Insights into the anticancer activity of chiral alkylidene-β-lactams and alkylidene-γ-lactams: Synthesis and biological investigation

Américo J S Alves; Nuno G Alves; Mafalda Laranjo; Clara S B Gomes; Ana Cristina Gonçalves; Ana Bela Sarmento-Ribeiro; M Filomena Botelho; Teresa M V D Pinho E Melo

doi:10.1016/j.bmc.2022.116738

Insights into the anticancer activity of chiral alkylidene-β-lactams and alkylidene-γ-lactams: Synthesis and biological investigation

Bioorg Med Chem. 2022 Jun 1:63:116738. doi: 10.1016/j.bmc.2022.116738. Epub 2022 Apr 1.

Authors

Américo J S Alves¹, Nuno G Alves¹, Mafalda Laranjo², Clara S B Gomes³, Ana Cristina Gonçalves⁴, Ana Bela Sarmento-Ribeiro⁴, M Filomena Botelho², Teresa M V D Pinho E Melo⁵

Affiliations

¹ University of Coimbra, Coimbra Chemistry Centre-Institute of Molecular Sciences and Department of Chemistry, 3004-535 Coimbra, Portugal.
² Institute of Biophysics and Institute for Clinical and Biomedical Research (iCBR), Area of Environment Genetics and Oncobiology (CIMAGO), Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal; Center for Innovative Biomedicine and Biotechnology (CIBB), University of Coimbra, 3000-548 Coimbra, Portugal; Clinical and Academic Centre of Coimbra, 3000-548 Coimbra, Portugal.
³ LAQV-REQUIMTE, Department of Chemistry, NOVA School of Science and Technology, Universidade Nova de Lisboa, 2829-516 Caparica, Portugal; Associate Laboratory i4 HB-Institute for Health and Bioeconomy, School of Science and Technology, NOVA University Lisbon, 2819-516 Caparica, Portugal; UCIBIO-Applied Molecular Biosciences Unit, Department of Chemistry, School of Science and Technology, NOVA University Lisbon, 2819-516 Caparica, Portugal.
⁴ Institute of Biophysics and Institute for Clinical and Biomedical Research (iCBR), Area of Environment Genetics and Oncobiology (CIMAGO), Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal; Center for Innovative Biomedicine and Biotechnology (CIBB), University of Coimbra, 3000-548 Coimbra, Portugal; Clinical and Academic Centre of Coimbra, 3000-548 Coimbra, Portugal; Laboratory of Oncobiology and Hematology, Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal.
⁵ University of Coimbra, Coimbra Chemistry Centre-Institute of Molecular Sciences and Department of Chemistry, 3004-535 Coimbra, Portugal. Electronic address: tmelo@ci.uc.pt.

PMID: 35421710
DOI: 10.1016/j.bmc.2022.116738

Abstract

Chiral alkylidene-β-lactams and alkylidene-γ-lactams were synthesized and screened for their in vitro activity against four human cancer cell lines (melanoma, esophageal, lung and fibrosarcoma carcinoma). Alkylidene-β-lactams were synthesized via Wittig reaction of diverse phosphorus ylides with benzhydryl 6-oxopenicillanate, derived from 6-aminopenicillanic acid. Moreover, novel chiral alkylidene-γ-lactams were synthesized through a multistep strategy starting from a chiral substrate (d-penicillamine). The in vitro assays allowed the identification of four compounds with IC₅₀ values < 10 μM for A375 cell line, and three compounds with IC₅₀ values < 10 μM for OE19 cell line. The effect of the most promising compounds on cell death mechanism, reactive oxygen species generation as well as the evaluation of their ability to act as MMP-9 inhibitors were studied. The reported results unveil the potential of alkylidene-β-lactams as anticancer agents.

Keywords: Alkylidene-β-lactam; Alkylidene-γ-lactam; Anticancer agents; Esophageal cancer; Fibrosarcoma; Lung cancer; Melanoma; Penicillanates.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antineoplastic Agents* / chemistry
Cell Line
Humans
Lactams
Neoplasms*
beta-Lactams

Substances

Antineoplastic Agents
Lactams
beta-Lactams