ABSTRACT
3-Arylidenechroman-4-ones and 2-arylidene-1-tetralones are hydrogenated to cis-benzylic alcohols in dr's and er's up to 99:1 via a CâC and CâO one-pot reduction in the presence of 2-5 mol % Noyori-Ikariya-type RuII chiral complexes and HCO2Na as a hydrogen source under asymmetric transfer hydrogenation-dynamic kinetic resolution (ATH-DKR) conditions. The oxidation of theses substrates resulted in the enantioselective synthesis of the natural homoisoflavanone dihydrobonducellin and its carba-analogues.
Subject(s)
Tetralones , Catalysis , Hydrogenation , Kinetics , StereoisomerismABSTRACT
α-aryl-α-tetralones and α-fluoro-α-aryl-α-tetralones derivatives were synthesized by palladium catalyzed α-arylation reaction of α-tetralones and α-fluoro-α-tetralones, with bromoarenes in moderate to good yields. These compounds were evaluated for their in vitro anti-proliferative effects against human breast cancer and leukemia cell lines with diverse profiles of drug resistance. The most promising compounds, 3b, 3c, 8a and 8c, were effective on both neoplastic models. 3b and 8a induced higher toxicity on multidrug resistant cells and were able to avoid efflux by ABCB1 and ABCC1 transporters. Theoretical calculations of the physicochemical descriptors to predict ADMETox properties were favorable concerning Lipinski's rule of five, results that reflected on the low effects on non-tumor cells. Therefore, these compounds showed great potential for development of pharmaceutical agents against therapy refractory cancers.
Subject(s)
Antineoplastic Agents/pharmacology , Drug Resistance, Neoplasm/drug effects , Software , Tetralones/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Humans , MCF-7 Cells , Mitochondria/drug effects , Mitochondria/metabolism , Molecular Structure , Structure-Activity Relationship , Tetralones/chemical synthesis , Tetralones/chemistryABSTRACT
Natural pterocarpans and synthetic 5-carba-pterocarpans are isosteres in which the oxygen atom at position 5 in the pyran-ring of pterocarpans is replaced by a methylene group. These 5-carba-analogues were obtained in good yields through the palladium-catalyzed oxyarylation of alcoxy-1,2-dihydronaphthalens with o-iodophenols in PEG-400. They were evaluated on human cancer cell lineages derived respectively from prostate tumor (PC3, IC50 = 11.84 µmol L-1, SI > 12)) and acute myeloid leukemia (HL-60, IC50 = 8.81 µmol L-1, SI > 16), highly incident cancer types presenting resistance against traditional chemotherapeutics. Compound 6c (LQB-492) was the most potent (IC50 = 3.85 µmol L-1, SI > 37) in SF-295 cell lineage (glioblastoma). Such findings suggest that 5-carba-pterocarpan can potentially be new hit compounds for further development of novel antiproliferative agents.
Subject(s)
Antineoplastic Agents/pharmacology , Pterocarpans/pharmacology , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Cell Line , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Humans , Mice , Molecular Structure , Pterocarpans/chemical synthesis , Pterocarpans/chemistry , Structure-Activity RelationshipABSTRACT
The synthesis of a series of 5-carba-pterocarpens derivatives involving the cyclization of α-aryl-α-tetralones is described. Several compounds demonstrated potent activity and selectivity in vitro against HCV replicon reporter cells. The best profile in Huh7/Rep-Feo1b replicon reporter cells was observed with 2h (EC50 = 5.5 µM/SI = 20), while 2e was the most active in Huh7.5-FGR-JC1-Rluc2A replicon reporter cells (EC50 = 1.5 µM/SI = 70). Hydroxy groups at A- and D-rings are essential for anti-HCV activity, and substitutions in the A-ring at positions 3 and 4 resulted in enhanced activity of the compounds.
Subject(s)
Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Guanidines/chemistry , Guanidines/pharmacology , Hepacivirus/drug effects , Anisoles/chemical synthesis , Anisoles/chemistry , Anisoles/pharmacology , Antiviral Agents/chemical synthesis , Catalysis , Cell Line , Guanidines/chemical synthesis , Hepacivirus/genetics , Hepatitis C/drug therapy , Hepatitis C/virology , Humans , Palladium/chemistry , Replicon/drug effects , Tetralones/chemical synthesis , Tetralones/chemistry , Tetralones/pharmacologyABSTRACT
The synthesis of a novel series of 1-carba-isoflavanones through the α-arylation of α-tetralones is described. Several of these compounds demonstrated potent activity and selectivity in-vitro against HCV replicon reporter cells. Compound 10 (LQB-314) exhibited the best profile being active and selective in both replicon reporter cells (IC50 1.8 µM, SI > 111 and IC50 4.3 µM, SI > 46 in Huh7/Rep-Feo1b and Huh7.5-FGR-JC1-Rluc2A, respectively). Compound 3 (LQB-307) was the more potent and selective for Huh7.5-FGR-JC1-Rluc2A replicon reporter cells (IC50 1.5 µM, SI > 101.4).
