Design and synthesis of 4-amino-2-phenylquinazolines as novel topoisomerase I inhibitors with molecular modeling.

4-Amino-2-phenylquinazolines 7 were designed as bioisosteres of 3-arylisoquinolinamines 6 that were energy minimized to provide stable conformers. Interestingly, the 2-phenyl ring of 4-amino-2-phenylquinazolines was parallel to the quinazoline ring and improved their DNA intercalation ability in the DNA-topo I complex. Among the synthesized 4-amino group-substituted analogs, 4-cyclohexylamino-2-phenylquinazoline 7h exhibited potent topo I inhibitory activity and strong cytotoxicity. Interestingly, consistency was observed between the cytotoxicities and topo I activities in these quinazoline analogs, suggesting that the target of 4-amino-2-phenylquinazolines is limited to topo I. Molecular docking studies were performed with the Surflex-Dock program to afford the ideal interaction mode of the compound into the binding site of the DNA-topo I complex in order to clarify the topo I activity of 7h.

Design, synthesis and docking study of 5-amino substituted indeno[1,2-c]isoquinolines as novel topoisomerase I inhibitors.

Various 5-amino group-substituted indeno[1,2-c]isoquinolines 7a-f were synthesized based on the previous QSAR study as rigid structures of 3-arylisoquinolines. Amino group-substituted compounds, especially 5-piperazinyl indeno[1,2-c]isoquinoline 7f, displayed potent topoisomerase I inhibitory activity as well as cytotoxicities against five different tumor cell lines. A Surflex-Dock docking model of 7f was also studied.

Synthesis of benzo[3,4]azepino[1,2-b]isoquinolin-9-ones from 3-arylisoquinolines via ring closing metathesis and evaluation of topoisomerase I inhibitory activity, cytotoxicity and docking study.

Benzo[3,4]azepino[1,2-b]isoquinolinones were designed and developed as constraint forms of 3-arylisquinolines with an aim to inhibit topoisomerase I (topo I). Ring closing metathesis (RCM) of 3-arylisoquinolines with suitable diene moiety provided seven membered azepine rings of benzoazepinoisoquinolinones. Spectral analyses of these heterocyclic compounds demonstrated that the methylene protons of the azepine rings are nonequivalent. The shielding environment experienced by these geminal hydrogens differs unusually by 2.21ppm. As expected, benzoazepinoisoquinolinones displayed potent cytotoxicity. However, cytotoxic effects of the compounds were not related to topo I inhibition which is explained by non-planar conformation of the rigid compounds incapable of intercalating between DNA base pairs. In contrast, flexible 3-arylisoquinoline 8d attains active conformation at drug target site to exhibit topo I inhibition identical to cytotoxic alkaloid, camptothecin (CPT).

Application of ring-closing metathesis for the synthesis of benzo[3,4]azepino[1,2-b]isoquinolin-9-ones.

Cycloaddition reaction between toluamides and benzonitriles was applied to prepare the 3-arylisoquinolines, and their chemical transformation to the dienes 4 was performed. The ring-closing metathesis (RCM) reaction afforded the desired heterocyclic compounds, benzo[3,4]azepino[1,2-b]isoquinolinones 5 in good yield.

Synthesis, in vitro and in vivo evaluation of 3-arylisoquinolinamines as potent antitumor agents.

In the search for potent water-soluble 3-arylisoquinolines, several 3-arylisoquinolinamines were designed and synthesized. Various substituted 3-arylisoquinolinamines exhibited strong cytotoxic activity against eight different human cancer cell lines. In particular, C-6 or C-7 dimethylamino-substituted 3-arylisoquinolinamines displayed stronger potency than the lead compound 7a. Interestingly, compounds 7b and 7c showed more effective activity against paclitaxel-resistant HCT-15 human colorectal cancer cell lines when compared to the original cytotoxic cancer drug, paclitaxel. We analyzed the cell cycle dynamics by flow cytometry and found that treatment of human HCT-15 cells with 3-arylisoquinolinamine 7b blocked or delayed the progression of cells from G0/G1 phase into S phase, and induced cell death. Treatment with compound 7b also significantly inhibited the growth of tumors and enhanced tumor regression in a paclitaxel-resistant HCT-15 xenograft model.

Structural modification of 3-arylisoquinolines to isoindolo[2,1-b]isoquinolinones for the development of novel topoisomerase 1 inhibitors with molecular docking study.

