Abstract:

3S-1,2,3,4-Tetrahydro-β-carboline-3-carboxylic acid (1) is a substance from an edible vegetable in China, and antiaggregation active. In the corresponding investigation we found that in both organic solvent and water 1 was purely soluble and had low bioavailability. It was also well kown that in some cases the bioavailability of some water insoluble compou nds may be enhanced by amino acid modification. In the present paper the L-amino acids were introduced into 3-position of 1 and the anti-thrombosis activ ities were assayed in vitro and in vivo. In the presence of H₂SO₂ the Pictet-Spengler condensation of L-tryptophane and formaldehyde provided 1 in 95% yield. The ami dation of 1 and Boc 2O offered 3S-N-Boc-1,2,3,4-tetrahydr o-β-carboline-3-carboxylic acid (2) in 76% yield. Couplling 2 and L-amino acid methyl esters 3S-N-Boc-1,2,3, 4-tetrahydro-β-carboline-3-carboxyl-L-amino acid esters 3 a-n were obtained in 90%-98% yields. The saponification of 3 a-n in aqueous sodium hydroxi de provided 3S-N-Boc-1,2,3,4-tetrahydro-β-carboline-3-carboxyl-L-amino acids 4 a-n in 90%-98% yields. In the solution of hydrigen chloride/ethyl acetate the Boc group 4 a-n was removed and 5 a-n were obtained in 80%-95% yields. The in vitro and in vivo assays indicated that introducing amino acids resulted in different change in the anti-thrombotic activity of 1. Fo r instance introducing amino acid with acidic or rigidly cyclic side chain did n ot enhance the anti-thrombotic activity of 1, introducing ami no acid with hydrophorbic side chain moduratly enhance the anti-thrombotic acti vity of 1, and introducing amino acid with heteroatomic or basic side chain significantly enhance the anti-thromboti c activity of 1. The apparent permeability coefficient experim ents demonstrated that introducing the amino acid with acidic or rigidly cyclic side chain does not increase the a pparent permeability coefficient of 1, introducing the amino acid with hydrophorbic side chain moduratly increases the a pparen t permeability coefficient of 1, and introducing the amino acid with heteroatomic or basic side chain significantly increase enhance the the a p parent permeability coefficient.