Synthesis and biological evaluations of novel indenoisoquinolines as topoisomerase I inhibitors

A series of novel indenoisoquinoline derivatives were synthesized. The anticancer activities of these molecules were tested in human cancer cell lines A549, HepG2, and HCT-116. These compounds were also tested for their activity of topoisomerase I (top1) inhibition. Among them, compound 25 was found to be 10-times more potent in cell-killing activity for both cell lines HepG2 and HCT-116 than reported compound 11, with IC(50) of 0.019 and 0.093μM, respectively. Compound 25 was also found to have stronger top1 inhibition activity than 11 in our inhibition assay. Further in vivo evaluations of compound 25 are in progress and will be reported in due course.     

Synthesis and biological evaluation of naphthoquinone-coumarin conjugates as topoisomerase II inhibitors

Based on previous Topoisomerase II docking studies of naphthoquinone derivatives, a series of naphthoquinone-coumarin conjugates was synthesized through a multicomponent reaction from aromatic aldehydes, 4-hydroxycoumarin and 2-hydroxynaphthoquinone. The hybrid structures were evaluated against the α isoform of human topoisomerase II (hTopoIIα), Escherichia coli DNA Gyrase and E. coli Topoisomerase I. All tested compounds inhibited the hTopoIIα-mediated relaxation of negatively supercoiled circular DNA in the low micromolar range. This inhibition was specific since neither DNA Gyrase nor Topoisomerase I were affected. Cleavage assays pointed out that naphthoquinone-coumarins act by catalytically inhibiting hTopoIIα. ATPase assays and molecular docking studies further pointed out that the mode of action is related to the hTopoIIα ATP-binding site.     

Synthesis and biological evaluation of novel carbazole-rhodanine conjugates as topoisomerase II inhibitors

In this study, a series of carbazole-rhodanine conjugates was synthesized and evaluated for their Topoisomerase II inhibition potency as well as cytotoxicity against a panel of four human cancer cell lines. Among these thirteen compounds, 3a, 3b, 3g, and 3h possessed Topoisomerase II inhibition potency at 20?μM. Mechanism study revealed that these compounds may function as Topo II catalytic inhibitors. It was found that the electron-withdrawing groups on the phenyl ring of compounds played an important role on enhancing both enzyme inhibition and cytotoxicity.     

Synthesis and biological evaluation of modified pentapeptides as potent proteinase K inhibitors

This communication reports the first demonstration of synthesis and biological validation of modified pentapeptides, such as methoxysuccinyl-Ala-Ala-Ala-Pro-Leu-chloromethyl ketone 6b as a potent proteinase K inhibitor. The efficacy of MeOSuc-AAAPL-CH₂Cl 6b analog in inhibiting the proteolytic activity of proteinase K was compared with the known MeOSuc-AAPV-CH₂Cl analog. The examination of inhibitory activity using RT-PCR assay in the presence of proteinase K revealed that the MeOSuc-AAAPL-CH₂Cl 6b inhibitor at a concentration of 0.05 mM allows a signal to be obtained for an exogenous target (‘Xeno RNA’) at 30 cycles (i.e., Ct = 30), whereas the control MeOSuc-AAPV-CH₂Cl requires a fivefold higher concentration (0.25 mM) to produce the same Ct. A plausible explanation for the higher efficiency of MeOSuc-AAAPL-CH₂Cl 6b over control is proposed based on the molecular modeling studies.     

Synthesis and biological evaluation of N-(7-indazolyl)benzenesulfonamide derivatives as potent cell cycle inhibitors

We herein describe a new synthesis of N-(7-indazolyl)benzenesulfonamide derivatives. These compounds were evaluated for their antiproliferative activities toward L1210 murine leukemia cells. One of them, 4-methoxy-N-(3-chloro-7-indazolyl)benzenesulfonamide, was identified as the most potent with an IC(50) of 0.44 microM.     

