title: Synthesis of novel 2,3,4-trisubstituted-oxazolidine derivatives and in vitro cytotoxic evaluation.
abstract: We have previously reported the discovery of cytotoxic and pro-apoptotic hit compound 1,1-dimethylethyl (S)- 2,2-dimethyl-4-[(3-nitrophenoxy)methyl]-3-oxazolidinecarboxylate 1 against leukemia cells. In the present work we describe the synthesis of 25 derivatives of this hit varying the substituent at ring or stereochemistry of the oxazolidine ring and evaluated them against human cancer cells lines. Six compounds exerted significant activity against HL60 promyelocytic leukemia cells with IC50 in low micromolar range (4-18 μM) and three compounds displayed activity against MDA-MB231 breast cancer cells (25-37 μM). In vitro cytotoxicity on normal cells PBMC (human peripheral blood mononuclear cells) was also evaluated. Compounds 7e (p-NO2, S) and 7m (p-COOCH3, S) showed good antiproliferative activity against HL60 (4 and 5 μM) and MDA-MB231 (37 and 25 μM) without affecting lymphocyte proliferation in PBMC, indicating low toxicity to normal cells. Besides, compound 7e induced DNA fragmentation on about 100% of HL60 cells at 50 μM. In this case, it was more potent than 7m and lead 1. This indicated that compound 7e has a great pro-apoptotic potential.
authors.forename: Saulo F
authors.initials: SF
authors.lastname: Andrad
authors.forename: Edmar F S
authors.initials: EF
authors.lastname: Campos
authors.forename: Claudia S
authors.initials: CS
authors.lastname: Teixeira
authors.forename: Cristiano C
authors.initials: CC
authors.lastname: Bandeira
authors.forename: Stefânia N
authors.initials: SN
authors.lastname: Lavorato
authors.forename: Nelilma C
authors.initials: NC
authors.lastname: Romeiro
authors.forename: Caryne M
authors.initials: CM
authors.lastname: Bertollo
authors.forename: Mônica C
authors.initials: MC
authors.lastname: Oliveira
authors.forename: Elaine M
authors.initials: EM
authors.lastname: Souza-Fagundes
authors.affiliation: Departamento de Produtos Farmaceuticos, Faculdade de Farmacia, Universidade Federal de Minas Gerais (UFMG), Av. Antonio Carlos, 6627, Belo Horizonte, MG 31.270- 901, Brazil. ricardodylan@farmacia.ufmg.br.
authors.forename: Ricardo J
authors.initials: RJ
authors.lastname: Alves
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity; D017209:Apoptosis / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D002522:Chlorocebus aethiops; D053938:DNA Fragmentation / Q000187:drug effects*; D018922:HL-60 Cells; D006801:Humans; D020128:Inhibitory Concentration 50; D007963:Leukocytes, Mononuclear / Q000187:drug effects; D015394:Molecular Structure; D010080:Oxazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity; D021281:Quantitative Structure-Activity Relationship; D014709:Vero Cells
chemical_list: D000970:Antineoplastic Agents; D010080:Oxazoles