Synthesis, Structure−Activity Relationships, and RARγ−Ligand Interactions of Nitrogen Heteroarotinoids

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Abstract
Three heteroarotinoids containing a nitrogen atom in the first ring and a C−O linking group between the two aryl rings were synthesized and evaluated for RAR and RXR retinoid receptor transactivation, tumor cell growth inhibition, and transglutaminase (TGase) induction. Ethyl 4-(N,4,4-trimethyl-1,2,3,4-tetrahydroquinolinyl)benzoate (1) contained an N-CH3 group and activated all retinoid receptors except for RARγ. Inceasing the hydrophobicity around the rings with analogues ethyl 4-(N,4,4,7-tetramethyl-1,2,3,4-tetrahydroquinolin-6-oyloxy)benzoate (2) [7-methyl group added] and ethyl 4-(4,4-dimethyl-N-isopropyl-1,2,3,4-tetrahydroquinolin-6-oyloxy)benzoate (3) [NCH(CH3)2 group at C-4] increased the potency and specificity for RARα, RARβ, and RXRα, compared to 1, but had little effect on RXRβ and RXRγ activation. Although 1 and 3 were unable to activate RARγ, 2 did activate this receptor with efficacy and high potency equal to that of 9-cis-retinoic acid (9-c-RA). All three heteroarotinoids exhibited 5−8-fold greater specificities for RARβ over RARα. In addition, esters 1−3 inhibited the growth of two cell lines each derived from cervix, vulvar, ovarian, and head/neck tumors with similar efficiencies to that of 9-c-RA through a mechanism independent of apoptosis. The vulvar cell lines were the most sensitive, and the ovarian lines were the least sensitive. Ester 2 was similar to 1 and 3 except that 2 was a much more potent growth inhibitor of the two vulvar cell lines, which is consistent with strong RARγ activation by 2 (but not by 1 and 3) and the high levels of RARγ expression in skin. All three heteroarotinoids induced production of TGase, a marker of retinoid activity in human erythroleukemic cells. Esters 2 and 3 were the more potent TGase activators than 1, in agreement with the stronger activation of the RAR receptors by 2 and 3. The biological activities of these agents, and the RARγ potency of 2 in particular, demonstrate the promise of these compounds as pharmaceutics for cancer and skin disorders.