title: Heteroarotinoids. Synthesis, characterization, and biological activity in terms of an assessment of these systems to inhibit the induction of ornithine decarboxylase activity and to induce terminal differentiation of HL-60 cells.
abstract: The synthesis of certain heteroarotinoids has been achieved, namely the systems (2E,4E,6E)-3,7-dimethyl-7-(1,2,3,4-tetrahydro-4,4-dimethyl-6 -thiochromanyl)-2,4,6-heptatrienoic acid (1a), ethyl (2E,4E,6E)-3,7-dimethyl-7- (1,2,3,4-teterahydro-4,4-dimethyl-6-thiochromanyl)-2,4,6- heptatrienoate (1b), (2E,4E,6E)-3,7-dimethyl-7-(1,2,3,4-tetrahydro-4,4-dimethyl-6 -chromanyl)-2,4,6-heptatrienoic acid (1c), 2-phthalimidoethyl 3,7-dimethyl-7-(1,2,3,4-tetrahydro-4 4-dimethyl-6-thiochromanyl)-2,4,6-heptatrienoate (1d), methyl (E)-p-[2-(4,4- dimethyl-6-chromanyl)-1-propenyl]benzoate (2a), (E)-p-[2-(4,4-dimethyl-6-chromanyl)-1-propenyl]benzyl alcohol (2b), (E)-p-[2-(4,4-dimethyl-6-chromanyl)-1-propenyl]benzonitrile (2c), (E)-p-[2-(4,4-dimethyl-6-chromanyl)-1-propenyl]benzaldehyde (2d), methyl 4-[2-(2,3-dihydro-3,3-dimethyl-5-benzofuranyl)-1-propenyl] benzoate (3a), and (E)-p-[2-(2,3-dihydro-3,3-dimethyl-5-benzofuranyl)-1- propenyl]benzoic acid (3b). Characterization via elemental, IR, 1H NMR, and 13C NMR analyses was completed for these heterocycles. The biological activity of these heteroarotinoids was assayed by either the suppression of the 12-O-tetradecanoylphorbol 13-acetate (TPA) induced synthesis of ornithine decarboxylase (ODC) in mouse skin or the induction of differentiation of human (HL-60) promyelocytic cells. In the ODC assay, systems 1a-c exhibited strong activity (within 10% of or less than the control) whereas alcohols 2b and 3a showed good activity (within 50% of the control) as compared to either 13-cis-retinoic acid or trans-retinoic acid. Moderate activity was observed with 2a and 2b while 1d and 2c were essentially inactive. With the HL-60 assay, 1a and 1c were approximately 2- and 5-fold less active, respectively, than trans-retinoic acid. In contrast, 2a, 3a, and 3b induced differentiation of only a very small percentage of the cells. Acids 1a and 1c were the most active heteroarotinoids in the two biological assays. Consequently, the presence of the heteroatom does not eradicate the activity of the heteroarotinoids and thus they may have potential as chemotherapeutic agents.
mesh_terms: D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D055598:Chemical Phenomena; D002621:Chemistry; D004790:Enzyme Induction / Q000187:drug effects; D006098:Granulocytes / Q000166:cytology*; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D065108:Ornithine Decarboxylase Inhibitors; D012176:Retinoids / Q000138:chemical synthesis / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014212:Tretinoin / Q000494:pharmacology
chemical_list: D065108:Ornithine Decarboxylase Inhibitors; D012176:Retinoids; D014212:Tretinoin