A Mini Review of Novel Topoisomerase II Inhibitors as Future Anticancer Agents.

Several reviews of inhibitors of topoisomerase II have been published, covering research before 2018. Therefore, this review is focused primarily on more recent publications with relevant points from the earlier literature. Topoisomerase II is an established target for anticancer drugs, which are further subdivided into poisons and catalytic inhibitors. While most of the topoisomerase II-based drugs in clinical use are mostly topoisomerase II poisons, their mechanism of action has posed severe concern due to DNA damaging potential, including the development of multi-drug resistance. As a result, we are beginning to see a gradual paradigm shift towards non-DNA damaging agents, such as the lesser studied topoisomerase II catalytic inhibitors. In addition, this review describes some novel selective catalytic topoisomerase II inhibitors. The ultimate goal is to bring researchers up to speed by curating and delineating new scaffolds as the leads for the optimization and development of new potent, safe, and selective agents for the treatment of cancer.

Synthesis, biological evaluation and virtual screening of some acridone derivatives as potential anticancer agents.

Eleven novel acridone derivatives were synthesized and evaluated for their anticancer activity against 60 human cancer cell lines. Five compounds 8b, 8d, 8g, 8h, and 8k displayed very good in vitro antiproliferative activities well over 95% of the panels. The most active compound is 8k (5, 7-dibromo-3-phenyl-3,4-dihydroacridin-1 (2H)-one). In addition, 8k was the most sensitive agent in all 9 panels starting with prostate (0.075 µm), leukemia (0.116 µm), non-small cell lung cancer (0.164 µm), colon cancer (0.193 µm), CNS cancer (0.264 µm), melanoma (0.317 µm), renal cancer (0.403 µm), ovarian cancer (0.410 µm), and breast cancer (0.608 µm). Virtual screening studies also revealed that nine of the eleven compounds formed good binding interaction with the active site ATPase domain of human topoisomerase IIα (PDB: 1zxm). All nine derivatives exhibited binding affinities that ranged in values from -8.5 to -7.9 kcal/mol, indicating that they could be catalytic inhibitors of the nuclear enzyme, topoisomerase.

Design, synthesis and anticonvulsant evaluation of fluorinated benzyl amino enaminones.

Inspite of progress made for the discovery of novel antiepileptic drugs, epilepsy remains an unmet medical need. We synthesized nine trifluoromethylated enaminone derivatives and tested them for their anticonvulsant activity using maximal electroshock seizure (MES) test, subcutaneous pentylenetetrazole (scPTZ) test, and rotorod test for neurotoxicity. Among the compounds tested 3-(4-fluoro-3-(trifluomethyl)benzylamino)-5-(trifluoromethyl)cyclohex-2-enone (4f) showed ED50 of 23.47 mg/kg, when given orally to rats, 3-(4-chlorophenylamino)-5-(trifluoromethyl)cyclohex-2-enone (5a), which was previously reported by us but for which no quantitative data was available at the time, exhibited an ED50 of 62.39 mg/kg. Under the same conditions commercially available carbamazepine showed an ED50 of 28.20 mg/kg. There were no neurotoxicity observed upto a dose of 300 mg/kg for all the tested compounds. Compounds 4f and 5a represent good lead compounds for further development.

Novel trifluoromethylated 9-amino-3,4-dihydroacridin-1(2H)-ones act as covalent poisons of human topoisomerase IIα.

A number of topoisomerase II-targeted anticancer drugs, including amsacrine, utilize an acridine or related aromatic core as a scaffold. Therefore, to further explore the potential of acridine-related compounds to act as topoisomerase II poisons, we synthesized a series of novel trifluoromethylated 9-amino-3,4-dihydroacridin-1(2H)-one derivatives and examined their ability to enhance DNA cleavage mediated by human topoisomerase IIα. Derivatives containing a H, Cl, F, and Br at C7 enhanced enzyme-mediated double-stranded DNA cleavage ∼5.5- to 8.5-fold over baseline, but were less potent than amsacrine. The inclusion of an amino group at C9 was critical for activity. The compounds lost their activity against topoisomerase IIα in the presence of a reducing agent, displayed no activity against the catalytic core of topoisomerase IIα, and inhibited DNA cleavage when incubated with the enzyme prior to the addition of DNA. These findings strongly suggest that the compounds act as covalent, rather than interfacial, topoisomerase II poisons.

5,7-Dibromo-3-trifluoro-methyl-3,4-dihydro-acridin-1(2H)-one.

In the title compound, C(14)H(8)Br(2)F(3)NO, the mol-ecule is disordered across an approximate non-crystallographic mirror plane, which is in the plane of the fused ring system [The tetrahedral C atom bearing the trifluormethyl substituent is disordered with site occupancy factors of 0.80 (2) and 0.20 (2)]. In the crystal, a one-dimensional stacking of mol-ecules involves inter-actions between the pyridine ring and symmetry-related Br and O atoms of adjacent mol-ecules. The stacking distance between the mean planes of adjacent mol-ecules is 3.395 (4) Å.

CoMFA and CoMSIA studies on fluorinated hexahydropyrimidine derivatives.

3D-QSAR models of a series of fluorinated hexahydropyrimidine derivatives with cytotoxic activities have been developed using CoMFA and CoMSIA. These models provide a better understanding of the mechanism of action and structure-activity relationship of these compounds. By applying leave-one-out (LOO) cross validation study, the best predictive CoMFA model was achieved with 3 as the optimum number of components, which gave rise to a non-cross-validated r(2) value of 0.978, and standard error of estimate of 0.059, and F value of 144.492. Similarly, the best predictive CoMSIA model was derived with 4 as the number of components, r(2) value of 0.999, F value of 4381.143, and standard error of estimate, 0.011. The above models will inspire the design and synthesis of novel hexahydropyrimidines with enhanced potency and selectivity.

Synthesis and in vitro cytotoxicity evaluation of some fluorinated hexahydropyrimidine derivatives.

A series of trifluoromethylated hexahydropyrimidine and tetrahydropyrimidine derivatives were synthesized and their in vitro cytotoxic activities were determined in colon cancer cell line (COLO 320 HSR). Compounds 4f, 4g, 4k, 5, and 7 proved to be the most active in this series of compounds. They represent promising new leads for the development of highly potent and selective anticancer compounds. All the compounds are lipophilic due to the trifluoromethyl group, and are thus expected to penetrate the membrane in appreciable concentration.

Novel fluorinated acridone derivatives. Part 1: synthesis and evaluation as potential anticancer agents.

We report on the synthesis of a novel series of fluorinated acridones from 5-trifluoromethyl-1,3-cyclohexanedione. The cytotoxic activities of the compounds were studied in several cancer cells. Compounds 9a, 9c, 9e, 9f, and 9h exhibited significant anticancer activities in selected cell lines. Compound 9c is the most active showing GI(50) that ranged in values from 0.13 to 26 microM, covering a wide range of cancer cell lines.

Inhibitors of phenylethanolamine N-methyltransferase devoid of alpha2-adrenoceptor affinity.

A series of 3-trifluoromethyl-1,2,3,4-tetrahydroisoquinolines was synthesized and evaluated for their phenylethanolamine N-methyltransferase (PNMT) inhibitory potency and affinity for the alpha(2)-adrenoceptor. Although their PNMT inhibitory potency decreased compared with corresponding 3-methyl-, 3-hydroxymethyl- or 3-unsubstituted-THIQs, some of them showed good selectivity due to their extremely low alpha(2)-adrenoceptor affinity.