Regulation of ATP-binding cassette subfamily B member 1 by Snail contributes to chemoresistance in colorectal cancer.

Although accumulating evidence has indicated the intimate association between epithelial-mesenchymal transition (EMT) and acquired resistance to chemotherapy for colorectal cancer (CRC), the underlying mechanisms remain elusive. Herein, we reported that Snail, a crucial EMT controller, was upregulated in CRC tissues. Colorectal cancer cells overexpressing Snail were found to be more resistant to 5-fluorouracil (5-Fu). Mechanistic studies reveal that Snail could increase the expression of ATP-binding cassette subfamily B member 1 (ABCB1) rather than the other 23 chemoresistance-related genes. Additionally, knockdown of ABCB1 significantly attenuated Snail-induced 5-Fu resistance in CRC cells. Oxaliplatin increased Snail and ABCB1 expression in CRC cells. Snail and ABCB1 were upregulated in 5-Fu-resistant HCT-8 (HCT-8/5-Fu) cells and inhibition of Snail decreased ABCB1 in HCT-8/5-Fu cells. These results confirm the vital role played by ABCB1 in Snail-induced chemoresistance. Further investigation into the relevant molecular mechanism revealed Snail-mediated ABCB1 upregulation was independent of ß-catenin, STAT3, PXR, CAR and Foxo3a, which are commonly involved in modulating ABCB1 transcription. Instead, Snail upregulated ABCB1 transcription by directly binding to its promoter. Clinical analysis confirms that increased Snail expression correlated significantly with tumor size (P = .018), lymph node metastasis (P = .033), distant metastasis (P = .025), clinical stage grade (P = .024), and poor prognosis (P = .045) of CRC patients. Moreover, coexpression of Snail and ABCB1 was observed in CRC patients. Our study revealed that direct regulation of ABCB1 by Snail was critical for conferring chemoresistance in CRC cells. These findings unraveled the mechanisms underlying the association between EMT and chemoresistance, and provided potential targets for CRC clinical treatment.

Transient receptor potential vanilloid 4 is a critical mediator in LPS mediated inflammation by mediating calcineurin/NFATc3 signaling.

Transient Receptor Potential Vanilloid 4 (TRPV4) ion channel is thought to be an essential component of inflammatory response. However, its role and mechanism in regulating acute lung injury (ALI) and macrophages activation are not well characterized. In our study, we observe that blockade of TRPV4 using GSK2193874 or HC-067047 greatly improve the pneumonedema, the lung pathologic changes, the up-regulation of proinflammatory cytokines and the neutrophil infiltration in LPS-induced lung injury. In vitro, knockdown of TRPV4 in macrophages reduces the levels of pro-inflammatory cytokines, ROS production, Ca2+ concentration in cytoplasma and the activation of calcineurin/NFATc3 signaling. Importantly, change of extracellular Ca2+ in culture medium prevents LPS-induced NFATc3 nuclear translocation, up-regulation of proinflammatory cytokines and ROS production in macrophages. Inhibition of calcineurin with cyclosporine A, FK506 down-regulates the levels of NFATc3 nuclear translocation and proinflammatory cytokines expression. Our results demonstrate that TRPV4-dependent Ca2+ influx contributes to LPS-induced macrophage activation by calcineurin-NFATc3 pathway.

Afatinib Decreases P-Glycoprotein Expression to Promote Adriamycin Toxicity of A549T Cells.

We investigated the reversal effect of afatinib (AFT) on activity of adriamycin (ADR) in A549T cells and clarified the related molecular mechanisms. A549T cells overexpressing P-glycoprotein (P-gp) were resistant to anticancer drug ADR. AFT significantly increased the antitumor activity of ADR in A549T cells. AFT increased the intracellular concentration of ADR by inhibiting the function and expression of P-gp at mRNA and protein levels in A549T cells. Additionally, the reversal effect of AFT on P-gp mediated multidrug resistance (MDR) might be related to the inhibition of PI3K/Akt pathway. Cotreatment with AFT and ADR could enhance ADR-induced apoptosis and autophagy in A549T cells. Meanwhile, the co-treatment significantly induced cell apoptosis and autophagy accompanied by increased expression of cleaved caspase-3, PARP, LC3B-II, and beclin 1. Apoptosis inhibitors had no significant effect on cell activity, while autophagy inhibitors decreased cell viability, suggesting that autophagy may be a self protective mechanism of cell survival in the absence of chemotherapy drugs. Interestingly, when combined with AFT and ADR, inhibition of apoptosis and/or autophagy could enhance cell viability. These results indicated that in addition to inhibit P-gp, ADR-induced apoptosis, and autophagy promoted by AFT contributed to the antiproliferation effect of combined AFT and ADR on A549T cells. These findings provide evidence that AFT combined ADR may achieve a better therapeutic effect to lung cancer in clinic. J. Cell. Biochem. 119: 414-423, 2018. © 2017 Wiley Periodicals, Inc.

