Antitumor Polycyclic Acridines. 8. Synthesis and Telomerase-Inhibitory Activity of Methylated Pentacyclic Acridinium Salts

Abstract

Two short routes to novel methylated pentacyclic quinoacridinium salts have been devised. New compounds display telomerase-inhibitory potency (<1 microM) in the TRAP assay. 3,11-Difluoro-6,8,13-trimethyl-8H-quino[4,3,2-kl]acridinium methosulfate (12d, RHPS4, NSC 714187) has a higher selectivity for triplex and quadruplex DNA structures than the 3,6,8,11,13-pentamethyl analogue (12c, RHPS3, NSC 714186) and a low overall growth-inhibitory activity in the NCI 60 cell panel (mean GI(50) 13.18 microM); in addition, the activity profile of 12d does not COMPARE with agents of the topoisomerase II class. Compound 12d is soluble in water, stable in the pH range of 5-9, efficiently transported into tumor cells, and is currently the lead structure for further elaboration in this new class of telomerase inhibitor.

Ascididemin and meridine stabilise G-quadruplexes and inhibit telomerase in vitro

“…The number of G4 ligands has grown rapidly over a few years: a range of molecules has been shown to inhibit telomerase through binding to its substrate [14,26,27,36,[44][45][46][47][48][49][50][51][52][53][54][55][56][57][58][59]. On the other hand, few natural products have been reported as G-quadruplex-mediated telomerase inhibitors, although one, telomestatin, is exceptionally potent with an IC50 of 5 nM against telomerase [25].…”

“…Therefore, specific recognition of unusual DNA structures such as triplexes and quadruplexes by small molecules such as pyridoacridines should be possible. RHPS4 (center) [27,54,66,67]…”

PARP1 is activated at telomeres upon G4 stabilization: possible target for telomere-based therapy

“…The following drugs were used: clinical-grade irinotecan (CAMPTO, Pfizer, Borgo S Michele, LT, Italy), pentacyclic acridine RHPS4 (Heald et al, 2002), NU1025 used at a concentration of 200 mM (Santa Cruz Biotechnology, Santa Cruz, CA, USA) and orally bioavailable PARP inhibitor GPI 15427 used at a concentration of 2 mM (Eisai, Baltimore, MD, USA). Drugs were freshly prepared before each experiment.…”

G-Quadruplex Ligands as Stabilizer Targeting Telomerase Enzyme as Anti Cancer Agents

“…In the acridine chromophore aniline substituent at 9 th position shows significant inhibitor activity for the Compound 6 (BRACO19) (IC 50 0.095 µM) and Compound 7 (IC 50 0.060 µM) [14]. The pentacyclic quinoa iridium salt RHPS4 (Compound 8) (IC 50 0.25 µM) shows good pharmaceutical properties and efficiently transported into tumor cells [15]. Other acridine compounds such as polycyclic acridines (Compound 9) (IC 50 0.37 µM) [16], quaternized quinoa [4, 3, 2-kl] acridinium salts (Compound 10) (IC 50 0.38 µM) [17], and 3, 6, 9-trisubstituted acridine derivatives (Compound 11) (IC 50 0.018 µM) have been reported [18] and showed best telomerase inhibitor activity.…”

“…Wheelhouse et al [24] reported cationic porphyrins, and among them, they found one of the Compound 23 (TMPyP4- [5,[10][11][12][13][14][15]20-tetra-(-N-Methyl-4-pyridyl)] porphine) as it stabilizes and stacked with G-Quadruplex DNA and inhibits telomerase enzyme with an IC 50 value of 6.5±1.4 µM. Analogs of TMPyP4 (e.g., Compound 24 -IC 50 5 µM) have been reported and found as the positively charged substituent's on meso positions, and the size of substitution are important, and the face of porphyrins should be available for stacking [25].…”