Synthesis and Cytotoxic Activity of Benzophenanthrolinone Analogues of Acronycine.

Abstract

The acridone alkaloid acronycine (1), which was first isolated from Acronychia baueri SCHOTT (Rutaceae) in 1948, was later found to be a potent anticancer agent. [1][2][3][4][5] It is of interest because of its activity against a broad spectrum of solid tumors, including numerous sarcomas, myelomas, carcinomas, and melanomas.2-6) Nevertheless, its low water-solubility and moderate potency have severely hampered its clinical trials, which have given so far only poor results.7) Consequently, the development of structural analogues possessing a basic nitrogen atom able to give water-soluble salts seems highly desirable. 8,9) The replacement of the dimethylpyran D ring of acronycine by a pyridine unit, present in numerous tetracyclic antitumor drugs including the linear ellipticines [10][11][12] and olivacines, [13][14][15] and their angular 7H-and 11H-pyridocarbazoles counterparts, [16][17][18][19] appeared to us an attractive way to look for new anticancer candidates. In addition, this approach was consistent with the antitumor activities of several recently described benzophenanthrolinones related to amsacrine. 20)This paper deals with the synthesis and cytotoxic properties of 12H-benzo[b] [1,7] and [1,10]phenanthrolinones related to acronycine, and also to 6-demethoxyacronycine (2) and 11-aminoacronycine (3), which were shown to exhibit cytotoxic activities within the same range of magnitude as acronycine itself. 9,21)Chemistry The key-step of our approach was an Ullmann condensation 22) of either 2-bromobenzoic acid (4) or 2-chloro-3-nitrobenzoic acid (5) with suitable aminoquinolines 6-8, to afford the carboxylic phenylquinolylamines 9-13. In contrast, all attempts towards the reduction of the nitro group of 15 failed, most probably due to the almost complete insolubility of this compound in usual organic solvents.Pharmacology The study of the biological properties of the new benzophenanthrolin-7-one derivatives was carried out in vitro on L1210 murine leukemia cell line. The results (IC 50 ) are reported in Condensation of either 2-bromobenzoic acid (4) or 2-chloro-3-nitrobenzoic acid (5)

Pyridoacridines in the 21st Century

“…In work to prepare analogues of the pyranoacridone alkaloid acronycine, from Acronychia baueri Schott (Rutaceae), which has antitumor properties, the tetracyclic acridone 238 was assembled, the key step being the intramolecular aroylation (237 → 238) (Scheme 81). [148] Using 1-bromonaphthalene-2-carboxylic acid instead of 2-bromobenzoic acid led to benzologue 239. [149] Scheme 81.…”

“…Synthesis of an analogue 238 of acronycine. [148] Amine 240 [150] was converted into the synthetically useful aldehyde 242 as shown in Scheme 82. [151] The formation of aminopyrido[2,3-c]acridine.…”

“…[177] A copper-catalysed amination and a Friedel-Crafts cyclisation figured in the preparation of acid 287 and its conversion into the pyridoacridone 288 (Scheme 95). [148] An analogous sequence using 1-bromonaphthalene-2-carboxylic acid, instead of 2-bromobenzoic, led to 289. [149] Scheme 95.…”

Microwave-Promoted synthesis of novel N-Arylanthranilic acids

“…It is also employed as precursor of biologically important compounds such as acridine [4][5][6] and acridone alkaloids. [7][8][9][10][11][12][13][14] The synthesis of N-aryl anthranilic acids can be usually achieved by the Ullmann condensation 15 between a 2-halobenzoic acid and an aryl amine 16,17 or an anthranilic acid and an aryl halide. 18,19 One of the major drawback of these methodologies is the need of heating during long reaction time.…”

Acronycine Analog: New Selective Synthesis of 6‐Methoxy‐3,3‐dimethyl‐3H,7H‐pyrano[2,3‐c]xanthen‐7‐one

“…[2,3] The synthesis of various analogs and the studies of their structure -activity relationships [4,5] showed that the 1,2-double bond on the pyran ring is essential for cytotoxic and antitumor properties. [6,7] Among the various prepared analogs of acronycine that present modifications of the pyran [8] or the chromene [9] part of the molecule, the dimethylpyrano[2,3-c]xanthen-7-one 6b and its 1,2-substituted derivatives present higher antitumor activity than the original alkaloid. [10] As a part of an ongoing program in connection with the synthesis of new derivatives of 3,3-dimethyl-3H,7H-pyrano[2,3-c]xanthen-7-one with potential antitumor activity, we were looking for a convenient and selective route to the key compound 6b as a starting intermediate.…”