ABSTRACT
A number of mono- or diaminoalkylated indeno[1,2-c]isoquinolin-5,11-diones analogs of 1 were synthesized and evaluated for their DNA binding affinities, topoisomerase inhibition properties and antiproliferative activities against human cancer cell lines (HL60). Impact of the side chain connected to the aromatic D ring and to the N6 lactam position on the biological profile will be discussed.
Subject(s)
DNA Topoisomerases, Type II/chemistry , DNA Topoisomerases, Type I/chemistry , Isoquinolines/chemistry , Topoisomerase I Inhibitors/chemical synthesis , Topoisomerase II Inhibitors/chemical synthesis , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Antineoplastic Agents/toxicity , Cell Line, Tumor , DNA Topoisomerases, Type I/metabolism , DNA Topoisomerases, Type II/metabolism , Humans , Isoquinolines/chemical synthesis , Isoquinolines/pharmacology , Structure-Activity Relationship , Topoisomerase I Inhibitors/chemistry , Topoisomerase I Inhibitors/toxicity , Topoisomerase II Inhibitors/chemistry , Topoisomerase II Inhibitors/toxicity , Transition TemperatureABSTRACT
Three series of indeno[1,2-c]isoquinolin-5,11-dione-amino acid conjugates were designed and synthesized. Amino acids were connected to the tetracycle through linkers with lengths of n=2 and 3 atoms using ester (series I), amide (series II), and secondary amine (series III) functions. DNA binding was evaluated by thermal denaturation and fluorescence measurements. Lysine and arginine substituted derivatives with n=3 provided the highest DNA binding. Arginine derivative 32 (n=2, series II) and glycine derivative 34 (n=2, series III) displayed high topoisomerase II inhibition. Incrementing the length of the N-6 side chain from two to three methylene units provided a significant increase in DNA affinity but a substantial loss in topoisomerase II inhibition. The most cytotoxic compounds toward HL60 leukemia cells were 19, 33, and 34 displaying micromolar IC(50) values. When tested with the topoisomerase II-mutated HL60/MX2 cell line, little variation of IC(50) values was found, suggesting that topoisomerase II might not be the main target of these compounds and that additional targets could be involved.
Subject(s)
Amino Acids/chemistry , Antineoplastic Agents/chemical synthesis , Arginine/analogs & derivatives , DNA Topoisomerases, Type II/chemistry , DNA/chemistry , Indenes/chemistry , Isoquinolines/chemistry , Topoisomerase II Inhibitors/chemical synthesis , Antineoplastic Agents/chemistry , Antineoplastic Agents/toxicity , Arginine/chemical synthesis , Arginine/chemistry , Arginine/toxicity , Cell Line, Tumor , DNA/metabolism , DNA Topoisomerases, Type II/genetics , DNA Topoisomerases, Type II/metabolism , Humans , Isoquinolines/chemical synthesis , Isoquinolines/toxicity , Mutation , Structure-Activity Relationship , Topoisomerase II Inhibitors/chemistry , Topoisomerase II Inhibitors/toxicity , Transition TemperatureABSTRACT
1,2-Cyclic sulfamidates undergo novel, efficient, and regiospecific intramolecular nucleophilic cleavage with aryllithiated species to provide an entry to poly-, diversely, and enantiopure N-substituted benzosultams.
Subject(s)
Oxygen/chemistry , Sulfonamides/chemistry , Sulfonamides/chemical synthesis , Sulfur Dioxide/chemistry , Cyclization , Molecular Structure , StereoisomerismABSTRACT
A convenient method for the generation of (+)-sedamine and (+)-allosedamine in high optical purity has been elaborated. The key steps are the highly stereoselective 1,2-nucleophilic addition to SAMP hydrazones allowing the installation of the stereogenic center at C2 and ring closing metathesis.
Subject(s)
Alkaloids/chemical synthesis , Hydrazones/chemistry , Piperidines/chemical synthesis , Stereoisomerism , Alkaloids/chemistry , Catalysis , Cyclization , Epoxy Compounds/chemistry , Molecular Structure , Phenylmercury Compounds , Phosphinic Acids/chemistry , Piperidines/chemistry , Potassium/chemistryABSTRACT
A variety of diolefinic hydrazides (1) have been assembled in a highly diastereoselective manner by addition of allyllithium to chiral SAMP hydrazones followed by N-acylation with acryloyl chloride. Substrates 1 undergo ring-closing metathesis to give the cyclic enehydrazides (5) which can be easily converted into virtually enantiopure 6-alkyl- or 6-arylpiperidin-2-ones (7). The versatility of this hydrazone addition-RCM protocol has been further exemplified by the conversion of the unsaturated heterocycle 5b into the piperidine alkaloid (S)-(+)-coniine.
ABSTRACT
A concise and efficient total synthesis of alkaloid narceine imide is disclosed. The key steps are based upon the sequential construction of the isoindolinone template followed by metalation and coupling with an isoquinolinium salt. Subsequent E1cb elimination enables the creation of the arylmethylene unit with the concomitant formation of the dimethylaminoethyl chain and ultimate deprotection completes the synthesis of the natural product.
Subject(s)
Alkaloids/chemical synthesis , Benzodioxoles/chemical synthesis , Indole Alkaloids/chemical synthesis , Alkaloids/chemistry , Benzodioxoles/chemistry , Indole Alkaloids/chemistry , Indolizines/chemistry , Lactams/chemistryABSTRACT
A concise and efficient total synthesis of the phytotoxin porritoxin is described. The key step of the synthesis is based upon a Parham cyclization methodology which enables the creation of the lactam unit embedded in the title compound framework with the concomitant formation of the tethered hydroxyakyl chain.
Subject(s)
Indoles/chemical synthesis , Indoles/chemistry , Isoindoles , Molecular StructureABSTRACT
The first total synthesis of the phytotoxins cichorine and zinnimidine is described. The synthetic tactics involve the sequential connection of the dense and diverse functionalities on the aromatic nucleus followed by a Parham cyclization process, giving rise to the lactam unit embedded in the title compound framework.
Subject(s)
Indoles/chemical synthesis , Toxins, Biological/chemical synthesis , Isoindoles , Magnetic Resonance Spectroscopy , Molecular StructureABSTRACT
A short and efficient synthesis of aristocularines, involving the sequential construction of phosphorylated 4-alkoxyisoindolinones, Horner-type reaction, and ultimate cyclization by diaryl ether coupling, is disclosed. The success of this new conceptual approach is demonstrated by the total synthesis of the aristocularine alkaloid aristoyagonine.
Subject(s)
Fumariaceae/chemistry , Isoquinolines/chemical synthesis , Cyclization , Molecular StructureABSTRACT
A new and concise synthesis of enantiopure antipodes of alkaloid cherylline has been devised. The synthetic strategy relies upon the reduction of a diversely and polyprotected diarylenamine bearing a chiral auxiliary. Separation of diastereopure intermediates, concomitant deprotections and intramolecular reductive amination complete the synthesis of the natural (S)-enantiomer and of the unnatural (R)-configured antipode.