The present invention relates to novel synthetic analogs I [wherein: R1 and R2 are independently selected from the group consisting of H, Me, straight or branched C2-10-alkyl, straight or branched C2-10-alkenyl or -alkadienyl, C4-6-cycloalkyl, C4-6-cycloalkenyl or -alkadienyl, alkoxyalkyl, (un)substituted benzyl; n is an integer ranging from I to 5;]. [A is a mono- or bicyclic aryl, or an (non)arom. heterocycle ring selected from the group consisting of pyrrole, pyrrolidine, 3-pyrroline, 2H-pyrrole, 2-pyrroline, indole, isoindole, 3H-indole, indolizine, indoline, carbazole, furan, benzofuran, isobenzofuran, 2H-pyran, 4H-pyran, benzo[b]thiophene, thiophene, pyridine, piperidine, 4H-quinolizine, isoquinoline, quinoline, tetrahydroquinoline, 1,8-naphthyridine, acridine, oxazole, isoxazole, benzoxazole, benzothiazole, isothiazole, thiazole, imidazole, 2-imidazole, imidazolidine, tetrazole, 1,2,3-triazole, 1,2,4-triazole, 1,2,3-oxadiazole, benzimidazole, purine, 1,4-dioxane, 1,3-dioxolane, 1,3-dithiane, 1,4-dithiane, 1,3,5-trithiane, morpholine, thiomorpholine, phenothiazine, pyrazole, 2-pyrazoline, pyrazolidine, quinazoline, cinnoline, pyrimidine, pyrazine, pteridine, phthalazine, 1,2,4-triazine, 1,3,5-triazine, pyridazine, piperazine, quinoxaline, phenazine, lH-indazole;]. [Wherein the substituents on ring A, independently from each other, are selected from the group consisting of H, O-alkyl, OCH3, Cl, F, Br, iodo, NO2, NH2, NHCH3, NH-alkyl, NHCOCH3, NHCO-alkyl, NHSO2CH3, NHSO2-alkyl, SO2CH3, SO2-alkyl, SO2NH2, SO2NHCH2, SO2NH-alkyl, SO2NHCOCH3, SO2NHCO-alkyl, CO2H, CONHCH3, CONH-alkyl, CO2CH3, CO2-alkyl, CONHSO2CH3, CONHSO2-alkyl, alkyl being as defined above for R1 and R2; wherein at least one of the substituents on the A ring is H;]. [Provided that the compd. of general formula I is not: (E)-3-phenyl-1-(2,4,6-trimethoxy-3-(3-methylbut-2-enyl)phenyl)prop-2-en-1-one or (E)-3-phenyl-1-(2-hydroxy-4,6-dimethoxy-3-(3-methylbut-2-enyl)phenyl)prop-2-en-1-one;] and tautomers, pharmaceutically acceptable salts and pro-drugs thereof, of xanthohumol (II) and the use thereof. Thus, (E)-1-[2,4-dihydroxy-6-methoxy-3-(3-methylbut-2-enyl)prenyl]-3-(4-fluorophenyl)prop-2-en-1-one (III) was prepd. from 2',4',6'-trihydroxyacetophenone monohydrate (IV·H2O) via regioselective O-protection with MOM-Cl in CH2Cl2 contg. DIPEA; O-etherification with 3-methyl-2-buten-1-ol in THF contg. PPh3 and DEAD;. Claisen rearrangement of the prenyl ether in N,N-dimethylaniline; O-methylation with Me2SO4 in acetone contg. K2CO3; aldol condensation with 4-FC6H4CHO in MeOH contg. aq. NaOH; and, demethoxymethylation with HCl in MeOH. The antitumor activity of III was detd. [significant inhibition of HUVEC cell growth at concn. of 20 μM after only 24 h; at the concn. of 10 μM it was proved able to reduce cell proliferation after 72 and 96 h treatment].
