Molecular Conformation; D018335:Rhabdoid Tumor / Q000188:drug therapy*; D014212:Tretinoin / Q000737:chemistry
D000970:Antineoplastic Agents; D002712:Chlorides; D017313:Fenretinide; D014212:Tretinoin