title: Structure-activity relationship studies of 4-methylcoumarin derivatives as anticancer agents.
abstract: BACKGROUND
  Cancer is a leading cause of death worldwide and novel chemotherapeutic agents with better efficacy and safety profiles are much needed. Coumarins are natural polyphenolic compounds with important pharmacological activities, which are present in many dietary plants and herbal remedies.
  
  
  OBJECTIVE
  The objective of this study is to investigate natural and synthetic coumarin derivatives with considerable anticancer capacity against three human cancer cell lines.
  
  
  METHODS
  We synthesized 27 coumarin derivatives (mostly having 4-methyl moiety) and examined their cytotoxic effect on three human cancer cell lines, K562 (chronic myelogenous leukemia), LS180 (colon adenocarcinoma), and MCF-7 (breast adenocarcinoma) by MTT reduction assay. Screened compounds included 7-hydroxy-4-methylcoumarins (7-HMCs), 7-acetoxy-4-methylcoumarins (7-AMCs), and different dihydroxy-4-methylcoumarin (DHMC) and diacetoxy-4-methylcoumarin (DAMC) derivatives. Some compounds with methoxy, amine, and bromine substitutions were also examined.
  
  
  RESULTS
  7,8-DHMCs bearing alkyl groups at C3 position were the most effective subgroup, and of which, the most potent is compound 11, with an n-decyl chain at C3, which had IC50 values of 42.4, 25.2, and 25.1 µM against K562, LS180, and MCF-7 cells, respectively. The second most active subgroup was 7,8-DAMCs containing ethoxycarbonylmethyl and ethoxycarbonylethyl moieties at C3 position. Compound 27 (6-bromo-4-bromomethyl-7-hydroxycoumarin), the only derivative containing bromine also showed reasonable cytotoxic activities (IC50 range: 32.7-45.8 µM).
  
  
  CONCLUSIONS
  This structure-activity relationship (SAR) study of 4-methylcoumarins shows that further investigation of these derivatives may lead to the discovery of novel anticancer agents.
authors.affiliation: a Medicinal and Natural Products Chemistry Research Center, Shiraz University of Medical Sciences , Shiraz , Iran .
authors.forename: Ramin
authors.initials: R
authors.lastname: Miri
authors.affiliation: a Medicinal and Natural Products Chemistry Research Center, Shiraz University of Medical Sciences , Shiraz , Iran .
authors.forename: Maryam
authors.initials: M
authors.lastname: Nejati
authors.affiliation: b Department of Physiology and Pharmacology "Vittorio Erspamer" , Sapienza University of Rome , Rome , Italy .
authors.forename: Luciano
authors.initials: L
authors.lastname: Saso
authors.affiliation: a Medicinal and Natural Products Chemistry Research Center, Shiraz University of Medical Sciences , Shiraz , Iran .
authors.forename: Fatemeh
authors.initials: F
authors.lastname: Khakdan
authors.affiliation: c Bioorganic Laboratory, Department of Chemistry , University of Delhi , Delhi , India , and.
authors.forename: Badri
authors.initials: B
authors.lastname: Parshad
authors.affiliation: c Bioorganic Laboratory, Department of Chemistry , University of Delhi , Delhi , India , and.
authors.forename: Divya
authors.initials: D
authors.lastname: Mathur
authors.affiliation: c Bioorganic Laboratory, Department of Chemistry , University of Delhi , Delhi , India , and.|d Laboratory of Experimental Cancer Research , University Hospital, University of Gent , Gent , Belgium.
authors.forename: Virinder S
authors.initials: VS
authors.lastname: Parmar
authors.affiliation: d Laboratory of Experimental Cancer Research , University Hospital, University of Gent , Gent , Belgium.
authors.forename: Marc E
authors.initials: ME
authors.lastname: Bracke
authors.affiliation: c Bioorganic Laboratory, Department of Chemistry , University of Delhi , Delhi , India , and.
authors.forename: Ashok K
authors.initials: AK
authors.lastname: Prasad
authors.affiliation: c Bioorganic Laboratory, Department of Chemistry , University of Delhi , Delhi , India , and.
authors.forename: Sunil K
authors.initials: SK
authors.lastname: Sharma
authors.affiliation: a Medicinal and Natural Products Chemistry Research Center, Shiraz University of Medical Sciences , Shiraz , Iran .
authors.forename: Omidreza
authors.initials: O
authors.lastname: Firuzi
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D003374:Coumarins / Q000138:chemical synthesis / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D020128:Inhibitory Concentration 50; D020014:K562 Cells; D061986:MCF-7 Cells; D008745:Methylation; D015394:Molecular Structure; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D003374:Coumarins
keywords: Cancer; MTT; cell; cytotoxic; methylcoumarins