ABSTRACT
A library of 26 novel carboxamides deriving from natural fislatifolic acid has been prepared. The synthetic strategy involved a bio-inspired Diels-Alder cycloaddition, followed by functionalisations of the carbonyl moiety. All the compounds were evaluated on Bcl-xL, Mcl-1 and Bcl-2 proteins. In this series of cyclohexenyl chalcone analogues, six compounds behaved as dual Bcl-xL/Mcl-1 inhibitors in micromolar range and one exhibited sub-micromolar affinities toward Mcl-1 and Bcl-2. The most potent compounds evaluated on A549 and MCF7 cancer cell lines showed moderate cytotoxicities.
Subject(s)
Amides/pharmacology , Antineoplastic Agents/pharmacology , Cyclohexanecarboxylic Acids/pharmacology , Myeloid Cell Leukemia Sequence 1 Protein/antagonists & inhibitors , bcl-X Protein/antagonists & inhibitors , Amides/chemical synthesis , Antineoplastic Agents/chemical synthesis , Apoptosis/drug effects , Cell Line, Tumor , Cyclohexanecarboxylic Acids/chemical synthesis , Drug Screening Assays, Antitumor , Humans , Small Molecule Libraries/chemical synthesis , Small Molecule Libraries/pharmacology , StereoisomerismABSTRACT
8-OxodGTP is generated by the reaction between dGTP and reactive oxygen species and a considered mutagenic nucleotide. It can be incorporated into the duplex DNA during replication processes by the DNA polymerase, and thus the repair enzyme removes oxodGTP from the nucleotide pools in living cells. On the other hand, the γ-modified triphosphates show interesting properties for use as biological tools. Therefore, the γ-N-pyrenylalkyl-oxodGTP derivatives were synthesized and their effect on the enzymatic reactions were evaluated. The γ-N-pyrenylmethyl-oxodGTP was found to be accepted by the DNA polymerase just like oxodGTP, but showed a competitive inhibition property for the human oxodGTPase.
Subject(s)
Deoxyguanine Nucleotides/chemical synthesis , Pyrenes/chemical synthesis , DNA-Directed DNA Polymerase/chemistry , Deoxyguanine Nucleotides/chemistry , Humans , Hydrolysis , Kinetics , Molecular Docking Simulation , Molecular Structure , Oxidation-Reduction , Pyrenes/chemistryABSTRACT
Resveratrol, a natural stilbene found in grapes and wines exhibits a wide range of pharmacological properties. Resveratrol is also known as a good chemopreventive agent for inhibiting carcinogenesis processes that target kinases, cyclooxygenases, ribonucleotide reductase and DNA polymerases. A total of 19 analogues with an amide moiety were synthesized and the cytotoxic effects of the analogues on a series of human cancer cell lines are reported. Three compounds 6d, 6i and 6n showed potent cytotoxicity against prostate cancer DU-145 (IC50=16.68 µM), colon cancer HT-29 (IC50=7.51 µM) and breast cancer MCF-7 (IC50=21.24 µM), respectively, which are comparable with vinblastine. The resveratrol analogues were synthesized using the Heck method.