Synthetic Vitamin E Amide Derivatives as Anti-Cancer Agents:Certain esters of Vitamin E (tocopherol) are known to display potent anti-tumor activity.  In particular, tocopheryl succinate inhibits DNA synthesis and cell proliferation in various cancer cell types by inducing apoptosis.  It has been postulated that tocopheryl esters display three distinct domains that contribute to their biological activity.  The functional domain mediates apoptosis, particularly when it contains an acidic moiety (e.g., succinate, malonate).  By contrast, a free phenol or aryl amino group results in powerful anti-oxidant activity, but such compounds are devoid of apoptotic activity.

Our research group is targeting amide derivatives of vitamin E as isosteric analogs of the corresponding esters. Prior to our work in this area, the only reported method for making amide derivatives of vitamin E is through total synthesis, by combining two smaller molecules [an amino phenol and a large alcohol (phytol)].  However, that method is very inefficient, and it produces a mixture of two diastereomers that are difficult to separate.  A key highlight of our recent work is the synthesis of -tocopheryl amine, the first new synthesis of this powerful anti-oxidant in over 60 years, and the only synthesis to date that provides stereochemically pure material.   We have developed two new synthetic methods for preparing stereochemically pure tocopheryl amides from natural tocopherols, and we have prepared several amide derivatives from those amines.  In vitro testing of our synthetic amide compounds against Jurkat leukemia cells by our collaborator (Dr. Jirka Neuzil, Griffith University, Southport, Australia) has shown that the tocopheryl amides are about an order of magnitude more effective in inducing apoptosis than the corresponding tocopheryl esters.

Selected Publications

Vitamin E analogues: A New Class of Inducers of Apoptosis with Selective Anti-Cancer Effects, Neuzil, J.; Tomasetti, M.; Mellick, A.S.; Alleva, R.; Salvatore, B.A.; Birringer,  M.; Fariss, M.W., Current Cancer Drug Targets 267-283 (2004).

Vitamin E analogs as Inducers of Apoptosis:  Structure-Function Relationship, Birringer, M.; EyTina, H.J.; Salvatore, B.A.; Neuzil, J.  British J. Cancer, 88, 1948-1955 (2003).

Origin of Archosaurian Integumentary Appendages: the Bristles of the Wild Turkey Beard Express Feather-Type Beta Keratins, Sawyer, R.H.; Washington L.D.; Salvatore, B.A.; Glenn, T.C.; Knapp, L.W. J. Exp. Zoology (Mol. Dev. Evol)., 297, 27-34 (2003).

Origin of Feathers: Feather Beta () Keratins Are Expressed in Discrete Epidermal Cell Populations of Embryonic Scutate Scales, Sawyer, R.H.; Salvatore, B.A.; Potylicki, T.-T.F.; French, J.O.; Glenn, T.C.; Knapp, L. J. Exp. Zoology (Mol. Dev. Evol)., 295B, 12-24 (2003).

Total Synthesis of (+)-Calyculin A and (-)-Calyculin B: Cyanotetraene Construction, Asymmetric Synthesis of the C(26-37) Oxazole, Fragment Assembly, and Final Elaboration, Smith, A.B., III; Friestad, G.K.; Barbosa, J.; Bertounesque, E.; Duan, J.J.W.; Hull, K.G.; Iwashima, M.; Qiu, Y.P.; Spoors, P.G.; Salvatore, B.A. J. Am. Chem. Soc., 121, 10478 (1999).

Total Synthesis of (+)-Calyculin A and (-)-Calyculin B: Asymmetric Synthesis of the C(9-25) Spiroketal Dipropionate Subunit, Smith, A.B., III.; Friestad, G.K.; Barbosa, J.; Bertounesque, E.; Hull, K.G.; Iwashima, M.; Qiu, Y.P.; Salvatore, B.A.; Spoors, P.G.; Duan J.J.W. J. Am. Chem. Soc., 121,  10468 (1999).

NMR Spectroscopy-II, Salvatore, B.A. Annual Reports on the Progress of Chemistry, Royal Society of Chemistry, 95, 395 (1999).

Synthesis of a ¹⁵N, ¹³C-Labeled Lactam Analog of a G_M4-Lactone Cell-Surface Glycolipid, Salvatore, B.A.; Prestegard, J.H. Tetrahedron Lett., 39, 9319 (1998).

NMR Spectroscopy, Salvatore, B.A.  Annual Reports on the Progress of Chemistry, Royal Society of Chemistry, 94, 361 (1998).