Isoindolo[2,1-b]isoquinolinones 9a-i were designed and synthesized as constrained forms of 3-arylisoquinolines through an intramolecular cyclization reaction. Among the synthesized compounds, 9d exhibited potent topoisomerase 1 inhibitory activity with cytotoxicities against three different tumor cell lines. A Surflex-dock docking study was performed to clarify the topoisomerase 1 inhibitory activity of 9d.

Molecular design, synthesis and docking study of benz[b]oxepines and 12-oxobenzo[c]phenanthridinones as topoisomerase 1 inhibitors.

Benz[b]oxepines 4a-g and 12-oxobenzo[c]phenanthridines 5a-d were designed and synthesized as constrained forms of 3-arylisoquinolines through an intramolecular radical cyclization reaction. Radical cyclization of O-vinyl compounds preferentially led to the 7-endo-trig cyclization pathway to the benz[b]oxepines and 12-oxobenzo[c]phenanthridines through 6-exo-trig path as minor products. Among the synthesized compounds, benz[b]oxepine derivative 4e exhibited potent in vitro cytotoxicity against three different tumor cell lines, as well as topoisomerase 1 inhibitory activity. A Surflex-Dock docking study was performed to clarify the topoisomerase 1 activity of 4e.

Application of coupling reaction between lithiated toluamide and benzonitrile for the synthesis of phenolic benzo[c]phenanthridine alkaloid, oxyterihanine.

The total synthesis of the natural phenolic benzo[c]phenanthridine alkaloid, oxyterihanine, was accomplished via substituted 3-arylisoquinoline intermediate. The key reaction was a coupling between the o-toluamide 4 and the benzonitrile 5.

Substituted 2-arylquinazolinones: Design, synthesis, and evaluation of cytotoxicity and inhibition of topoisomerases.

A series of 2-arylquinazolinones with structural homology to known 3-arylisoquinolines were designed and synthesized in order to develop safe, effective, and selective cytotoxic agents targeting topoisomerases (topos). 2-Arylquinzolinones with various substitutions on the aromatic rings were obtained by thermal cyclodehydration/dehydrogenation on reacting anthranilamides and benzaldehydes. The compounds had superior topo I-inhibitory activities but were generally inactive against topo IIα. Among the 6-methyl-, 6-amino-, and 7-methylquinazolinones, 6-amino-substituted derivatives displayed potent cytotoxicity at submicromolar to nanomolar concentrations against human colorectal adenocarcinoma cells (HCT-15), human ductal breast epithelial tumor cells (T47D), and cervical cancer cells (HeLa). There was a good correlation between topo I inhibition and the cytotoxic effects of 6-aminoquinazolinones. Docking models demonstrated that topo I inhibition by these compounds is owing to intercalation and H-bond interactions with the DNA bases and amino acid residues at the enzymatic site.

SAR based design of nicotinamides as a novel class of androgen receptor antagonists for prostate cancer.

Molecular knowledge of pure antagonism and systematic SAR study offered a direction for structural optimization of DIMN to provide nicotinamides as a novel series of AR antagonists. Nicotinamides with extended linear scaffold bearing sterically bulky alkoxy groups on isoquinoline end were synthesized for H12 displacement. AR binding affinity and molecular basis of antiandrogenic effect establish the optimized derivatives, 7au and 7bb, as promising candidates of second generation AR antagonists for advanced prostate cancer.

Development of 3-aryl-1-isoquinolinamines as potent antitumor agents based on CoMFA.

Various substituted 3-aryl-1-isoquinolinamines were designed and synthesized based on the previously constructed CoMFA model. Most of the synthesized compounds showed excellent potency in eight different human tumor cell lines as expected. In order to find the exact cytotoxic mechanism of these 3-aryl-1-isoquinolinamines, we analyzed the cell cycle dynamics by flow cytometry and found that 3-aryl-1-isoquinolinamine 6k-treated HeLa cells were arrested in G2/M phase, which is related to apoptosis.

Convenient synthesis of indeno[1,2-c]isoquinolines as constrained forms of 3-arylisoquinolines and docking study of a topoisomerase I inhibitor into DNA-topoisomerase I complex.

11-hydroxyindeno[1,2-c]isoquinolines 12a-c were prepared as constrained forms of 3-arylisoquinolines through an intramolecular cyclization reaction. Among the synthesized compounds, the 11-(i)butoxy analog 15l displayed potent in vitro cytotoxicity against four different tumor cell lines as well as topoisomerase 1 inhibitory activity. A FlexX docking study was performed to explain the topoisomerase 1 activity of 15l.