Synthesis and biological evaluation of novel indole-pyrazoline hybrid derivatives as potential topoisomerase 1 inhibitors

A series of novel indole-pyrazoline hybrid derivatives were designed, synthesized, and evaluated for topoisomerase 1 (Top1) inhibitory activity. Top1-mediated relaxation assays showed that our synthesized compounds had variable Top1 inhibitory activity. Among these compounds, 3-(5-(naphthalen-1-yl)-1-phenyl-4,5-dihydro-1H-pyrazol-3-yl)-1-(phenylsulfonyl)-1H-indole (6n) was found to be a strong Top1 inhibitor with better inhibitory activity than CPT and hit compounds. Our further experiments rationalized the mode of action for this new type of inhibitors, which showed no significant binding to supercoiled DNA.     

Synthesis of nitrated indenoisoquinolines as topoisomerase I inhibitors

Indenoisoquinolines and dihydroindenoisoquinolines have been synthesized possessing a nitro-substituted isoquinoline ring in an effort to explore the effects of electron-withdrawing substituents on biological activity. The in vitro anticancer activities of these molecules have been tested in the National Cancer Institute's screen of 55 cell lines. The compounds have also been tested for topoisomerase I (top1) inhibition. The results indicate that these substances are a potent class of top1 inhibitors with sub-micromolar cytotoxicity mean graph midpoints (MGM) and top1 inhibition equal to camptothecin.     

Synthesis and biological evaluation of benzyl styrylsulfonyl derivatives as potent anticancer mitotic inhibitors

We herein report the synthesis, biological activity and structure activity relationship of derivatives of benzylstyrylsulfone, benzylstyrylsulfine and benzylsulfonyl-N-phenylacetamide. A lead compound 7 represents a new class of mitotic inhibitors that demonstrates potent anti-proliferative activity and selectively induces cancer cell apoptosis while sparing non-transformed lung fibroblast.     

Synthesis and biological evaluation of 1H-benzimidazol-5-ols as potent HBV inhibitors

A new series of 1-methyl-1H-benzimidazol-5-ol derivatives were synthesized and evaluated for their anti-hepatitis B virus (HBV) activity and cytotoxicity in the HepG2.2.15 cell line. Some of the analogues in this series displayed inhibitory activity superior to lamivudine. Of them, compound 13b was the most potent one, showing an IC(50) value of 7.8 μM and a SI value of 13.0.     

Synthesis and evaluation of pyrido-thieno-pyrimidines as potent and selective Cdc7 kinase inhibitors

Cdc7 kinase plays a critical role in the regulation of DNA replication in eukaryotic cells and has been proposed as a target for cancer therapy. We have identified a class of Cdc7/Dbf4 inhibitors with a pyrido-thieno-pyrimidine core structure. Synthesis of a focused pyrido-thieno-pyrimidine library yielded potent and selective Cdc7 inhibitors with antiproliferative activity against cancer cells in vitro. Their synthesis and SAR data are presented herein.     

Synthesis and biological evaluation of thiazole derivatives as novel USP7 inhibitors

Herpesvirus-associated Ubiquitin-Specific Protease (HAUSP, also called USP7) interacts with and stabilizes Mdm2, and represents one of the first examples that deubiquitinases oncogenic proteins. USP7 has been regarded as a potential drug target for cancer therapy. Inhibitors of USP7 have been recently shown to suppress tumor cell growth in vitro and in vivo. Based on leading USP7 inhibitors P5091 and P22077, we designed and synthesized a series of thiazole derivatives. The results of in vitro assays showed that the thiazole compounds exhibited low micromolar inhibition activity against both USP7 enzyme and cancer cell lines. The compounds induced cell death in a p53-dependent and p53-independent manner. Taken together, this study may provide thiazole compounds as a new class of USP7 inhibitors.     

