Zhengchao Tu

Design, synthesis, and in vitro biological evaluation of 1H-1,2,3-triazole-4-carboxamide derivatives as new anti-influenza A agents targeting virus nucleoprotein.

The influenza virus nucleoprotein (NP) is an emerging target for anti-influenza drug development. Nucleozin (1) and its closely related derivatives had been identified as NP inhibitors displaying anti-influenza activity. Utilizing 1 as a lead molecule, we successfully designed and synthesized a series of 1H-1,2,3-triazole-4-carboxamide derivatives as new anti-influenza A agents. One of the most potent compounds, 3b, inhibited the replication of various H3N2 and H1N1 influenza A virus strains with IC(50) values ranging from 0.5 to 4.6 μM. Compound 3b also strongly inhibited the replication of H5N1 (RG14), amantidine-resistant A/WSN/33 (H1N1), and oseltamivir-resistant A/WSN/1933 (H1N1, 274Y) virus strains with IC(50) values in sub-μM ranges. Further computational studies and mechanism investigation suggested that 3b might directly target influenza virus A nucleoprotein to inhibit its nuclear accumulation.

Design, Synthesis, and Biological Evaluation of Novel Conformationally Constrained Inhibitors Targeting Epidermal Growth Factor Receptor Threonine790 → Methionine790 Mutant

The EGFR(T790M) mutant contributes approximately 50% to clinically acquired resistance against gefitinib or erlotinib. However, almost all the single agent clinical trials of the second generation irreversible EGFR inhibitors appear inadequate to overcome the EGFR(T790M)-related resistance. We have designed and synthesized a series of 2-oxo-3,4-dihydropyrimido[4,5-d]pyrimidinyl derivatives as novel EGFR inhibitors. The most potent compounds, 2q and 2s, inhibited the enzymatic activities of wild-type and mutated EGFRs, with IC(50) values in subnanomolar ranges, including the T790M mutants. The kinase inhibitory efficiencies of the compounds were further validated by Western blot analysis of the activation of EGFR and downstream signaling in cancer cells harboring different mutants of EGFR. The compounds also strongly inhibited the proliferation of H1975 non small cell lung cancer cells bearing EGFR(L858R/T790M), while being significantly less toxic to normal cells. Moreover, 2s displayed promising anticancer efficacy in a human NSCLC (H1975) xenograft nude mouse model.

Asperterrestide A, a Cytotoxic Cyclic Tetrapeptide from the Marine-Derived Fungus Aspergillus terreus SCSGAF0162

A new cytotoxic and antiviral cyclic tetrapeptide, asperterrestide A (1), a new alkaloid, terremide C (2), and a new aromatic butenolide, aspernolide E (3), together with 10 known compounds were isolated from the fermentation broth of the marine-derived fungus Aspergillus terreus SCSGAF0162. Their structures were elucidated by spectroscopic analysis, and the absolute configuration of 1 was determined by the Mosher ester technique and analysis of the acid hydrolysates using a chiral-phase HPLC column. Compound 1 contains a rare 3-OH-N-CH3-Phe residue and showed cytotoxicity against U937 and MOLT4 human carcinoma cell lines and inhibitory effects on influenza virus strains H1N1 and H3N2.

Discovery and Optimization of 3-(2-(Pyrazolo[1,5-a]pyrimidin-6-yl)ethynyl)benzamides as Novel Selective and Orally Bioavailable Discoidin Domain Receptor 1 (DDR1) Inhibitors

Discoidin domain receptor 1 (DDR1) is an emerging potential molecular target for new anticancer drug discovery. We have discovered a series of 3-(2-(pyrazolo[1,5-a]pyrimidin-6-yl) ethynyl)benzamides that are selective and orally bioavailable DDR1 inhibitors. The two most promising compounds (7rh and 7rj) inhibited the enzymatic activity of DDR1, with IC50 values of 6.8 and 7.0 nM, respectively, but were significantly less potent in suppressing the kinase activities of DDR2, Bcr-Abl, and c-Kit. Further study revealed that 7rh bound with DDR1 with a Kd value of 0.6 nM, while it was significantly less potent to the other 455 kinases tested. The S(35) and S(10) selectivity scores of 7rh were 0.035 and 0.008, respectively. The compounds also potently inhibited the proliferation of cancer cells expressing high levels of DDR1 and strongly suppressed cancer cell invasion, adhesion, and tumorigenicity. Preliminary pharmacokinetic studies suggested that they possessed good PK profiles, with oral bioavailabilities of 67.4% and 56.2%, respectively.

Discovery of pteridin-7(8H)-one-based irreversible inhibitors targeting the epidermal growth factor receptor (EGFR) kinase T790M/L858R mutant.

The EGFR T790M variant is an important mutation, resulting in approximately 50% of the clinically acquired resistance to approved EGFR inhibitors. Starting with a previously reported pyrimidine-based EGFR inhibitor, a novel pteridin-7(8H)-one scaffold with a high 3D similarity was found and transformed into irreversible inhibitors of the EGFR T790M mutant. The most potent compounds, 3q and 3x, exhibited excellent enzyme inhibitory activities, with subnanomolar IC50 values for both the wild-type and T790M/L858R double mutant EGFRs, as well as potent cellular antiproliferative activities against both gefitinib-sensitive and -resistant cancer cell lines. The in vivo antitumor efficacy study demonstrated that compound 3x significantly inhibited tumor growth and induced tumor stasis in an EGFR-T790M/L858R-driven human nonsmall-cell lung cancer xenograft mouse model. This work demonstrated the utility of this sophisticated computational design strategy for fast 3D scaffold hopping with competitive bioactivities to meet an important clinical need.

