Synthesis And Biological Evaluation Of 1-Alkyltrytophan And 1-[¹⁸F]FETrp

Objective:Tryptophan occupies a unique position on the interface between biochemistry and immunology because the concentration of tryptophan from the cellular microenvironment may regulate T-cell activation and survival. Indoleamine 2,3-dioxygenase (IDO) mediated tryptophan catabolism is emerging as an important pathway in immune regulation. Most studies suggested the common IDO inhibitor 1-methyl-DL-tryptophan (1-MT) could trigger antitumor immunity and also act synergistically with conventional or experimental chemotherapies. These findings have prompted our interest in the development of other tryptophan analogs for cancer chemiotherapy. Gastric cancer and cervical carcinoma are the most common cancers in China, and the main current treatment of these diseases is chemotherapy with other assistant therapeutics in clinic. In order to find new antitumor agents, we decorated the indole ring and synthesized 4 novel 1-alkyltryptophan to observe their effects on SGC7901 and HeLa cells proliferation in vitro, compared to 1-MT. In addition, positron-emitting amino acids have been reported to be better than [18F]FDG in the diagnosis of some tumors, so we also synthesized a novel [18F]fluoro amnio acid analogue, 1-[18F]fluoroethyl-L-tryptophan (1-[18F]FETrp), in order to find new promising PET tracer for differentiating the tumors and inflammation.Methods:Starting from tryptophan, we used simple chemical reactions to synthesize 1-alkyltryptophan and 1-[19F]fluoroethyl-L-tryptophan (1-[19F]FETrp). We studied the toxicity of 1-alkyltryptophan on the proliferation of SGC-7901 and HeLa cells line with different dose by MTT assay in vitro, compared with equiponderant 1-MT. Then we used fluoro-multifunctional chemistry process control unit (CPCU) to radiosynthesize 1-[18F]FETrp by nucleophilic fluorination.Results:1-Ethyltryptophan (1-ET),1-Propyltryptophan (1-PT),1-Isopropyl tryptophan (1-isoPT),1-Butyltryptophan (1-BT) and 1-[19F]FETrp were synthesized by five-step reactions. The structures of the step-by-step intermediates and the final products have been identified by MS,1H NMR and 13C NMR. 1-Alkyltryptophan efficiently inhibited SGC-7901 and HeLa cells proliferation at 1 mmol/L and 2 mmol/L. Among these targeted compounds,1-BT showed the most powerful cytotoxicity against those cancer cells. 1-[18F]FETrp was synthesized in two-step semi-automated process. The radiochemical yield without decay correction of 1-[18F]FETrp was 1.5% within 50 min total reaction time.Conclusion:1-Alkyltryptophan, especially 1-BT, inhibited the proliferation of SGC-7901 and HeLa cells. So it is possible to develop 1-BT as a potential anti-neoplastic agent. The synthesis and biological evaluation of 1-alkyltryptophan may give us a clue for seeking novel anti-neoplastic agents. Although we successfully synthesized 1-[18F]FETrp in two-step semi-automated manipulation, the radiochemical yield was very low. The synthetic route of 1-[18F]FETrp needs to be optimized. In order to use this PET tracer for differentiating the tumors and inflammations, further experimental work is needed to improve the radiochemical yield.