Synthesis and biological evaluation of histone deacetylase and DNA topoisomerase II-Targeted inhibitors

HDAC inhibitors enable histones to maintain a high degree of acetylation. The resulting looser state of chromatin DNA may increase the accessibility of DNA drug targets and consequently improve the efficiency of anticancer drugs targeting DNA, such as Topo II inhibitors. A novel class of nucleoside-SAHA derivatives has been designed and synthesized based on the synergistic antitumor effects of topoisomerase II and histone deacetylase inhibitors. Their inhibitory activities toward histone deacetylases and Topo II, and their cytotoxicities in cancer cell lines, were evaluated. Among the synthesized hybrid compounds, compound 16b showed the potent HDAC inhibitory activity at a low nanomolar level and exhibited antiproliferative activity toward cancer cell lines including MCF-7 (breast), HCT-116 (colon), and DU-145 (prostate) cancer cells at a low micromolar level. Moreover, compound 16a showed HDAC6-selectivity 20-fold over HDAC1.     

Design,synthesis and biological evaluation of lapachol derivatives possessing indole scaffolds as topoisomerase I inhibitors

A series of novel lapachol derivatives possessing indole scaffolds was designed and synthesized. The in vitro anti-proliferative activity of these novel compounds was evaluated in Eca109 and Hela cell lines. Almost all the tested compounds showed manifested potent inhibitory activity against the two tested cancer cell lines. Topo I-mediated DNA relaxation activity indicated that these novel compounds have potent Topoisomerase I inhibition activity. The most potent compounds 4n and 4k demonstrated more cytotoxicity than camptothecin and was comparable to camptothecin in inhibitory activities on Topoisomerase I in our biological assay. In addition, the Hoechst 33342 staining method also showed that the complex can induce Hela cell apoptosis.     

Synthesis and biological evaluation of novel azole derivatives as selective potent inhibitors of brassinosteroid biosynthesis

Brassinosteroids (BRs) are phytohormones that control several important agronomic traits, such as flowering, plant architecture, seed yield, and stress tolerance. To manipulate the BR levels in plant tissues using specific inhibitors of BR biosynthesis, a series of novel azole derivatives were synthesized and their inhibitory activity on BR biosynthesis was investigated. Structure–activity relationship studies revealed that 2RS, 4RS-1-[4-(2-allyloxyphenoxymethyl)-2-(4-chlorophenyl)-[1,3]dioxolan-2-ylmethyl]-1H-[1,2,4]triazole (G₂) is a highly selective inhibitor of BR biosynthesis, with an IC₅₀ value of approximately 46 ± 2 nM, which is the most potent BR biosynthesis inhibitor observed to date. Use of gibberellin (GA) biosynthesis mutants and BR signaling mutants to analyze the mechanism of action of this synthetic series indicated that the primary site of action is BR biosynthesis. Experiments feeding BR biosynthesis intermediates to chemically treated Arabidopsis seedlings suggested that the target sites of this synthetic series are CYP90s, which are responsible for the C-22 and/or C-23 hydroxylation of campesterol.     

Synthesis,biological evaluation,and molecular modeling of berberine derivatives as potent acetylcholinesterase inhibitors

By targeting the dual active sites of acetylcholinesterase (AChE), a new series of berberine derivatives was designed, synthesized, and evaluated as AChE inhibitors. Most of the derivatives inhibited AChE in the sub-micromolar range. Compound 8c, berberine linked with phenol by a 4-carbon spacer, showed the most potent inhibition of AChE. A kinetic study of AChE and BuChE indicated that a mix-competitive binding mode existed for these berberine derivatives. Molecular modeling studies confirmed that these hybrids target both the catalytic active site (CAS) and the peripheral anionic site (PAS) of AChE. This is the first report where AChE inhibitory activity has been associated with berberine as a lead molecule.     

Synthesis and biological evaluation of substituted 6-alkynyl-4-anilinoquinazoline derivatives as potent EGFR inhibitors

A series of C-6 or C-3' alkynyl-substituted 4-anilinoquinazoline derivatives was prepared straightforwardly by a Sonogashira reaction of the corresponding bromo-substituted 4-anilinoquinazolines. Bioactive assay of these compounds for in vitro EGFR kinase inhibition demonstrated that the novel 6-hydroxypropynyl-4-anilinoquinazoline 5e was a very potent EGFR kinase inhibitor with an IC(50) of 14 nM.     