Antiviral Merosesquiterpenoids Produced by the Antarctic Fungus Aspergillus ochraceopetaliformis SCSIO 05702

Five new highly oxygenated α-pyrone merosesquiterpenoids, ochraceopones A-E (1-5), together with one new double bond isomer of asteltoxin, isoasteltoxin (6), and two known asteltoxin derivatives, asteltoxin (7) and asteltoxin B (8), were isolated from an Antarctic soil-derived fungus, Aspergillus ochraceopetaliformis SCSIO 05702. Their structures were determined through extensive spectroscopic analysis, CD spectra, quantum mechanical calculations, and X-ray single-crystal diffraction. Ochraceopones A-D (1-4) are the first examples of α-pyrone merosesquiterpenoids possessing a linear tetracyclic carbon skeleton, which has not been previously described. All the isolated compounds were tested for their antiviral, cytotoxic, antibacterial, and antitubercular activities. Among these compounds, ochraceopone A (1), isoasteltoxin (6), and asteltoxin (7) exhibited antiviral activities against the H1N1 and H3N2 influenza viruses with IC50 values of >20.0/12.2 ± 4.10, 0.23 ± 0.05/0.66 ± 0.09, and 0.54 ± 0.06/0.84 ± 0.02 μM, respectively. A possible biosynthetic pathway for ochraceopones A-E (1-5) was proposed.

Design and synthesis of pinanamine derivatives as anti-influenza A M2 ion channel inhibitors.

The adamantanes are a class of anti-influenza drugs that inhibit the M2 ion channel of the influenza A virus. However recently, the clinical effectiveness of these drugs has been called into question due to the emergence of adamantane-insensitive A/M2 mutants. Although we previously reported (1R,2R,3R,5S)-3-pinanamine 3 as a novel inhibitor of the wild type influenza A virus M2 protein (WT A/M2), limited inhibition was found for adamantane-resistant M2 mutants. In this study, we explored whether newly synthesized pinanamine derivatives were capable of inhibiting WT A/M2 and selected adamantane-resistant M2 mutants. Several imidazole and guanazole derivatives of pinanamine were found to inhibit WT A/M2 to a comparable degree as amantadine and one of these compounds 12 exhibits weak inhibition of A/M2-S31N mutant and it is marginally more effective in inhibiting S31NM2 than amantadine. This study provides a new insight into the structural nature of drugs required to inhibit WT A/M2 and its mutants.

Alkaloids from the Deep-Sea-Derived Fungus Aspergillus westerdijkiae DFFSCS013

Two new benzodiazepine alkaloids, circumdatins K and L (1, 2), two new prenylated indole alkaloids, 5-chlorosclerotiamide (3) and 10-epi-sclerotiamide (4), and one novel amide, aspergilliamide B (5), together with six known alkaloids were isolated from the deep-sea-derived fungus Aspergillus westerdijkiae DFFSCS013. Their structures were elucidated by extensive spectroscopic analysis. All of the compounds were tested for cytotoxicity toward human carcinoma A549, HL-60, K562, and MCF-7 cell lines.

Discovery of Benzo[cd]indol-2(1H)-ones as Potent and Specific BET Bromodomain Inhibitors: Structure-Based Virtual Screening, Optimization, and Biological Evaluation

The discovery of inhibitors of bromodomain and extra terminal domain (BET) has achieved great progress, and at least seven inhibitors have progressed into clinical trials for the treatment of cancer or inflammatory diseases. Here, we describe the identification, optimization, and evaluation of benzo[cd]indol-2(1H)-one containing compounds as a new class of BET bromodomain inhibitors, starting from structure-based virtual screening (SBVS). Through structure-based optimization, potent compounds were obtained with significantly improved activity. The two most potent compounds bind to the BRD4 bromodomain, with Kd values of 124 and 137 nM. Selected compounds exhibited high selectivity over other non-BET subfamily members. Notably, compound 85 demonstrated a reasonable antiproliferation effect on MV4;11 leukemia cells and exhibited a good pharmacokinetic profile with high oral bioavailability (75.8%) and moderate half-life (T1/2 = 3.95 h). The resulting lead molecule 85 represents a new, potent, and selective class of BET bromodomain inhibitors for the development of therapeutics to treat cancer and inflammatory diseases.

Identification of GZD824 as an orally bioavailable inhibitor that targets phosphorylated and nonphosphorylated breakpoint cluster region-Abelson (Bcr-Abl) kinase and overcomes clinically acquired mutation-induced resistance against imatinib.

Bcr-Abl(T315I) mutation-induced imatinib resistance remains a major challenge for clinical management of chronic myelogenous leukemia (CML). Herein, we report GZD824 (10a) as a novel orally bioavailable inhibitor against a broad spectrum of Bcr-Abl mutants including T315I. It tightly bound to Bcr-Abl(WT) and Bcr-Abl(T315I) with K(d) values of 0.32 and 0.71 nM, respectively, and strongly inhibited the kinase functions with nanomolar IC(50) values. The compound potently suppressed proliferation of Bcr-Abl-positive K562 and Ku812 human CML cells with IC(50) values of 0.2 and 0.13 nM, respectively. It also displayed good oral bioavailability (48.7%), a reasonable half-life (10.6 h), and promising in vivo antitumor efficacy. It induced tumor regression in mouse xenograft tumor models driven by Bcr-Abl(WT) or the mutants and significantly improved the survival of mice bearing an allograft leukemia model with Ba/F3 cells harboring Bcr-Abl(T315I). GZD824 represents a promising lead candidate for development of Bcr-Abl inhibitors to overcome acquired imatinib resistance.