Design and Synthesis of 1,2-Bis(hydroxymethyl)pyrrolo[2,1-a]phthalazine Hybrids as Potent Anticancer Agents that Inhibit Angiogenesis and Induce DNA Interstrand Cross-links
| Autor: | Anilkumar S. Patel, Tsann-Long Su, Jiao-Ren Huang, Yi-Wen Lin, Anamik Shah, Vicky Jain, Hima Bindu Pidugu, Sue-Ming Chang, Ming-Hsi Wu, Han-Chung Wu, Te-Chang Lee, Tai-Lin Chen |
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| Rok vydání: | 2019 |
| Předmět: |
Angiogenesis
DNA damage Angiogenesis Inhibitors Antineoplastic Agents Apoptosis 01 natural sciences Mice Structure-Activity Relationship 03 medical and health sciences chemistry.chemical_compound Cell Line Tumor Drug Discovery Animals Humans Structure–activity relationship Hydroxymethyl Phosphorylation 030304 developmental biology 0303 health sciences Neovascularization Pathologic Chemistry Vascular Endothelial Growth Factor Receptor-2 Xenograft Model Antitumor Assays Molecular biology 0104 chemical sciences 010404 medicinal & biomolecular chemistry Cell culture Phthalazines Molecular Medicine Phthalazine DNA DNA Damage |
| Zdroj: | Journal of Medicinal Chemistry. 62:2404-2418 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/acs.jmedchem.8b01689 |
| Popis: | Hybrid molecules are composed of two pharmacophores with different biological activities. Here, we conjugated phthalazine moieties (antiangiogenetic pharmacophore) and bis(hydroxymethyl)pyrrole moieties (DNA cross-linking agent) to form a series of bis(hydroxymethyl)pyrrolo[2,1- a]phthalazine hybrids. These conjugates were cytotoxic to a variety of cancer cell lines by inducing DNA damage, arresting cell cycle progression at the G2/M phase, triggering apoptosis, and inhibiting vascular endothelial growth factor receptor 2 (VEGFR-2) in endothelial cells. Among them, compound 29d encapsulated in a liposomal formulation (e.g., 29dL) significantly suppressed the growth of small-cell lung cancer cell (H526) xenografts in mice. Based on immunohistochemical staining, the tumor xenografts in mice treated with 29dL showed time-dependent decreases in the intensity of CD31, a marker of blood vessels, whereas the intensity of γ-H2AX, a marker of DNA damage, increased. The present data revealed that the conjugation of antiangiogenic and DNA-damaging agents can generate potential hybrid agents for cancer treatment. |
| Databáze: | OpenAIRE |
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