Synthesis and in Vitro Bioactivity of Polyunsaturated Fatty Acid Conjugates of Combretastatin A-4

Abstract

Combretastatin A-4 (CA-4) (1) is a plant-derived anticancer agent binding to the tubulin colchicine site. Polyunsaturated fatty acids (PUFAs) are readily taken up by cancer cells and have been used to improve cell targeting. In the present study, four CA-4-PUFA conjugates were synthesized by coupling combretastatin A-4 (1) with several polyunsaturated fatty acids. The conjugates (2a-d) were characterized using spectroscopic methods. Their cytotoxicity was evaluated against human breast cancer cells (MCF-7), and the inhibition of tubulin polymerization was determined in vitro. All conjugates influenced tubulin polymerization, with the arachidonic acid conjugate (2c) displaying cytotoxicity similar in potency to the natural product CA-4 (1).

Synthesis and Cytotoxicity Studies of Stilbene Long-Chain Fatty Acid Conjugates

“…Compound 11 : 1 H NMR (400 MHz, CDCl 3 ) δ 0.17 (6H, s), 1.01 (9H, s), 3.87 (6H, s), 3.91 (6H, s), 6.72 (2H, s), 6.84 (1H, d, J = 8.1 Hz), 6.89 (1H, d, J = 16.2 Hz), 6.96 (1H, d, J = 16.1 Hz), 6.98 (1H, dd, J = 2.0, 8.2 Hz), 7.02 (1H, d, J = 1.9 Hz). Physical data and spectroscopic information for compounds 8 and 10 were consistent with such data that have been reported in the literature …”

“…Concurrently and independently, our team synthesized and characterized the targeted series of 16 fatty acid–stilbene conjugates, which were tested against four tumor cell lines. Varying degrees of antiproliferative activities were observed, consistent with previously reported findings and with the outcomes from the studies performed by the Lavignac group …”

“…Indeed, the potential to modify the biological properties of chemotherapeutic agents through conjugation with fatty acids has been harnessed by other investigators. Most recently, Ojike et al reported their findings on the antiproliferative activities of four polyunsaturated fatty acid–CA4 (PUFA–CA4) conjugates, attributing the observed cytotoxicity to the inhibition of microtubule assembly . Concurrently and independently, our team synthesized and characterized the targeted series of 16 fatty acid–stilbene conjugates, which were tested against four tumor cell lines.…”

“…Most recently, Ojike et al reported their findings on the antiproliferative activities of four polyunsaturated fatty acid−CA4 (PUFA−CA4) conjugates, attributing the observed cytotoxicity to the inhibition of microtubule assembly. 12 Concurrently and independently, our team synthesized and characterized the targeted series of 16 fatty acid−stilbene conjugates, which were tested against four tumor cell lines. Varying degrees of antiproliferative activities were observed, consistent with previously reported findings and with the outcomes from the studies performed by the Lavignac group.…”

More Than Resveratrol: New Insights into Stilbene-Based Compounds

“…Ojike et al proved that polyunsaturated fatty acids (PUFAs) derivatives possess similar activity as CA-4 towards MCF-7 cell line, while all tested compounds displayed a lower inhibitory activity to tubulin compared to the parental drug [136]. Interestingly, Gu et al also synthesized several prodrugs with fatty chains attached at the 3 -position of the CA-4 B-ring varying in length, such as 6, 10, 14, 16, and 18 carbons ( Figure 6) [137].…”