CONFORMATIONALLY DEFINED RETINOIC ACID ANALOGS - 4 - POTENTIAL NEW AGENTS FOR ACUTE PROMYELOCYTIC AND JUVENILE MYELOMONOCYTIC LEUKEMIAS

We recently synthesized several conformationally constrained retinoic acid (RA) analogues ohexen-1'-ylidene)-3,7-dimethyl-2,4,6-octatrienoic acids with different alkyl substituents at 2' (R-1) and 3' (R-2) posi tions on the cyclohexene ring] (Muccio et al. J. Med. Chem. 1996, 39, 3625) as cancer chemopreventive agents. UAB8 (R-1 = Et; R-2 = Pr-i), w hich contains sufficient steric bulk at the terminal end of the polyen e chain to mimic the trimethylcyclohexenyl ring of RA, displayed biolo gical properties similar to those of RA. To explore the efficacy of th is retinoid in acute promyelocytic leukemia (APL) and juvenile myelomo nocytic leukemia (JMML), we evaluated UAB8 isomers in in vitro assays which measure the capacity of retinoids to inhibit aberrant myeloid co lony growth from blood or bone marrow cells obtained from human JMML p atients and in assays measuring the potential of retinoids to differen tiate NB4 cells tan APL cell line). Both (all-E)- and (13Z)-UAB8 were 2-fold more active than RA in the NB4 cell differentiation assay; howe ver, only (all-E)-UAB8 had comparable activity to the natural retinoid s in the JMML cell assays. These results were compared to the biologic al effectiveness of a new retinoid, UAB30 thalen-1'-ylidene)-3,7-dimet hyl-2,4,6-octatrienoic acid], which had different nuclear receptor bin ding and transactivational properties than UAB8. Relative to (all-E)-R A and (all-E)-UAB8, (all-E)-UAB30 bound well to RAR alpha but did not activate transcription-mediated RAR alpha homodimers, even though it w as effective in RAR beta- and RAR gamma-mediated transactivational ass ays. In APL assays, this retinoid had much reduced activity and was on ly moderately effective in JMML assays and in cancer chemoprevention a ssays.