Synthesis and Evaluation of Novel Anticancer Compounds Derived from the Natural Product Brevilin A

Abstract

Cancer is the second leading cause of death globally, responsible for an estimated 9.6 million deaths in 2018, and this burden continues to increase. Therefore, there is a clear and urgent need for novel drugs with increased efficacy for the treatment of different cancers. Previous research has demonstrated that brevilin A (BA) exerts anticancer activity in various cancers, including human multiple myeloma, breast cancer, lung cancer, and colon carcinoma, suggesting the anticancer potential present in the chemical scaffold of BA. Here, we designed and synthesized a small library of 12 novel BA derivatives and evaluated the biological anticancer effects of the compounds in various cancer cell lines. The results of this structure–activity relationship study demonstrated that BA derivatives BA-9 and BA-10 possessed significantly improved anticancer activity toward lung, colon, and breast cancer cell lines. BA-9 and BA-10 could more effectively reduce cancer cell viability and induce DNA damage, cell-cycle arrest, and apoptosis when compared with BA. Our findings represent a significant step forward in the development of novel anticancer entities.

An Insight into the Mechanism of Holamine- and Funtumine-Induced Cell Death in Cancer Cells

“…However, the results presented in Figure 5 show that cancer cells react to the apoptotic influence of these two compounds differently. This scenario is not completely unexpected, because they expressed different sensitivities towards the cytotoxic effects of these two compounds as presented here and as reported previously for another compound [32]. All the three cancer cell lines showed significant apoptotic sensitivity to holamine at 15 µg/mL, while MCF-7 appeared more sensitive to funtumine-induced apoptotic effects at 3.75 and 7.5 µg/mL concentrations.…”

Natural and Synthetic Lactones Possessing Antitumor Activities

“…It is also noteworthy that Brevilin A ( 189 ) specifically inhibits JAKs without other signaling proteins such as p65, AKT, GSK-3β, and Src. A number of Brevilin A ( 189 ) derivatives were synthesized and their anticancer potential was evaluated in a structure-activity relationships study conducted by Lee et al [ 187 ]. During the course of the study, it was found out that the alkene or carbonyl of the enone moiety is crucial in achieving cytotoxicity.…”

“…In the MDA-MB-231 and A549 cell lines, BA-9 ( 304 ) and BA-10 ( 305 ) displayed a GI 50 value of 4.647 μM and 6.385 μM against MDA-MB-231 and 6.239 μM and 6.392 μM against A549, respectively ( Figure 14 ). These values exhibited by the derivatives are roughly two-fold greater than that of the parent compound Brevilin A ( 189 ) (GI 50 in MDA-MB-231 = 7.03 μM, A549 = 10.09 μM), indicating potential of BA-9 ( 304 ) and BA-10 ( 305 ) as promising candidates for further development as cancer therapeutics [ 187 ].…”

“…To the best of our knowledge, there are no reports elucidating total synthesis of EM23 ( 188 ) and Brevilin A ( 189 ) up-to-date. Semi-synthetic derivatives of Brevilin A ( 189 ) were prepared by Lee et al [ 187 ]. Key intermediate BA-8 ( 306 ) was obtained via aldol reaction between Brevilin A ( 189 ) and paraformaldehyde in the presence of sodium carbonate ( Scheme 67 ).…”

Plantas Que Agem No Sistema Nervoso Central: O Uso Dos Fitoterápicos Kava Kava, Passiflora E Valeriana No Tratamento De Transtorno De Ansiedade

“…Compostos de origem natural, como aqueles derivados de plantas, animais e microrganismos provem uma gama de novas moléculas que têm sido amplamente descritas na literatura por seu potencial antitumoral (AUNG et al, 2017;NEWMAN;CRAGG;SNADER, 2003;ZHUet al, 2020). Da mesma forma, a síntese e/ou modificação de estruturas químicas derivadas de compostos naturais se destacam como uma nova estratégia no descobrimento de novas moléculas com potencial antineoplásico (GUO, 2017;KOSTOVA, 2005;LEE et al, 2020).…”