Soliseptide A, A Cyclic Hexapeptide Possessing Piperazic Acid Groups from <i>Streptomyces solisilvae</i> HNM30702

Soliseptide A (<b>1</b>), a cyclic hexapeptide possessing piperazic acid groups, together with two known azalomycin derivatives (<b>2</b> and <b>3</b>) were isolated from <i>Streptomyces solisilvae</i> HNM30702. Their structures were determined through spectroscopic methods and single crystal X-ray diffraction analysis. Soliseptide A (<b>1</b>) possessed a cyclic hexapeptide core featured with two piperazic acid units rarely discovered in nature, and exhibited weak antibacterial and antiviral activities. Besides, compounds <b>2</b> and <b>3</b> displayed significant fungicidal effects

Discovery of Novel Class I Histone Deacetylase Inhibitors with Promising in Vitro and in Vivo Antitumor Activities

A successful structure-based design of novel cyclic depsipeptides that selectively target class I HDAC isoforms is described. Compound <b>11</b> has an IC₅₀ of 2.78 nM for binding to the HDAC1 protein, and the prodrugs <b>12</b> and <b>13</b> also exhibit promising antiproliferative activities in the nanomolar range against various cancer cell lines. Compounds <b>12</b> and <b>13</b> show more than 20-fold selectivity toward human cancer cells over human normal cells in comparison with romidepsin (FK228), demonstrating low probability of toxic side effects. In addition, compound <b>13</b> exhibits excellent in vivo anticancer activities in a human prostate carcinoma (Du145) xenograft model with no observed toxicity. Thus, prodrug <b>13</b> has therapeutic potential as a new class of anticancer agent for further clinical translation

Discovery of Novel Class I Histone Deacetylase Inhibitors with Promising in Vitro and in Vivo Antitumor Activities

A successful structure-based design of novel cyclic depsipeptides that selectively target class I HDAC isoforms is described. Compound <b>11</b> has an IC₅₀ of 2.78 nM for binding to the HDAC1 protein, and the prodrugs <b>12</b> and <b>13</b> also exhibit promising antiproliferative activities in the nanomolar range against various cancer cell lines. Compounds <b>12</b> and <b>13</b> show more than 20-fold selectivity toward human cancer cells over human normal cells in comparison with romidepsin (FK228), demonstrating low probability of toxic side effects. In addition, compound <b>13</b> exhibits excellent in vivo anticancer activities in a human prostate carcinoma (Du145) xenograft model with no observed toxicity. Thus, prodrug <b>13</b> has therapeutic potential as a new class of anticancer agent for further clinical translation

Axinelline A, a new COX-2 inhibitor from <i>Streptomyces axinellae</i> SCSIO02208

<div><p>Axinelline A, a new cyclooxygenase-2 (COX-2) inhibitor, was isolated from <i>Streptomyces axinellae</i> SCSIO02208. The structures of compounds <b>1</b>–<b>9</b> were determined by analysing the NMR and MS data. The absolute configuration of <b>1</b> was determined by using optical rotation and comparing with the reported data. Compound <b>1</b> exhibited COX-2 inhibitory activity, the IC₅₀ value being 2.8 μM.</p></div

Discovery of Pteridin-7(8<i>H</i>)‑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(8<i>H</i>)-one scaffold with a high 3D similarity was found and transformed into irreversible inhibitors of the EGFR T790M mutant. The most potent compounds, <b>3q</b> and <b>3x</b>, 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 <b>3x</b> 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

Identification and Optimization of New Dual Inhibitors of B‑Raf and Epidermal Growth Factor Receptor Kinases for Overcoming Resistance against Vemurafenib

Epidermal growth factor receptor (EGFR) amplification has been demonstrated to be critical for the inherent and/or acquired resistance against current B-Raf^V600E inhibitor therapy for melanoma and colorectal cancer patients. We describe the discovery and structure–activity relationship study of a series of 1<i>H</i>-pyrazolo­[3,4-<i>b</i>]­pyridine-5-carboxamide analogues as novel dual inhibitors of EGFR and B-Raf^V600E mutant. One of the most promising compounds, <b>6a</b>, potently inhibited both of the kinases with IC₅₀ values of 8.0 and 51 nM, respectively. The compound also strongly suppressed the proliferation of a panel of intrinsic and acquired resistant melanoma and/or colorectal cancer cells harboring overexpressed EGFR with submicromolar IC₅₀ values. Further mechanism investigation revealed that <b>6a</b> could sustainably inhibit the activation of the MAPK path way in the resistant SK-MEL-28 PR30 melanoma cancer cells and WiDr colorectal cancer cells with EGFR amplification. Our results support the hypothesis that the EGFR/B-Raf^V600E dual inhibition might be a tractable strategy to overcome the intrinsic and acquired resistance of melanoma and/or colorectal cancers against the current B-Raf^V600E inhibitor therapy

