Structure-activity relationship study of cytotoxic neolignan derivatives using multivariate analysis and computation-aided drug design

Fernanda S de Sousa; João L Baldim; Ricardo A Azevedo; Carlos R Figueiredo; Pauline Pieper; Claire E Sear; Edward A Anderson; João Henrique G Lago

doi:10.1016/j.bmcl.2020.127349

Structure-activity relationship study of cytotoxic neolignan derivatives using multivariate analysis and computation-aided drug design

Bioorg Med Chem Lett. 2020 Aug 15;30(16):127349. doi: 10.1016/j.bmcl.2020.127349. Epub 2020 Jun 12.

Authors

Fernanda S de Sousa¹, João L Baldim², Ricardo A Azevedo³, Carlos R Figueiredo⁴, Pauline Pieper⁵, Claire E Sear⁵, Edward A Anderson⁵, João Henrique G Lago⁶

Affiliations

¹ Institute of Environmental, Chemical and Pharmaceutical Sciences, Federal University of São Paulo, São Paulo 09972-270, Brazil.
² Center of Natural and Human Sciences, Federal University of ABC, Santo André 09210-580, Brazil; Federal Institute of Education, Science and Technology of South of Minas Gerais - IFSULDEMINAS, Minas Gerais 37890-000, Brazil.
³ Department of Immunology, MD Anderson Cancer Center, The University of Texas, Houston, TX 77054, USA.
⁴ Department of Microbiology, Immunology and Parasitology, Federal University of São Paulo, São Paulo 04021-001, Brazil.
⁵ Chemistry Research Laboratory, 12 Mansfield Road, Oxford OX1 3TA, UK.
⁶ Center of Natural and Human Sciences, Federal University of ABC, Santo André 09210-580, Brazil. Electronic address: joao.lago@ufabc.edu.br.

PMID: 32631547
DOI: 10.1016/j.bmcl.2020.127349

Abstract

Dehydrodieugenol B and five related natural neolignans were isolated from the Brazilian plant species Nectandra leucantha. Three of these compounds were shown to be active against murine (B16F10) and human (A2058) melanoma cells but non-toxic to human fibroblasts (T75). These results stimulated the preparation of a series of 23 semi-synthetic derivatives in order to explore structure-activity relationships and study the biological potential of these derivatives against B16F10 and A2058 cell lines. These structurally-related neolignan derivatives were analyzed by multivariate statistics and machine learning, which indicated that the most important characteristics were related to their three-dimensional structure and, mainly, to the substituents on the neolignan skeleton. The results suggested that the presence of hydroxyl or alkoxyl groups at positions 3, 4 and 5 (with appropriate sidechains) promoted an increase in electropological and charge density, which seem to be important for biological activity against murine (B16F10) and human (A2058) melanoma cells.

Keywords: A2058; B16F10; Cytotoxic; Multivariate analysis; Neolignans; Semi-synthetic derivatives.

Publication types

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

MeSH terms

Animals
Antineoplastic Agents, Phytogenic / chemical synthesis
Antineoplastic Agents, Phytogenic / chemistry
Antineoplastic Agents, Phytogenic / pharmacology*
Cell Line, Tumor
Cell Proliferation / drug effects
Dose-Response Relationship, Drug
Drug Design*
Drug Screening Assays, Antitumor
Humans
Lignans / chemical synthesis
Lignans / chemistry
Lignans / pharmacology*
Machine Learning
Mice
Molecular Structure
Multivariate Analysis
Structure-Activity Relationship

Substances

Antineoplastic Agents, Phytogenic
Lignans