Synthesis of Novel Heteroarotinoids with Receptor Activation Capabilities and Tgase Activity. Single Crystal Analysis of (E)-4-[(2,3-dihydro- 2,2,4,4,-tetramethyl-2H-1-benzo- [b]thiopyran-6-Yl)- 1-propenyl]-2-methylbenzoic Acid

Abstract

The syntheses of ethyl (E)-4-[(2,3-dihydro-2,2,4,4-tetramethyl-2H-1-benzo[b]thiopyran-6-yl)-1-propenyl]-2-methylbenzoate (1) and (E)-4- [(2,3-dihydro-2,2,4,4-tetramethyl-2H-1-benzo[b]thiopyran-6-yl)-1-pro- penyl]-2-methylbenzoic acid (2) have been achieved. In comparison to ester 1, acid 2 exhibited greater efficacy in activating RARα, RARβ, and RARγ as well as greater potency in activating RARα and RARβ. Interestingly, both the ester 1 and acid 2 exhibited nearly equal potency in activating RARγ. Both compounds also induced tissue transglutaminase (TGase) activity approximately 50% of the level induced by trans-retinoic acid. An X-ray diffraction analysis of (E)- 2 revealed the aryl rings as nearly orthogonal [74, ^[2] ] and a torsional angle of 46.5(2)° between the thiochroman group and the propenyl group. Conjugation between such groups may not be a stringent requirement for receptor activation.

ACKNOWLEDGMENTS

We gratefully acknowledge the National Science Foundation for a Departmental grant (DMB-860-3864) for funds to upgrade the XL-300 NMR spectrometer and a separate grant (CHE-8718150) to purchase the XL-400 NMR spectrometer. Thanks are extended (KDB) to the College of Arts & Sciences. The NIH is also thanked for partial support via the National Cancer Institute [CA-73639; CA077711 (DMB)]. We are pleased for partial funding for a new Varian Inova 400 MHz NMR spectrometer in the Oklahoma Statewide Shared NMR Facility by the National Science Foundation (BIR-9512269), the Oklahoma State Regents for Higher Education, the W. M. Keck Foundation, and Conoco, Inc.

Notes

^a Percent maximal activity of the test compound/precent maximal activity of 9-c-RA (100).

^b EC₅₀ is the concentration required to produce 50% maximal activity. Values for 9-c-RA and 1 and 2 were calculated.

^{c c} Ratio of TGase activity (in nM) of heteroarotinoid to that of t-RA.

*NRCVAX—An Interactive Program System for Structure Analysis, E. J. Gabe, Y. LePage, J. P. Charland, F. L. Lee, and P. S. White, J. Appl. Cryst., 22, 383 (1989).

Tables of all X-ray data have been deposited with the Cambridge Crystallographic Data Centre (CCDC), United Kingdom. CCDC 213322.