Organocatalytic Synthesis and Antitumor Activity of Novel 1,2,3-triazoles Derived from Fatty β-ketoesters

Abstract

Background: Developing methods to synthesize highly functionalized and complex 1,2,3-triazoles from various combinations of substrates remains a significant challenge in organic synthesis. Thus, to the best of our knowledge, an organocatalytic approach to synthesize 1,2,3-triazoles derived from fatty acids has not been explored. Objective: In this sense, we describe here the organocatalyzed synthesis and preliminary results of antitumor and cytotoxic activity of a range of 1,2,3-triazoles derived from fatty esters. Methods: To synthesize 1,2,3-triazoles 3 derived from fatty β-ketoesters, we performed the reaction of appropriate aryl azides 2a-j with β-ketoesters 1a-c in the presence of 5 mol% of DBU using DMSO as a solvent at 70 °C for 24 h. The viability of 5637 cells was determined by measuring the reduction of soluble MTT to water-insoluble formazan. The IC50 concentration that inhibits 50% of cell growth and the results were obtained by at least three independent experiments in triplicate for each test. Results: Through enolate-mediated organocatalysis, 1,2,3-triazoles 3 derived from fatty β-ketoesters were synthesized in moderate to excellent yields by reacting fatty esters 1 with aryl azides 2 in the presence of a catalytic amount of 1,8-diazabicyclo[5.4.0]undec-7-ene (5 mol%). All compounds derived from palmitic acetoacetate 1a were evaluated regarding induced cytotoxicity in vitro in a human bladder cancer cell line, and compounds 3a, 3d, 3e, and 3g were shown to be promising alternatives for bladder cancer treatment and presented the lowest inhibitory concentration of IC50. Conclusion: We described a synthetic procedure to prepare 1,2,3-triazoles derived from fatty β-ketoesters by DBU-catalyzed 1,3-dipolar cycloaddition reactions of fatty esters with different aryl azides. Compounds derived from palmitic acetoacetate were screened for antitumor and cytotoxic activity in vitro in human bladder cancer cell lines, and compounds 3a, 3d, 3e, and 3g showed potential to treat bladder cancer.

Tandem Cycloaddition of Azides to 3,3-Diaminoacrylonitriles (2-Cyanoacetamidines) and Cornforth-Type Rearrangement as an Approach to 5-Amino-1,2,3-triazole-4-N-substituted Imidamides

“…These processes often proceed via unusual mechanisms, expanding our knowledge on the reactivity of organic compounds . On the other hand, cycloaddition of azides onto double and triple bonds including metal- and organocatalytic reactions represents a method of choice for the synthesis of 1,2,3-triazoles and 1,2,3-triazolines, including mono-, bi-, and polycyclic compounds …”