Synthesis and antimetastatic activity evaluation of cinnamic acid derivatives containing 1,2,3-triazolic portions

Abstract

It is herein described the preparation and evaluation of antimetastatic activity of twenty-six cinnamic acid derivatives containing 1,2,3-triazolic portions. The compounds were prepared using as the key step the Copper(I)-catalyzed azide (A)-alkyne (A) cycloaddition (C) (CuAAC reaction), also known as click reaction, between alkynylated cinnamic acid derivatives and different benzyl azides. The reactions were carried in CHCl/HO (1:1 v/v) at room temperature, and the triazole derivatives were obtained in yields ranging from 73%99%. Reaction times varied from 5 to 40 min. The identity of the synthesized compounds was confirmed by IR and NMR (H and C) spectroscopic techniques. They were then submitted to in vitro bioassays to investigate how they act over metastatic behavior of murine melanoma. The most potent compound, namely 3-(1-benzyl-1H-1,2,3-triazol-4-yl)propyl cinnamate (9a), showed significant antimetastatic and antiproliferative activities against B16-F10 cells. In addition, gelatin zymography and molecular docking analyses pointed to the fact that this compound has potential to interact with matrix metalloproteinase 9 (MMP-9) and MMP-2, which are directly involved in melanoma progression. Therefore, these findings suggest that cinnamic acid derivatives containing 1,2,3-triazolic portions may have potential for development of novel candidates for controlling malignant metastatic melanoma.

Cinnamic Acid Derivatives and Their Biological Efficacy

“…Cinnamic acid derivatives are known for their antimicrobial activity and researchers are searching for antimicrobial agents which are more effective than the currently used standard drugs [20]. Deng and styrenes, cinnamic acid derivatives exhibit antibacterial, antifungal, anti-inflammatory [10], neuroprotective [11], anticancer [12] and antidiabetic activities [13]. Cinnamic acid derivatives that have been reported by researchers include ferulic acid, curcumin [11], caffeic acid, phydroxycinnamic acid [14] coumaric and chlorogenic acids [15], etc.…”

“…Atmaram Upare et al synthesized cinnamic acid derivatives (10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26) (Figure 4) in which the carboxyl group was replaced with bioisostere 1,2,4-oxadiazole followed by substituting the phenyl ring of the cinnamic acid resulting in a series of novel styryl oxadiazoles. The compounds were tested in vitro at day 8 for their anti-tubercular activity against H37Ra strain of Mycobacterium tuberculosis (Table 2).…”

“…Vero and fibroplast (NIH3T3) cells appeared somewhat sensitive to compound 42a at 100 µmol/L and no hemolysis was significant at different concentrations. Molecular binding prediction indicated that the compound 42a inhibitory ability is due to its interaction with MMP-9 and MMP-2, enzymes involved directly in melanoma progression [40] The heteroatoms in compound 42a have the capability to form hydrogen bonds with proteins thereby inhibiting the two enzymes [10].…”

“…due to its interaction with MMP-9 and MMP-2, enzymes involved directly in melanoma progression [40] The heteroatoms in compound 42a have the capability to form hydrogen bonds with proteins thereby inhibiting the two enzymes [10].…”

“…Besides the cinnamic acid derivatives that occur naturally in plants [ 2 ], the presence of a benzene ring and the acrylic acid group makes it possible to modify it resulting in synthetic cinnamic acid derivatives [ 9 ]. Apart from them being intermediates in producing other compounds like stilbenes and styrenes, cinnamic acid derivatives exhibit antibacterial, antifungal, anti-inflammatory [ 10 ], neuroprotective [ 11 ], anticancer [ 12 ] and antidiabetic activities [ 13 ]. Cinnamic acid derivatives that have been reported by researchers include ferulic acid, curcumin [ 11 ], caffeic acid, p-hydroxycinnamic acid [ 14 ] coumaric and chlorogenic acids [ 15 ], etc.…”