Bioactive Dibenzocyclooctadiene Lignans from the Stems of <i>Schisandra neglecta</i>

Seven new unusual dibenzocyclooctadiene lignans, neglignans A–G (<b>1</b>–<b>7</b>), together with 16 known dibenzocyclooctadiene lignans, were isolated from the stems of <i>Schisandra neglecta</i>. Compounds <b>1</b> and <b>2</b> are the first dibenzocyclooctadiene lignans bearing a carboxyl group at C-4, and compounds <b>3</b> and <b>4</b> are the first 7,8-<i>seco</i>-dibenzocyclooctadiene lignans found from Nature. The new compounds (<b>1</b>–<b>7</b>) and several of the known compounds were evaluated for their anti-HIV activity and cytotoxicity. Compounds <b>2</b> and <b>6</b> showed anti-HIV-1 activities with therapeutic index values greater than 50, and compound <b>4</b> showed cytotoxicity against the NB4 and SHSY5Y cancer cell lines with IC₅₀ values of 2.9 and 3.3 μM, respectively

Discovery of a Novel HIV‑1 Integrase/p75 Interacting Inhibitor by Docking Screening, Biochemical Assay, and in Vitro Studies

Protein–protein interaction between lens epithelium-derived growth factor (LEDGF/p75) and HIV-1 integrase becomes an attractive target for anti-HIV drug development. The blockade of this interaction by small molecules could potentially inhibit HIV-1 replication. These small molecules are termed as LEDGINs; and several newly identified LEDGINs have been reported to significantly reduce HIV-1 replication. Through this project, we have finished the docking screening of the Maybridge database against the p75 binding site of HIV-1 integrase using both DOCK and Autodock Vina software. Finally, we have successfully identified a novel scaffold LEDGINs inhibitor DW-D-5. Its antiviral activities and anticatalytic activity of HIV-1 integrase are similar to other LEDGINs under development. We demonstrated that the combination of DW-D-5 and FDA approved anti-HIV drugs resulted in additive inhibitory effects on HIV-1 replication, indicating that DW-D-5 could be an important component of combination pills for clinic use in HIV treatment

Dibenzocyclooctadiene Lignans and Norlignans from Fruits of <i>Schisandra wilsoniana</i>

Seven new dibenzocyclooctadiene lignans, marlignans M–S (<b>1</b>–<b>7</b>), four new norlignans, marphenols C–F (<b>8</b>–<b>11</b>), and 21 known compounds (<b>12</b>–<b>32</b>) were isolated from the fruits of <i>Schisandra wilsoniana</i>. The structures of <b>1</b>–<b>11</b> were elucidated by spectroscopic methods including 1D- and 2D-NMR techniques and CD experiments. Compounds <b>1</b>–<b>11</b> were evaluated for their anti-HIV activities and showed EC₅₀ values in the range 2.97–6.18 μg/mL and therapeutic index values of 5.33–29.13

Cytotoxicity of DB-02 in C8166, MT-4 and PBMC using MTT methods.

<p>DB-02 showed low cytotoxicity to all the three types of aforementioned cells above. CC₅₀ of these cells were all >1000μM, respectively.</p

RT activity of DB-2 <i>in</i><i>vitro</i>.

<p>The RT activity was measured by ELISA using DIG-labeled dNTPs, which were incorporated into the newly synthesized cDNA. The figure represents three independent experiments.</p

Structures of <i>S</i>-DABO and DB-02.

