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.

Heteroarotinoids Inhibit Head and Neck Cancer Cell Lines in Vitro and in Vivo Through Both RAR and RXR Retinoic Acid Receptors

“…Evaporation of the solvent gave a solid which was recrystallized (hexane) to yield 40 (1. 6 2,2,4,4-Tetramethyl-6-aminothiochroman (41). To chroman 40 (0.800 g, 3.18 mmol) in acetic acid (29 mL) and water (6 mL) was added dropwise with stirring TiCl3/HCl (33.00 g, 21.39 mmol).…”

Synthesis of Flexible Sulfur-Containing Heteroarotinoids That Induce Apoptosis and Reactive Oxygen Species with Discrimination between Malignant and Benign Cells

“…9,10 Consequently, heteroarotinoids are currently under extensive investigation for the potential treatment of a variety of disorders. 9,10 Heteroarotinoids such as 6-10 constitute a class of synthetic retinoids 9,10 that structurally resemble arotinoids in that at least one aryl moiety is present within the molecular structure. However, heteroarotinoids contain an aryl-fused heterocyclic ring as a modification, and several studies have shown that some heteroarotinoids demonstrate promising inhibition of various cancers as well as reduced toxicity.…”

Synthesis of the heteroarotinoid ethyl (E)‐4‐[2‐(3,4‐dihydro‐4,4‐dimethyl‐2H‐1‐benzopyran‐6‐YL)‐1‐ propenyl]benzoate‐9,10,11,20‐14C4

“…A few heteroarotinoids have been synthesized and have exhibited good p h m a c ological activity in such assays as the tracheal organ culture (1,2), the omithine decarboxylase assay (1)(2)(3) and, to a limited degree, in the differentiation of HL-60 cells (3). h the omithine decarboxylase (ODC) assay (1,2), ethyl (E)-4-[2-(3,4-dihydro-4,4-dimethyl-2H-I-benzopyran-6-y1)-1 -propenyl]benzoate (2) exhibited excellent activity compared to the standard trans-retinoic acid (3) (2).…”

“…h the omithine decarboxylase (ODC) assay (1,2), ethyl (E)-4-[2-(3,4-dihydro-4,4-dimethyl-2H-I-benzopyran-6-y1)-1 -propenyl]benzoate (2) exhibited excellent activity compared to the standard trans-retinoic acid (3) (2). Both Nh4R (1,2) and UV (4) analyses 0362-4803/90/060673 -07$05. 00 suggested that both rings in 2 were twisted and only partially conjugated with the internal double bond in solution.…”