Synthesis, cytotoxicity and topoisomerase inhibition properties of multifarious aminoalkylated indeno[1,2-c]isoquinolin-5,11-diones.

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.

Indeno[1,2-c]isoquinolin-5,11-diones conjugated to amino acids: Synthesis, cytotoxicity, DNA interaction, and topoisomerase II inhibition properties.

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.

Cyclic sulfamidates as vehicles for the synthesis of poly- and diversely substituted benzosultams via unusual S(O)2-O bond cleavage.

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.

Stereoselective asymmetric synthesis of (+)-sedamine and (+)-allosedamine.

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.

Asymmetric synthesis of 6-alkyl- and 6-arylpiperidin-2-ones. Enantioselective synthesis of (S)-(+)-coniine.

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.

A concise first total synthesis of narceine imide.

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.

A new total synthesis of porritoxin.

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.

First total synthesis of cichorine and zinnimidine.

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.

A new route to aristocularine alkaloids: total synthesis of aristoyagonine.

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.

A new synthesis of (+)- and (-)-cherylline.

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.

Benzoindolizine derivatives of N-acylphenothiazine. Synthesis and characterization.

A variety of unsaturated or partly and differentially saturated benzoindolizine derivatives of N-acylphenothiazine 1-3 has been efficiently synthesized by cyclocondensation of acetylenic or olefinic dipolarophiles with azomethineylide 4 derived from N-acetylisoquinolinium salt 5 flanking a phenothiazine unit.

Synthesis and biological evaluation of aristolactams.

A variety of aristolactam derivatives were synthesized and evaluated for cytotoxicity. Modulations were carried out on the phenanthrene nucleus and the lactam moiety as well. N-(N-dialkylaminoalkyl) derivatives exhibited interesting cytotoxic activity against the L1210 leukemia cell line.

Total synthesis of amaryllidaceae alkaloid buflavine.

A concise synthesis of the amaryllidaceae alkaloid buflavine (1) and its regioisomer (2) involving sequential Meyers' biaryl coupling, enecarbamate formation, and hydrogenation followed by ultimate intramolecular reductive amination is presented.

Metalation of 4-oxazolinyloxazole derivatives. A convenient route to 2,4-bifunctionalized oxazoles.

The synthesis of an array of 5-phenyloxazole derivatives bearing a variety of hydroxyalkyl groups at the C-2 position of the heterocyclic nucleus and possessing a formyl or a carboxyl function at C-4 is reported. These bifunctionalized compounds have been efficiently prepared by addition of carbonylated electrophiles to the 2-lithio derivative of 5-phenyloxazole preliminarily equipped with an oxazoline unit at the 4-position of the oxazole nucleus. It is demonstrated that this protocol offers a double advantage since it suppresses the troublesome electrocyclic ring-opening reaction and allows access to the target compounds by simple chemical transformation of the oxazoline ring system.