Synthetic strategies to a telomere-targeted pentacyclic heteroaromatic salt

Abstract

Three routes have been explored to synthesise the telomere-targeted agent 3,11-difluoro-6,8,13-trimethyl-8H-quino[4,3,2-kl]acridinium methosulfate . Application of a 6-(2-azidophenyl)phenanthridine precursor gave an entry to the indazolo[2,3-f]phenanthridine ring system not the required quino[4,3,2-kl]acridine. A six step synthesis starting from 2,6-dibromo-4-methylbenzonitrile via a 1-arylacridin-9(10H)-one intermediate, or , gave the required in low overall yield (<10%). The most efficient route entailed the one-pot (five step) conversion of 1,2-dimethyl-6-fluoroquinolinium methosulfate to in 33% yield employing triethylamine as base and nitrobenzene as solvent.

On and off-target effects of telomere uncapping G-quadruplex selective ligands based on pentacyclic acridinium salts

“…Methylation of 5 with dimethyl sulphate in refluxing nitromethane furnished the dark red pentacyclic salt 1 (48%). However the overall yield of 1 from suitable precursors to 4 was disappointingly low at < 10% [20]. A more practicable route for the large-scale synthesis of salt 1 involved the multi-step, but ‘one-pot’, conversion of the N- methylquinolinium methosulfate salt 7 to 1 with triethylamine in nitrobenzene at 120°C in an optimized 33% yield [21].…”

“…2-Acetylamino- (2) and 3-acetylamino-8,13-dimethyl-8 H -quino[4,3,2- kl ]-acridinium iodide (3) were prepared according to published methods [20]. …”

“…The compound shows high efficacy in in-vitro tumor cell growth inhibition assays [14-16] and is particularly effective against human tumor xenografts in combination with taxol, [17] irinotecan [18] and, spectacularly so, in a triple combination with irinotecan and a PARP-1 inhibitor [19]. In addition, the compound has some desirable chemical and pharmaceutical properties such as ease of synthesis by a two-step route [20], high solubility, stability, and predicted freedom from metabolic liabilities [21]. However, in this paper we report that the prototypic quinoacridinium salt 1 also exhibits some undesirable off-target effects, but that these effects can be ameliorated to some extent in related non-fluorinated compounds 2 and 3 without compromising on-target properties.…”

Arylxanthones and arylacridones: a synthetic overview

“…To facilitate purification, a resin bound catalyst (Deloxan resin) under aqueous conditions was used but once again the hydrolysis of triflate groups occurred [51]. Later, it was reported the Suzuki-Miyaura cross-coupling reaction of bromoacridin-9(10H)-one 75 with the dioxaborolane 76 as an alternative coupling partner giving the 1-arylacridin-9(10H)-one 77 in 47 % yield with dichloro[1,1-bis(diphenylphosphino)ferrocene]palladium(II) and Na 2 CO 3 in 1,4-dioxane (Scheme 16) [52]. …”

Pyridoacridines in the 21st Century

“…Quantification of relative quadruplex and duplex binding affinity constants places some of these ligands among the most selective quadruplex DNA interactive agents reported to date , …”