Conformationally defined retinoic acid analogues. 4. Potential new agents for acute promyelocytic and juvenile myelomonocytic leukemias
| Autor: | Theodore R. Breitman, Peter D. Emanuel, Wayne J. Brouillette, Mohammed Taimi, Guo-quan Chen, Donald L. Hill, Muzaffar Alam, Lakshmi Reddy, Brahma P. Sani, Donald D. Muccio, Pratap Venepally, Linda Simpson-Herren, Xiao-kun Zhang |
|---|---|
| Rok vydání: | 1998 |
| Předmět: |
Acute promyelocytic leukemia
Myeloid Skin Neoplasms Transcription Genetic medicine.drug_class Receptors Retinoic Acid Retinoic acid Molecular Conformation Antineoplastic Agents HL-60 Cells Tretinoin In Vitro Techniques Naphthalenes Cell Line chemistry.chemical_compound Mice Radioligand Assay Leukemia Promyelocytic Acute Drug Discovery medicine Animals Humans Retinoid Child Tumor Stem Cell Assay Skin Juvenile myelomonocytic leukemia Papilloma Biological activity Leukemia Myelomonocytic Chronic Stereoisomerism medicine.disease In vitro medicine.anatomical_structure Biochemistry chemistry Cancer research Fatty Acids Unsaturated Molecular Medicine Bone marrow Chickens |
| Zdroj: | Journal of medicinal chemistry. 41(10) |
| ISSN: | 0022-2623 |
| Popis: | We recently synthesized several conformationally constrained retinoic acid (RA) analogues [8-(2'-cyclohexen-1'-ylidene)-3, 7-dimethyl-2,4,6-octatrienoic acids with different alkyl substituents at 2' (R1) and 3' (R2) positions on the cyclohexene ring] (Muccio et al. J. Med. Chem. 1996, 39, 3625) as cancer chemopreventive agents. UAB8 (R1 = Et; R2 = iPr), which contains sufficient steric bulk at the terminal end of the polyene chain to mimic the trimethylcyclohexenyl ring of RA, displayed biological properties similar to those of RA. To explore the efficacy of this retinoid in acute promyelocytic leukemia (APL) and juvenile myelomonocytic leukemia (JMML), we evaluated UAB8 isomers in in vitro assays which measure the capacity of retinoids to inhibit aberrant myeloid colony growth from blood or bone marrow cells obtained from human JMML patients and in assays measuring the potential of retinoids to differentiate NB4 cells (an APL cell line). Both (all-E)- and (13Z)-UAB8 were 2-fold more active than RA in the NB4 cell differentiation assay; however, only (all-E)-UAB8 had comparable activity to the natural retinoids in the JMML cell assays. These results were compared to the biological effectiveness of a new retinoid, UAB30 [8-(3', 4'-dihydro-1'(2'H)-naphthalen-1'-ylidene)-3,7-dimethyl-2,4, 6-octatrienoic acid], which had different nuclear receptor binding and transactivational properties than UAB8. Relative to (all-E)-RA and (all-E)-UAB8, (all-E)-UAB30 bound well to RARalpha but did not activate transcription-mediated RARalpha homodimers, even though it was effective in RARbeta- and RARgamma-mediated transactivational assays. In APL assays, this retinoid had much reduced activity and was only moderately effective in JMML assays and in cancer chemoprevention assays. |
| Databáze: | OpenAIRE |
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