New Vistas in Quinoline Synthesis.

Atechian, Sarkis; Nock, Nadine; Norcross, Roger D.; Ratni, Hassen; Thomas, Andrew W.; Verron, Julien; Masciadri, Raffaello

doi:10.1002/chin.200727122

Cited by 2 publications

(3 citation statements)

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“…Compound 2 , which can be regarded as an oxidised derivative of the alkaloid vasicinone, was prepared using a literature method [29] . Some of the compounds 1 , namely 1a – d , were commercially available, while access to 1e was secured by a literature method involving the bromination of 1c with potassium bromide under oxidative conditions [20] . Finally, compounds 1f and 1g were prepared by treatment of the corresponding derivatives of 2-aminobenzonitrile with 3,5-dimethylphenylmagnesium bromide followed by acidic hydrolysis ( Figure 2 ).…”

Section: Resultsmentioning

confidence: 99%

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B-Ring-Aryl Substituted Luotonin A Analogues with a New Binding Mode to the Topoisomerase 1-DNA Complex Show Enhanced Cytotoxic Activity

et al. 2014

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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.

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Section: Resultsmentioning

confidence: 99%

“…2-Aminobenzaldehyde 1a , 2-aminoacetophenone 1b , 2-aminobenzophenone 1c and (4-chloro-2-amino)benzophenone 1d were purchased from Aldrich. (5-Bromo-2-amino)benzophenone 1e was prepared according to a literature method [20] .…”

Section: Methodsmentioning

confidence: 99%

B-Ring-Aryl Substituted Luotonin A Analogues with a New Binding Mode to the Topoisomerase 1-DNA Complex Show Enhanced Cytotoxic Activity

et al. 2014

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“…The Friedländer synthesis involves an acid or base catalyzed condensation between 2-aminoaryl ketone and a second carbonyl compound containing a reactive α-methylene group followed by a cyclodehydration. Brønsted acids and Lewis acids are known to promote these reactions [ 13 , 14 , 15 , 16 , 17 , 18 , 19 ]. Brønsted acid catalysts, such as hydrochloric acid [ 20 ], perchloric acid [ 15 ], sulfamic acid [ 21 ], oxalic acid [ 22 ], silver phosphotungstate [ 23 ] and NiCl 2 ·2H 2 O [ 24 ] have been used in Friedländer reactions.…”

Section: Introductionmentioning

confidence: 99%