RESUMO
Derivatives of alpha-conidendrin, podophyllotoxin, and sikkimotoxin were prepared to evaluate the cytotoxic contributions of C-4 configuration and pendant and fused arene substitutions. Dimethyl-alpha-conidendryl alcohol (5), 9-deoxypodophyllol (6), and 9-deoxysikkimol (17) were dehydrated to their respective oxolane derivatives 4, 3, and 9. Diols 5 and 6 were converted via oxabicyclo[3.2.1]octanols 10 and 14 to target oxolanes 8 and 7 where C-4 had been inverted relative to that in 3 and 4. Cytotoxicities of the five oxolanes were determined in two drug-sensitive human leukemia and two multidrug-resistant cell lines expressing P-glycoprotein or multidrug-resistance associated protein (MRP). Changing the pendant arene configuration or replacing a m-methoxy by hydrogen resulted in a 100-fold cytotoxicity loss. Replacing a methylenedioxy group in the fused arene by two methoxy substituents reduced cytotoxicity by 10-fold. Drug-resistant cell lines were equally resistant to compounds 3, 4, 8, and 9 indicating that these four compounds do not serve as substrates of the transport proteins P-glycoprotein and MRP.
Assuntos
Antineoplásicos/síntese química , Lignanas , Podofilotoxina/análogos & derivados , Podofilotoxina/síntese química , Tetra-Hidronaftalenos/síntese química , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Transportadores de Cassetes de Ligação de ATP/metabolismo , Antineoplásicos/química , Antineoplásicos/farmacologia , Resistência a Múltiplos Medicamentos , Resistencia a Medicamentos Antineoplásicos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Espectroscopia de Ressonância Magnética , Espectrometria de Massas , Conformação Molecular , Proteínas Associadas à Resistência a Múltiplos Medicamentos , Podofilotoxina/farmacologia , Relação Estrutura-Atividade , Tetra-Hidronaftalenos/química , Tetra-Hidronaftalenos/farmacologia , Células Tumorais CultivadasRESUMO
The action of the drinking water mutagen 3,4-dichloro-5-hydroxy-2(5H)-furanone (MCA) on the plasmid phi X174 converted this initially closed circular, supercoiled (SC) DNA to its relaxed (R) and linear (L) forms. Kinetic analysis of this process gave results coinciding with a sequential, two-step cleavage model whereby the SC was cleaved to the R form, which in its turn was cleaved to the L form. The actions of two additional chlorine-substituted 2(5H)-furanones, reduced MCA (RMCA) and the C-5 isopropyl ether of MCA (MCA-IPE), were compared to that of MCA. Incubation of SC-phi X174 with RMCA gave R form only while MCA-IPE had virtually no effect. Likewise, neither methyl methanesulfonate nor sodium azide cleaved SC-phi X174 to its L form, under conditions whereby MCA caused the formation of L form. Also, 3-chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone (MX) caused formation of R form, but no apparent L form. Increasing concentration of glutathione diminished cleavage of SC phi X174 by MCA, but increased cleavage for MX. The DNA cleavage action of MCA was unique, among the several stronger and weaker mutagens investigated, in its action phi X174.
