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

Raffaella Cincinelli; Loana Musso; Roberto Artali; Mario Guglielmi; Erminia Bianchino; Francesco Cardile; Fabiana Colelli; Claudio Pisano; Sabrina Dallavalle

doi:10.1016/j.ejmech.2017.11.021

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

Eur J Med Chem. 2018 Jan 1:143:2005-2014. doi: 10.1016/j.ejmech.2017.11.021. Epub 2017 Nov 8.

Authors

Raffaella Cincinelli¹, Loana Musso¹, Roberto Artali², Mario Guglielmi³, Erminia Bianchino³, Francesco Cardile³, Fabiana Colelli³, Claudio Pisano³, Sabrina Dallavalle⁴

Affiliations

¹ Department of Food, Environmental and Nutritional Sciences, Division of Chemistry and Molecular Biology, Università degli Studi di Milano, via Celoria 2, 20133 Milan, Italy.
² Scientia Advice, di Roberto Artali, 20832 Desio, MB, Italy.
³ Biogem, Research Institute, Ariano Irpino, AV, Italy.
⁴ Department of Food, Environmental and Nutritional Sciences, Division of Chemistry and Molecular Biology, Università degli Studi di Milano, via Celoria 2, 20133 Milan, Italy. Electronic address: [email protected].

PMID: 29150335
DOI: 10.1016/j.ejmech.2017.11.021

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 IC₅₀ 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.

Keywords: Antiproliferative activity; Antitumor activity; Camptothecin; Dual-action inhibitors; HDAC inhibitors; Psammaplin.

MeSH terms

Animals
Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Camptothecin / chemistry
Camptothecin / pharmacology*
Cell Proliferation / drug effects
Cells, Cultured
DNA Topoisomerases, Type I / metabolism
Disulfides / chemistry
Disulfides / pharmacology*
Dose-Response Relationship, Drug
Drug Screening Assays, Antitumor
Histone Deacetylase Inhibitors / chemical synthesis
Histone Deacetylase Inhibitors / chemistry
Histone Deacetylase Inhibitors / pharmacology*
Histone Deacetylases / metabolism
Humans
Mice
Mice, Nude
Models, Molecular
Molecular Structure
Neoplasms, Experimental / drug therapy
Neoplasms, Experimental / pathology
Structure-Activity Relationship
Topoisomerase I Inhibitors / chemical synthesis
Topoisomerase I Inhibitors / chemistry
Topoisomerase I Inhibitors / pharmacology*
Tyrosine / analogs & derivatives*
Tyrosine / chemistry
Tyrosine / pharmacology

Substances

Antineoplastic Agents
Disulfides
Histone Deacetylase Inhibitors
Topoisomerase I Inhibitors
psammaplin A
Tyrosine
Histone Deacetylases
DNA Topoisomerases, Type I
Camptothecin