A Series of Novel Terpyridine-Skeleton Molecule Derivants Inhibit Tumor Growth and Metastasis by Targeting Topoisomerases

Abstract

A series of novel terpyridine-skeleton molecules containing conformational rigidity, 14 containing benzo[4,5]furo[3,2-b]pyridine core and 15 comprising chromeno[4,3-b]pyridine core, were synthesized, and their biological activities were evaluated. 3-(4-Phenylbenzo[4,5]furo[3,2-b]pyridin-2-yl)phenol (8) was determined to be a nonintercalative topo I and II dual catalytic inhibitor and 3-(4-phenylchromeno[4,3-b]pyridine-2-yl)phenol (22) was determined to be a nonintercalative topo IIα specific catalytic inhibitor by various assays. These two catalytic inhibitors induced apoptosis in addition to G1 arrest in T47D human breast cancer cells with much less DNA toxicity than etoposide. Compounds 8 and 22 significantly inhibited tumor growth in HCT15 subcutaneously implanted xenografted mice. The modification of compounds 8 and 22 with the introduction of a methoxy instead of a hydroxy group enhanced endogenous topo inhibitory activity, metabolic stability in diverse types of liver microsomes and improved pharmacokinetic parameters in rat plasma such as augmentation of bioavailability (41.3% and 33.2% for 2-(3-methoxyphenyl)-4-phenylbenzofuro[3,2-b]pyridine (8-M) and 3-(4-phenylchromeno[4,3-b]pyridine-2-yl)methoxybenzene (22-M), respectively).

Carbazole Aminoalcohols Induce Antiproliferation and Apoptosis of Human Tumor Cells by Inhibiting Topoisomerase I

“…1 Ha nd 13 CNMR spectra were recorded on aB ruker AM-400 spectrometer (400 MHz). Chemical shifts (d)a re given in ppm relative to TMS as internal standard, and signals are denoted with the following abbreviations:s ,s inglet; General procedures for the synthesis of carbazole aminoalcohols (3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18):T oas olution of 9-(oxiran-2-ylmethyl)-9H-carbazole (2a-c,2mmol) in EtOH (20 mL), corresponding amines (6 mmol) was added. For low reactive amines (e.g.,a rylamines), BiCl 3 (1 mmol) was also added.…”

“…In general, all test compounds exhibited moderate cytotoxicity,w ith IC 50 values in the micromolar range. The derivatives with aliphatic amino and benzylamino groups (3-7,a nd 15-18)w ere slightly more potent than those possessing aromatic amino groups (8)(9)(10)(11)(12)(13)(14)i n both cell lines. Amongt hem, alkylamine tails (in 5-7)w ere found to be the preferred substituents for cytotoxicity.…”

“…[6,7] Thus, the discoveryo fn ovel topo Ii nhibitors with dis-tinct scaffolds is an attractive drug development strategy for tumor treatment. [8][9][10] Carbazole is ap rominentc ore structure found in numerous natural and syntheticc ompounds with awide range of biological activities, including antimalarial, antineoplastic,a nd neuroprotectivee ffects. [11][12][13] In view of anticancer agents, many carbazoled erivatives have been shown to exhibit antitumora ctivity by targeting diverse enzymes or kinases.…”

Modified 2,4-diaryl-5H-indeno[1,2-b]pyridines with hydroxyl and chlorine moiety: Synthesis, anticancer activity, and structure–activity relationship study

“…DNA topo II inhibitory activity of compounds were measured as follows [21]. The mixture of Corp., USA) was incubated without and with the prepared compounds in the assay buffer (10 mM Tris-HCl (pH 7.9) containing 50 mM NaCl, 5 mM MgCl 2 , 1 mM EDTA, 1 mM ATP, and 15 μg/mL bovine serum albumin) for 30 min at 30 °C.…”

A Dual Topoisomerase Inhibitor of Intense Pro‐Apoptotic and Antileukemic Nature for Cancer Treatment

“…In this regard, the complete inhibition of topoisomerase activity in tumor cells was shown to be extremely effective in vitro and in vivo in ab road range of tumor types. [1,[14][15][16][17][18][19][20] Consequently,d ualt opo I/II inhibitors were evaluated in phase I/II clinicalt rials: pyrazoloacridine (PZA, 1), benzopyridoindole intoplicine (2), phenazine derivatives XR11576 (3)a nd XR5944( 4), batracylin (5), and the indenoquinolinone TAS-103( 6)( Figure 1), as well as the etoposide derivativet afluposide and the homocamptothecin elomotecan. [1,14,[21][22][23][24][25][26][27][28] Althoughp reclinical studies were very promising fort hese derivatives, their effectiveness could not be transferredt ot he clinic yet.…”