Synthetic analogs of xanthohumol for use in the prevention and/or treatment of tumors
ROSSELLO, ARMANDO;NUTI, ELISA;ORLANDINI, ELISABETTA;NENCETTI, SUSANNA;
2014-01-01
Abstract
The present invention relates to novel synthetic analogs I [wherein: R1 and R2 are independently selected from the group consisting of H, Me, straight or branched C2-10-alkyl, straight or branched C2-10-alkenyl or -alkadienyl, C4-6-cycloalkyl, C4-6-cycloalkenyl or -alkadienyl, alkoxyalkyl, (un)substituted benzyl; n is an integer ranging from I to 5;]. [A is a mono- or bicyclic aryl, or an (non)arom. heterocycle ring selected from the group consisting of pyrrole, pyrrolidine, 3-pyrroline, 2H-pyrrole, 2-pyrroline, indole, isoindole, 3H-indole, indolizine, indoline, carbazole, furan, benzofuran, isobenzofuran, 2H-pyran, 4H-pyran, benzo[b]thiophene, thiophene, pyridine, piperidine, 4H-quinolizine, isoquinoline, quinoline, tetrahydroquinoline, 1,8-naphthyridine, acridine, oxazole, isoxazole, benzoxazole, benzothiazole, isothiazole, thiazole, imidazole, 2-imidazole, imidazolidine, tetrazole, 1,2,3-triazole, 1,2,4-triazole, 1,2,3-oxadiazole, benzimidazole, purine, 1,4-dioxane, 1,3-dioxolane, 1,3-dithiane, 1,4-dithiane, 1,3,5-trithiane, morpholine, thiomorpholine, phenothiazine, pyrazole, 2-pyrazoline, pyrazolidine, quinazoline, cinnoline, pyrimidine, pyrazine, pteridine, phthalazine, 1,2,4-triazine, 1,3,5-triazine, pyridazine, piperazine, quinoxaline, phenazine, lH-indazole;]. [Wherein the substituents on ring A, independently from each other, are selected from the group consisting of H, O-alkyl, OCH3, Cl, F, Br, iodo, NO2, NH2, NHCH3, NH-alkyl, NHCOCH3, NHCO-alkyl, NHSO2CH3, NHSO2-alkyl, SO2CH3, SO2-alkyl, SO2NH2, SO2NHCH2, SO2NH-alkyl, SO2NHCOCH3, SO2NHCO-alkyl, CO2H, CONHCH3, CONH-alkyl, CO2CH3, CO2-alkyl, CONHSO2CH3, CONHSO2-alkyl, alkyl being as defined above for R1 and R2; wherein at least one of the substituents on the A ring is H;]. [Provided that the compd. of general formula I is not: (E)-3-phenyl-1-(2,4,6-trimethoxy-3-(3-methylbut-2-enyl)phenyl)prop-2-en-1-one or (E)-3-phenyl-1-(2-hydroxy-4,6-dimethoxy-3-(3-methylbut-2-enyl)phenyl)prop-2-en-1-one;] and tautomers, pharmaceutically acceptable salts and pro-drugs thereof, of xanthohumol (II) and the use thereof. Thus, (E)-1-[2,4-dihydroxy-6-methoxy-3-(3-methylbut-2-enyl)prenyl]-3-(4-fluorophenyl)prop-2-en-1-one (III) was prepd. from 2',4',6'-trihydroxyacetophenone monohydrate (IV·H2O) via regioselective O-protection with MOM-Cl in CH2Cl2 contg. DIPEA; O-etherification with 3-methyl-2-buten-1-ol in THF contg. PPh3 and DEAD;. Claisen rearrangement of the prenyl ether in N,N-dimethylaniline; O-methylation with Me2SO4 in acetone contg. K2CO3; aldol condensation with 4-FC6H4CHO in MeOH contg. aq. NaOH; and, demethoxymethylation with HCl in MeOH. The antitumor activity of III was detd. [significant inhibition of HUVEC cell growth at concn. of 20 μM after only 24 h; at the concn. of 10 μM it was proved able to reduce cell proliferation after 72 and 96 h treatment].I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.