<p>Structures of <i>S</i>-DABO and DB-02.</p

Structure-Based Design of Tropane Derivatives as a Novel Series of CCR5 Antagonists with Broad-Spectrum Anti-HIV‑1 Activities and Improved Oral Bioavailability

Blocking the entry of an HIV-1 targeting CCR5 coreceptor has emerged as an attractive strategy to develop HIV therapeutics. Maraviroc is the only CCR5 antagonist approved by FDA; however, serious side effects limited its clinical use. Herein, 21 novel tropane derivatives (6–26) were designed and synthesized based on the CCR5-maraviroc complex structure. Among them, compounds 25 and 26 had comparable activity to maraviroc and presented more potent inhibitory activity against a series of HIV-1 strains. In addition, compound 26 exhibited synergistic or additive antiviral effects in combination with other antiretroviral agents. Compared to maraviroc, both 25 and 26 displayed higher Cmax and AUC0–∞ and improved oral bioavailability in SD rats. In addition, compounds 25 and 26 showed no significant CYP450 inhibition and showed a novel binding mode with CCR5 different from that of maraviroc-CCR5. In summary, compounds 25 and 26 are promising drug candidates for the treatment of HIV-1 infection

Structure-Based Design of Tropane Derivatives as a Novel Series of CCR5 Antagonists with Broad-Spectrum Anti-HIV‑1 Activities and Improved Oral Bioavailability

Blocking the entry of an HIV-1 targeting CCR5 coreceptor has emerged as an attractive strategy to develop HIV therapeutics. Maraviroc is the only CCR5 antagonist approved by FDA; however, serious side effects limited its clinical use. Herein, 21 novel tropane derivatives (6–26) were designed and synthesized based on the CCR5-maraviroc complex structure. Among them, compounds 25 and 26 had comparable activity to maraviroc and presented more potent inhibitory activity against a series of HIV-1 strains. In addition, compound 26 exhibited synergistic or additive antiviral effects in combination with other antiretroviral agents. Compared to maraviroc, both 25 and 26 displayed higher Cmax and AUC0–∞ and improved oral bioavailability in SD rats. In addition, compounds 25 and 26 showed no significant CYP450 inhibition and showed a novel binding mode with CCR5 different from that of maraviroc-CCR5. In summary, compounds 25 and 26 are promising drug candidates for the treatment of HIV-1 infection

Structure-Based Design of Tropane Derivatives as a Novel Series of CCR5 Antagonists with Broad-Spectrum Anti-HIV‑1 Activities and Improved Oral Bioavailability

Blocking the entry of an HIV-1 targeting CCR5 coreceptor has emerged as an attractive strategy to develop HIV therapeutics. Maraviroc is the only CCR5 antagonist approved by FDA; however, serious side effects limited its clinical use. Herein, 21 novel tropane derivatives (6–26) were designed and synthesized based on the CCR5-maraviroc complex structure. Among them, compounds 25 and 26 had comparable activity to maraviroc and presented more potent inhibitory activity against a series of HIV-1 strains. In addition, compound 26 exhibited synergistic or additive antiviral effects in combination with other antiretroviral agents. Compared to maraviroc, both 25 and 26 displayed higher Cmax and AUC0–∞ and improved oral bioavailability in SD rats. In addition, compounds 25 and 26 showed no significant CYP450 inhibition and showed a novel binding mode with CCR5 different from that of maraviroc-CCR5. In summary, compounds 25 and 26 are promising drug candidates for the treatment of HIV-1 infection

Structure-Based Design of Tropane Derivatives as a Novel Series of CCR5 Antagonists with Broad-Spectrum Anti-HIV‑1 Activities and Improved Oral Bioavailability

Blocking the entry of an HIV-1 targeting CCR5 coreceptor has emerged as an attractive strategy to develop HIV therapeutics. Maraviroc is the only CCR5 antagonist approved by FDA; however, serious side effects limited its clinical use. Herein, 21 novel tropane derivatives (6–26) were designed and synthesized based on the CCR5-maraviroc complex structure. Among them, compounds 25 and 26 had comparable activity to maraviroc and presented more potent inhibitory activity against a series of HIV-1 strains. In addition, compound 26 exhibited synergistic or additive antiviral effects in combination with other antiretroviral agents. Compared to maraviroc, both 25 and 26 displayed higher Cmax and AUC0–∞ and improved oral bioavailability in SD rats. In addition, compounds 25 and 26 showed no significant CYP450 inhibition and showed a novel binding mode with CCR5 different from that of maraviroc-CCR5. In summary, compounds 25 and 26 are promising drug candidates for the treatment of HIV-1 infection