B-ring-aryl substituted luotonin A analogues with a new binding mode to the topoisomerase 1-DNA complex show enhanced cytotoxic activity.

Topoisomerase 1 inhibition is an important strategy in targeted cancer chemotherapy. The drugs currently in use acting on this enzyme belong to the family of the camptothecins, and suffer severe limitations because of their low stability, which is associated with the hydrolysis of the δ-lactone moiety in their E ring. Luotonin A is a natural camptothecin analogue that lacks this functional group and therefore shows a much-improved stability, but at the cost of a lower activity. Therefore, the development of luotonin A analogues with an increased potency is important for progress in this area. In the present paper, a small library of luotonin A analogues modified at their A and B rings was generated by cerium(IV) ammonium nitrate-catalyzed Friedländer reactions. All analogues showed an activity similar or higher than the natural luotonin A in terms of topoisomerase 1 inhibition and some compounds had an activity comparable to that of camptothecin. Furthermore, most compounds showed a better activity than luotonin A in cell cytotoxicity assays. In order to rationalize these results, the first docking studies of luotonin-topoisomerase 1-DNA ternary complexes were undertaken. Most compounds bound in a manner similar to luotonin A and to standard topoisomerase poisons such as topotecan but, interestingly, the two most promising analogues, bearing a 3,5-dimethylphenyl substituent at ring B, docked in a different orientation. This binding mode allows the hydrophobic moiety to be shielded from the aqueous environment by being buried between the deoxyribose belonging to the G(+1) guanine and Arg364 in the scissile strand and the surface of the protein and a hydrogen bond between the D-ring carbonyl and the basic amino acid. The discovery of this new binding mode and its associated higher inhibitory potency is a significant advance in the design of new topoisomerase 1 inhibitors.

Diastereoselective, multicomponent access to trans-2-aryl-4-arylamino-1,2,3,4-tetrahydroquinolines via an AA'BC sequential four-component reaction and their application to 2-arylquinoline synthesis.

The CAN-catalyzed reaction between 3,5-disubstituted anilines, vinyl ethers and aromatic aldehydes leads to trans-2-aryl-4-arylaminotetrahydroquinolines, in an AA'BC sequential multicomponent transformation related to the Povarov reaction that was also extended to the use of a second aniline as the C-4 substituent. The unusual trans stereochemistry was explained by stabilization of the corresponding intermediate by intramolecular hydrogen bonding. The presence of the 4-anilino substituent allowed adapting the method to the synthesis of 4-unsubstituted 2-arylquinolines, by treatment of the crude product from the MCR with FeCl(3) in methanol.

New types of reactivity of α,ß-unsaturated N,N-dimethylhydrazones: chemodivergent diastereoselective synthesis of functionalized tetrahydroquinolines and hexahydropyrrolo[3,2-b]indoles.

The indium trichloride-catalyzed reaction between aromatic imines and α,ß-unsaturated N,N-dimethylhydrazones in acetonitrile afforded 1,2,3,4-tetrahydroquinolines bearing a hydrazone function at C4 through a one-pot diastereoselective domino process that involves the formation of two C-C bonds and the controlled generation of two stereocenters, one of which is quaternary. This reaction constitutes the first example of an α,ß-unsaturated dimethylhydrazone that behaves as a dienophile in a hetero Diels-Alder reaction. The related reaction between anilines, aromatic aldehydes, and methacrolein dimethylhydrazone in CHCl(3) with BF(3)⋅Et(2)O as catalyst afforded polysubstituted 1,2,3,3a,4,8b-hexahydropyrrolo[3,2-b]indoles as major products through a fully diastereoselective ABB'C four-component domino process that generates two cycles, three stereocenters, two C-C bonds, and two C-N bonds in a single operation.

Synthesis of polysubstituted, functionalized quinolines through a metal-free domino process involving a C4­C3 functional group rearrangement.

4-Alkyl-1,2,3,4-tetrahydroquinolines bearing a 4-vinyl unit ending in an electron-withdrawing group were efficiently transformed into polysubstituted, C(3)-functionalized quinolines upon heating in refluxing o-dichlorobenzene, in a domino reaction involving an unusual C(4)-C(3) functional group rearrangement.

Cerium(IV) ammonium nitrate is an excellent, general catalyst for the Friedländer and Friedländer-Borsche quinoline syntheses: very efficient access to the antitumor alkaloid luotonin A.

The use of cerium(IV) ammonium nitrate as a catalyst of the Friedländer reaction allows the synthesis of polysubstituted quinoline derivatives in excellent yields, avoiding the traditional harshly basic or acidic conditions. Unlike most other previously known reagents, CAN allows double condensations and is also an excellent catalyst for the Borsche variation of the Friedländer reaction, which has been applied to the very efficient synthesis of the antitumor alkaloid luotonin A.

Influence of pectin fine structure on the mechanical properties of calcium-pectin and acid-pectin gels.

The in vitro and in vivo functionality of the anionic plant polysaccharide pectin depends not only on the amount of ion-binding groups attached to the polymer but also on the distribution of such groups along the backbone. It has been proposed recently that information regarding this intramolecular distribution can be quantified by defining a degree of blockiness (DB or DB(abs)), and the usefulness of such measures in discriminating qualitatively between pectins originating from different sources has been demonstrated. Despite this, the value of these parameters in predicting the pseudoequilibrium elastic modulus of gels remains untested. This study seeks to address this problem through the sourcing and in-house modification of a variety of pectins in order to produce a library of distinct representative fine structures. These were subsequently characterized in terms of their relevant properties, including the determination of the proposed DB and DB(abs), and the formation of gels of these samples was monitored using small deformation mechanical spectroscopy. In addition to ionotropic calcium gels the effect of the fine structure on acid gelation was also studied.