Camptothecin-psammaplin A hybrids as topoisomerase I and HDAC dual-action inhibitors

Abstract

Recent studies have demonstrated enhanced anticancer effects of combination therapy consisting of camptothecin derivatives and HDAC inhibitors. To exploit this synergy in a single active compound, we designed new dual-acting multivalent molecules simultaneously targeting topoisomerase I and HDAC. In particular, a selected compound containing a camptothecin and the psammaplin A scaffold showed a broad spectrum of antiproliferative activity, with IC values in the nanomolar range. Preliminary in vivo results indicated a strong antitumor activity on human mesothelioma primary cell line MM473 orthotopically xenografted in CD-1 nude mice and very high tolerability.

Hybrid topoisomerase I and HDAC inhibitors as dual action anticancer agents

“…Analyses indicated by the symbols of the elements or functions were within ±0.4% of the theoretical values. Compounds 2a [ 25 ], 1a , 2b , 2c , [ 3 ], 5 [ 26 ], 7-formylcamptothecin and 10-hydroxy-7-formylcamptothecin ( 1b ) [ 27 ] were prepared according to literature procedures.…”

“…The ligand molecules were obtained using a systematic conformer search followed by geometry optimisation of the lowest energy structure with MOPAC7 (PM3 Method, RMS gradient 0.0100). The DNA-Topoisomerase-I and HDAC-II models were derived from the deposited X-ray structures (Protein Data Bank entry 1T8I and 5IWG, respectively) as previously described [ 3 ].…”

Chimeric HDAC inhibitors: Comprehensive review on the HDAC‐based strategies developed to combat cancer

“…In 2017, Cincinelli et al . developed hybrid compounds by merging the structural features of the topoisomerase‐1 inhibitor camptothecin ( 68 ) and the marine HDAC inhibitor psammaplin‐A ( 82 ) which is a natural pro‐drug contains disulfide bond that requires in vivo activation by reduction to thiol moiety giving the active two identical active monomers that potently inhibit HDACs.…”

“…Further SAR studies and modifications can be performed on this promising hybrid using different linkers other than the aliphatic linker such as cinnamoyl linker and aryl linker using the 2-aminobenzamide as ZBG. Also, further studies on resistant cell lines are required.In 2017, Cincinelli et al84 developed hybrid compounds by merging the structural features of the topoisomerase-1 inhibitor camptothecin (68) and the marine HDAC inhibitor psammaplin-A (82) which is a natural pro-drug contains disulfide bond that requires in vivo activation by reduction to thiol moiety giving the active two identical active monomers that potently inhibit HDACs. SAR studies on psammaplin A revealed that hydroxyiminoamide moiety and the disulfide bridge are essential features for the HDAC inhibitory activities of psammaplin A, while structural variations on the aromatic ring are permitted.…”

Novel platinum agents and mesenchymal stromal cells for thoracic malignancies: state of the art and future perspectives

“…Starting from the established ability to synergistically block cell proliferation between histone deacetylases inhibitors (HDAC) and camptothecin derivatives, a series of new compounds based on the psammaplin A scaffold, known for exerting a potent HDAC inhibitory activity, and camptothecin were synthesized showing a significant antitumor activity, with IC50 values in the nanomolar range on different mesothelioma cell lines(Figure 3, compounds X, XI and XII). Moreover, when tested in vivo on human a mesothelioma model, derivative XI showed a potent antiproliferative activity along with high tolerability, making it a particularly intriguing compound with encouraging future perspectives 42.…”