Design, Synthesis, and Biological Evaluation of 2‑Oxo-3,4-dihydropyrimido[4,5‑<i>d</i>]pyrimidinyl Derivatives as New Irreversible Epidermal Growth Factor Receptor Inhibitors with Improved Pharmacokinetic Properties

Structural optimization of a series of 2-oxo-3,4-dihydropyrimido­[4,5-<i>d</i>]­pyrimidinyl compounds, potential new irreversible EGFR inhibitors, was performed to improve pharmacokinetic properties of the compounds. This led to compound <b>2v</b> with improved aqueous solubility and good pharmacokinetic properties which at the nanomolar level potently inhibits gefitinib-resistant EGFR^L858R/T790M kinase and displays strong antiproliferative activity against H1975 nonsmall cell lung cancer cells. The new inhibitor also shows promising antitumor efficacy in a murine EGFR^L858R/T790M-driven H1975 xenograft model without effect on body weight. These studies provide new lead compounds for further development of drugs for treatment of gefitinib-resistant nonsmall cell lung cancer patients

Three new polyketides from the marine sponge-derived fungus <i>Trichoderma</i> sp. SCSIO41004

<p>Three new polyketides named trichbenzoisochromen A (<b>1</b>), 5,7-dihydroxy-3-methyl -2-(2-oxopropyl)naphthalene-1,4-dione (<b>2</b>) and 7-acetyl-1,3,6-trihydroxyanthracene-9,10- dione (<b>3</b>) together with six known compounds (<b>4</b>–<b>9</b>) were isolated from a sponge-derived fungus <i>Trichoderma</i> sp. SCSIO41004. The structures of three new polyketides (<b>1</b>–<b>3</b>) were determined by the extensive spectroscopic analysis, including 1D, 2D NMR and HRESIMS data. The absolute configuration of compound <b>1</b> was confirmed by the specific optical rotation value and CD spectra analyses. Compound <b>4</b> exhibited significant inhibitory activity against EV71 with the IC₅₀ value of 25.7 μM.</p

Discovery and Optimization of 3‑(2-(Pyrazolo[1,5‑<i>a</i>]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-<i>a</i>]­pyrimidin-6-yl) ethynyl)­benzamides that are selective and orally bioavailable DDR1 inhibitors. The two most promising compounds (<b>7rh</b> and <b>7rj</b>) 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 <b>7rh</b> bound with DDR1 with a <i>K</i>_d 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 <b>7rh</b> 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

Tetramic acid derivatives and polyphenols from sponge-derived fungus and their biological evaluation

<div><p>Fifteen compounds, including two tetramic acid derivatives, penicillenol A₁ (<b>1</b>) and penicillenol A₂ (<b>2</b>), six polyphenols containing both phenolic bisabolane sesquiterpenoid and diphenyl ether units, expansols A–F (<b>3</b>–<b>8</b>), together with six phenolic bisabolane sesquiterpenoids (<b>9</b>–<b>14</b>) and diorcinol (<b>15</b>), were isolated from the fermentation broth of the marine-derived fungus ZSDS1-F11 isolated from the sponge <i>Phakellia fusca</i> Thiele collected in the Yongxing island of Xisha. Their structures were elucidated mainly by using extensive NMR spectroscopic and mass spectrometric analyses. Compounds <b>3</b>–<b>5</b>, <b>7</b> and <b>8</b> showed potent COX-1 inhibitory activity with IC₅₀ values of 5.3, 16.2, 30.2, 41.0 and 56.8 μM, respectively. Meanwhile, compounds <b>3</b>–<b>8</b> showed potent COX-2 inhibitory activity with IC₅₀ values of 3.1, 5.6, 3.0, 5.1, 3.2 and 3.7 μM, respectively. In addition, compound <b>1</b> exhibited antituberculosis activity with 96.1% inhibition at concentration of 10 μM.</p></div