Synthesis and biological evaluation of 2,7-Dihydro-3H-dibenzo[de,h]cinnoline-3,7-dione derivatives, a novel group of anticancer agents active on a multidrug resistant cell line

Yoropyrazone, a new naphthopyridazone alkaloid isolated from Streptomyces sp. IFM 11307 and evaluation of its TRAIL resistance-overcoming activity

“…The 1 H NMR spectrum of 1 in DMSO-d 6 solution showed a signal due to the amino group at d H 13.5 (2H, broad singlet), which was consistent with the chemical shift value (d H 13.2, 2H) of the corresponding amino group of a synthetic compound, 8-amino-2-methyl-2,7-dihydro-3H-dibenzo[de,h]cinnoline-3,7-dione. 10 By combining all of the above evidence, the structure of yoropyrazone was concluded as 1, shown in Figure 1. The assignment of the relative configuration of yoropyrazone (1) was established from the NOE observed between the vicinal protons H-3¢ and H-4¢, and their coupling constant of 3.9 Hz (J HÀ3¢,HÀ4¢ ¼4.0 Hz in 4¢-deacetyl-(À)-griseusin B).…”

A New Method for the Preparation of Intermediates for 2,6‐Substituted Anthrapyridazones

“…These analogs exhibit a high cytostatic activity against MDR tumor cells with the overexpression of different exporting pumps, MDR‐1, BCRP, and MRP, and against a broad spectrum of resistant cell lines derived from different tissues and patient organs. Although the new MDR compound class was successfully synthetized in a small laboratory scale, we observed several problems during the preparation of their two intermediates in a multigram scale: anthraquinone acid ( 2 ) and 2‐substituted anthrapyridazones ( 6 , Scheme ) .…”

“…Another major problem in the synthesis of anthrapyridazones 8 is obtaining their monosubstituted intermediates 6 . According to the known literature methodology , 2,7‐dihydro‐3 H ‐dibenz[ de , h ]cinnoline‐3,7‐diones with the (alkylamino)alkyl substituent in position 2 of the tetracyclic ring can be obtained through the condensation of 4‐chloroanthraquinone‐1‐carboxylic acid ( 2 ), previously converted to the respective chloride, and (alkylamino)alkyl hydrazine derivative ( 5 ) (Scheme , reaction d). Thereby, a group of 2‐substituted 2,7‐dihydro‐3 H ‐dibenz[ de , h ]cinnoline‐3,7‐diones with (dimethylamino)ethyl, (dietylamino)ethyl, (morfoline)ethyl, and (piperidineamino)ethyl spacers was isolated in the yield of only 20–60% after the purification by column chromatography.…”

NaIO4/Br- as a mild system for the oxidation of 1-methyl-anthra-9,10-quinones

“…These natural or synthetic anthraquinones find their application as building blocks in the synthesis of the compounds with a biological activity.Recently, 4-substituted anthra-9,10-quinone-1-carboxylic acids (2) have been used as key intermediates in the synthesis of patented compounds (3) with anticancer activity against multidrug resistant cell lines [1,2]. Although 2,7-dihydro-3H-dibenz [de,h]cinnolin-3,7-diones (3) were successfully synthetized in a small laboratory scale, several problems were observed during the preparation of their acid intermediates (2) in a multi-gram scale.…”

“…The known methods for the preparation of 2 are based on the oxidation of the methyl group in anthra-9,10-quinones (1). The most common are: the oxidation with the diluted nitric acid under high pressure in a sealed tube at the temperature of 195-220 o C [3,4], the oxidation in nitrobenzene by passing chlorine gas through the reaction mixture at the temperature of 160-170 o C [5] or in a presence of the fuming sulphuric acid [6,7].…”