Improving Properties of Podophyllic Aldehyde-Derived Cyclolignans: Design, Synthesis and Evaluation of Novel Lignohydroquinones, Dual-Selective Hybrids against Colorectal Cancer Cells

Author:

Hernández Ángela-Patricia12ORCID,Díez Paula2ORCID,García Pablo A.1ORCID,Pérez-Andrés Martín2,Veselinova Anzhela3ORCID,Jambrina Pablo G.3,San Feliciano Arturo14ORCID,Díez David5ORCID,Fuentes Manuel26ORCID,Castro Mᵃ Ángeles1ORCID

Affiliation:

1. Department of Pharmaceutical Sciences: Organic Chemistry, Faculty of Pharmacy, University of Salamanca, CIETUS, IBSAL, 37007 Salamanca, Spain

2. Department of Medicine and General Cytometry Service-Nucleus, CIBERONC CB16/12/00400, Cancer Research Centre (IBMCC/CSIC/USAL/IBSAL), 37007 Salamanca, Spain

3. Departamento de Química Física, Facultad de Ciencias Químicas, Universidad de Salamanca, 37008 Salamanca, Spain

4. Programa de Pós-Graduaçao em Ciências Farmacêuticas, Universidade do Vale do Itajaí, UNIVALI, Itajaí 88302-202, SC, Brazil

5. Departamento de Química Orgánica, Facultad de Ciencias Químicas, Universidad de Salamanca, 37008 Salamanca, Spain

6. Proteomics Unit, Cancer Research Centre (IBMCC/CSIC/USAL/IBSAL), 37007 Salamanca, Spain

Abstract

New lignohydroquinone conjugates (L-HQs) were designed and synthesized using the hybridization strategy, and evaluated as cytotoxics against several cancer cell lines. The L-HQs were obtained from the natural product podophyllotoxin and some semisynthetic terpenylnaphthohydroquinones, prepared from natural terpenoids. Both entities of the conjugates were connected through different aliphatic or aromatic linkers. Among the evaluated hybrids, the L-HQ with the aromatic spacer clearly displayed the in vitro dual cytotoxic effect derived from each starting component, retaining the selectivity and showing a high cytotoxicity at short (24 h) and long (72 h) incubation times (4.12 and 0.0450 µM, respectively) against colorectal cancer cells. In addition, the cell cycle blockade observed by flow cytometry studies, molecular dynamics, and tubulin interaction studies demonstrated the interest of this kind of hybrids, which docked adequately into the colchicine binding site of tubulin despite their large size. These results prove the validity of the hybridization strategy and encourage further research on non-lactonic cyclolignans.

Publisher

MDPI AG

Subject

Pharmaceutical Science

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