Synthesis and identification of quinoline derivatives as topoisomerase I inhibitors with potent antipsoriasis activity in an animal model

Psoriasis is a chronic inflammatory and immune-mediated skin disease. Although certain agents have shown clinical success in treating psoriasis, development of safe and effective strategies for the treatment of this condition remains important. Research suggests that DNA topoisomerase I (Topo I) inhibitors may have potent psoriasis-ameliorating effects. Here, 25 quinoline derivatives were synthesized and identified as Topo I inhibitors. These compounds inhibited the 12–O–tetradecanoylphorbol-13-acetate-induced mouse ear inflammation. The most potent analogs, 5i and 5l, suppressed the expression of inflammatory cytokines in lipopolysaccharide-stimulated HaCaT cells. Additionally, the lead compounds significantly improved imiquimod-induced psoriasis-like inflammation in mice. Moreover, the expression levels of cytokines and inflammatory mediators, such as interleukin (IL)-17A, IL-22, IL-23, nuclear factor-κB subunit p65, tumor necrosis factor-α, and interferon-γ, were dramatically inhibited in the dorsal skin of 5i- and 5l-treated mice. These findings indicate that the inhibition of Topo I activity may potentially be an effective strategy for psoriasis treatment.     

Synthesis,molecular docking and biological evaluation of some benzimidazole derivatives as potent pancreatic lipase inhibitors

In this study, a new series of benzimidazole and bisbenzimidazole derivatives were prepared via the reaction of iminoester hydrochlorides and o-phenylenediamines and then screened for their lipase inhibition properties. Among the synthesized molecules, compounds 7a, 8a and 8c showed the best inhibitory effect against lipase enzyme with IC₅₀ values of 1.72 ± 0.12 µM, 1.92 ± 0.28 and 0.98 ± 0.07 µM, respectively. Moreover, molecular modeling studies were performed in order to understand to the inhibitory activity of the molecules. Binding poses of the studied compounds were determined at the target sites using induced fit docking (IFD) algorithms.     

Synthesis and biological evaluation of 3-aryl-4-indolyl-maleimides as potent mutant isocitrate dehydrogenase-1 inhibitors

A series of 3-aryl-4-indolylmaleimide IDH1/R132H inhibitors with a novel structure was obtained by high-throughput screening and structure-based optimization. Most compounds such as 7a, 7d, 7h, 7i, 7k and 7o showed high inhibitory effects on IDH1/R132H and were highly selective against IDH1/WT, IDH2/WT, GDH, GK, and FBP. Evaluation of the biological activities and function at cellular level showed that compounds 7h, 7i and 7k could effectively suppress the production of 2-hydroxyglutaric acid in U87MG cells expressing IDH1/R132H. Additionally, 7h could reversed the differentiation block of the myeloid leukemic cell line, TF-1, caused by the overexpression of IDH1/R132H. We also explore the structure-activity relationship based on the experimental data, with an attempt to pave the way for future studies.     

Synthesis and biological evaluation of new fluorinated and chlorinated indenoisoquinoline topoisomerase I poisons

Fluorine and chlorine are metabolically stable, but generally less active replacements for a nitro group at the 3-position of indenoisoquinoline topoisomerase IB (Top1) poisons. A number of strategies were employed in the present investigation to enhance the Top1 inhibitory potencies and cancer cell growth inhibitory activities of halogenated indenoisoquinolines. In several cases, the new compounds’ activities were found to rival or surpass those of similarly substituted 3-nitroindenoisoquinolines, and several unusually potent analogs were discovered through testing in human cancer cell cultures. A hydroxyethylaminopropyl side chain on the lactam nitrogen of two halogenated indenoisoquinoline Top1 inhibitors was found to also impart inhibitory activity against tyrosyl DNA phosphodiesterases 1 and 2 (TDP1 and TDP2), which are enzymes that participate in the repair of DNA damage induced by Top1 poisons.