Synthesis And Antitumor Activity Evaluation Of Novel 2,3-disubstituted-3-nitro-4-chromanone Derivatives

4-Chromanones,which possessed a wide range of biological activity,exhibited good antiproliferative activity against human tumor cell lines in vitro by introducing nitro group at C-3 position.3-Nitro-4-chromanones also showed potent inhibitory activity against DNA methyltransferase,aminopeptidase N and telomerase,which suggested a promising prospect on development of 3-nitro-4-chromanones as new chemotherapeutics in treating cancer especially advanced cancer.This dissertation focused on synthesis and antitumor activity evaluation of novel 2,3-disubstituted-3-nitro-4-chromanone derivatives.Part 1.Diastereoselective synthesis of 2-alkoxycarbonylmethyl-3-alkyl-3-nitro-4-chromanones1.Starting from 2-hydroxyl-benzaldehyde,nitroalkane and alkynyl esters,a convenient method to construct 2-alkoxycarbonylmethyl-3-alkyl-3-nitro-4-chromanones was developed.As the key step,t Bu OK-catalyzed intramolecular Michael-type cyclization was carried out successfully with high yields and excellent diastereoselectivities.The method was of nice substrate applicability.The relative configuration of the dominant product was determined by the X-ray crystallographic analysis,and a possible reaction mechanism was provided.The reaction was carried out on gram scale without decreasing its original efficiency.2.A series of novel racemic 2-alkoxycarbonylmethyl-3-alkyl-3-nitro-4-chromanones were synthesized with up to >20:1 d.r.diastereoselectivities by the new method.Other 3-nitro-4-chromanones with carboxylic,hydroxyl or amide groups at C-2 position were obtained by functional group transformation.21 of racemic 2,3-multisubstituted 4-chromanones were synthesized as the major products,which facilitated the further biologic activity screening.Part 2.Design,synthesis and anti-prostate cancer activity evaluation of 2-(alkyloxy/amido)formylmethyl-3-alkyl-3-nitro-4-chromanones1.Results of antiproliferative activity screening on various human cancer cell lines showed that some of novel structures were active on inhibiting human prostate cancer cell lines DU145 and PC3.This series of structures revealed no significant toxicity to normal human fibroblast(HAF)cell line.Based on the above results,68 of new racemic 2-(alkyloxy/amido)formylmethyl-3-alkyl-3-nitro-4-chromanones were designed and synthesized by the new method described in Part 1 followed with derivatization and modification.2.Antiproliferative activities of new structures against AR-negative DU145,PC3/PC3 M cells in vitro were tested and the primary structure-activity relationship was concluded as below:In structure A unit,amide derivatives were more potent than their corresponding esters.N-alkyl substitutions were more beneficial to the activity than N-aryl,alkenyl or alkynyl substitutions and more effective with long or branched chain.N-cycloalkyl substitutions were more effective than N-linear alkyl substitutions.In structure B unit,introduction of electron-withdrawing groups showed better activity than electron-donating groups.In structure C unit,3-nitro group was important for maintaining the activity.The activity decreased when prolonged the 3-alkyl chain.3.The dominant products(trans-)synthesized by the new method were more potent than the minors(cis-).AR-negative prostate cancer cells were more sensitive to 70 than AR-positive ones.Almost all new structures were not toxic to HAF cell line except for 74.4.Further biological investigation indicated that 70 could inhibit the colony formation of DU145 cell line remarkably,suppress its migration and induce S phase cell cycle arrest and apoptosis.70 suppressed the growth of prostate RM-1 tumor in vivo in murine tumor model.The effects of 70 in human tumor xenograft model were under evaluation.Part 3.Tentative study on asymmetric synthesis of 2,3-disubstituted-3-alkyl-3-nitro-4-chromanonesIt was found that there was significant difference of the antiproliferative activities between 70's enantiomers,which suggested the potential value of development for asymmetric synthesis of those compounds.Using ?-nitro aryl ketones with ortho-alkoxycarbonyl-vinyl ether groups as substrates,an asymmetric synthesis of 2,3-disubstituted-3-nitro-4-chromanones bearing adjacent tertiary and quaternary stereocenters with high yields and high enantioselectivities was developed with chiral thiourea organocatalyst.The enantioselectivities was up to 94% ee under the optimized conditions.The absolute configuration of compound ent-86 A was determined by the X-ray crystallographic analysis.All results of the three parts above enriched the methods for synthesis of 2,3-disubstituted-3-nitro-4-chromanones with controlled enantio-and diastereoselectivities.The novel 2,3-disubstituted-3-nitro-4-chromanones exhibited inhibitory activity on human prostate cancer cell lines with no significant toxicity to human normal cell line HAF.The preliminary structure-activity relationship revealed the active site of these structures and was potential for further modification.These results could accumulate the lead compound discovery based on 3-nitro-4-chromanones.