Design, synthesis and evaluation of multi-pharmacophore-containing spiropolycyclic harmaline-based hybrids as anticancer agents

Here, we demonstrate the first example of natural product harmaline and its derivatives serving as useful N-C synthons in formal [3+2] cycloadditions with isothiocyanates for the construction of a library of spiropolycyclic harmaline-based hybrids containing two adjacent quaternary stereocentres. These products were smoothly afforded in up to 90% yield, 20 : 1 dr with Et3N as the catalyst under mild conditions. To the best of our knowledge, this also represents the first example of the synthesis of natural product harmaline-based spiropolycyclic scaffolds, and expands the chemical space of biologically significant harmaline derivative species. The newly synthesized structurally diverse compounds were evaluated for their in vitro anticancer activities. These studies indicate that some compounds displayed good anticancer activity against three tumor cells (A549, K562, and PC-3). Among them, compound 3cb displayed the best activity when applied to A549, which is similar to that of cisplatin. Preliminary mechanistic studies indicate that compound 3cb induces apoptosis in A549 cells through a caspase-dependent pathway. These results show that compound 3cb can be prepared as a good lead for drug development.

Automated summary

In this study, the natural product harmaline and its derivatives were utilized as N-C synthons in formal [3+2] cycloadditions with isothiocyanates, leading to the construction of a library of spiropolycyclic harmaline-based hybrids with two adjacent quaternary stereocentres. These compounds were obtained in high yield and selectivity, under mild conditions using Et3N as the catalyst. The synthesized compounds were evaluated for their anticancer activities, and compound 3cb showed the best activity similar to cisplatin against A549 cells, indicating its potential as a lead compound for drug development.