[Design, synthesis, and biological evaluation of phenylpropenamides compounds as anti-platelet aggregation].

Twenty phenylpropenamide analogs with structural novelty were designed and synthesized upon pharmacophore-combination strategy. The structures of target compounds were elucidated by IR, 1H NMR, 13C NMR and MS, and all the target compounds were biologically evaluated for the inhibitory activities of platelet aggregation induced by adenosine diphoshate（ADP） and（AA） arachidonic acid via Bron method. As a result, compounds 6b, 9b, 9d and 9h demonstrated potent inhibitory activity against platelet aggregation induced by AA. Meanwhile, compounds 6b, 6d, 6j, 9b and 9g exhibited significant suppression of platelet aggregation induced by ADP.

[The anti-HIV-1 activities of benzophenones non-nucleoside reverse transcriptase inhibitors in vitro].

To evaluate the anti-HIV-1 activities of 5 benzophenones non-nucleoside reverse transcriptase inhibitors (NNRTIs) such as DY1203, DY1204, DY1119, DY1208 and DY1209 in vitro, the cytotoxicity of 5 compounds were tested on C8166, MT-4, H9 and PBMC with the MTT assay. The anti-HIV-1 activities of compounds were evaluated on laboratory-adapted strain, drug-resistant strains and primary isolated strains by p24 antigen expression ELISA. The inhibition of HIV-1 recombinant reverse transcriptase activity was assessed by ELISA assay. Among 5 compounds, DY1203 and DY1204 showed low cytotoxicities with CC(50) greater than 200 µg·m L(-1). DY1119, DY1208 and DY1209 showed strong anti-HIV-1 activities against HIV-1(IIIB,) HIV-1(74V,) HIV-1(RF/V82F/184V,) HIV-1(NL4-3) (gp41(36G)N42S,) HIV-1(KM018,) HIV-1(TC-1) and HIV-1(Wan.) However, NNRTIs drug-resistant strain HIV-1(A17) showed different resistance to these compounds. The 5 compounds proved active against HIV-1 recombinant reverse transcriptase. DY1208 is expected to become a new lead compound for its high therapeutic index. The results can provide new information for HIV-1 drug research and promote the development of new HIV-1 drugs.

[Phenotypic modulation of vascular smooth muscle cells in diabetes mellitus and intervention of traditional Chinese medicines].

Proliferation and migration of vascular smooth muscle cells (VSMC) are common pathological features of diabetic vascular complications,such as atherosclerosis and hypertension. Phenotypic modulation of VSMC is the basis for VSMC proliferation and migration. Therefore, studies on VSMC phenotypic modulation and its mechanisms in diabetes mellitus were of important significance to the prevention and therapy of diabetic vascular complications. This paper introduces VSMC phenotypic modulation and the underlying mechanisms in diabetes mellitus, and summarizes advance of studies on traditional Chinese medicine intervention upon VSMC phenotypic modulation, so as to provide reference for preventing and treating diabetic vascular complications with traditional Chinese medicines.

Modelling the dynamic gas/particle partitioning process of semi-volatile organic compounds emitted from point sources: Quantitative analysis and impact assessment.

The deleterious impact of pollution point sources on the surrounding environment and human has long been a focal point of environmental research. When considering the local atmospheric dispersion of semi-volatile organic compounds (SVOCs) around the emission sites, it is essential to account the dynamic process for the gas/particle (G/P) partitioning, which involves the transition from an initial state to a steady state. In this study, we have developed a model that enables the prediction of the dynamic process for G/P partitioning of SVOCs, particularly considering the influence from emission. It is important to note that the dynamic processes of the concentrations of SVOCs in particle phase (CP) and in gas phase (CG) differ significantly. These differences arise due to the influence of two critical factors: particulate proportion of SVOCs in the emissions (ϕ0) and octanol-air partitioning coefficient (KOA). The validity of our model was assessed by comparing its predictions of the extremum value of the G/P partitioning quotient (KP) with the results obtained from the steady-state model. Remarkably, the characteristic time (tC), used to evaluate the timescale required for SVOCs to reach steady state, demonstrated different variations with KOA for CP and CG. Additionally, the values of tC were quite different for CP and CG, which were markedly influenced by ϕ0. For some SVOCs with high KOA values, it took approximately 35 h to reach steady state. Furthermore, it was found that the time to achieve 95 % of steady state (t95 ≈ 3tC) could reach approximately 105 h. This duration is sufficient for chemicals to disperse from their emission site to the surrounding areas. Therefore, it is crucial to consider the dynamic process of G/P partitioning in local atmospheric transport studies. Moreover, the influence of ϕ0 should be incorporated into future investigations examining the dynamic process of G/P partitioning.

Comparative skin histological and transcriptomic analysis of Rana kukunoris with two different skin colors.

This study compares the skin structures of Rana kukunoris with two different skin colors living in the same area of Haibei in the Northeastern Qinghai-Tibet Plateau. The skin thickness of the khaki R. kukunoris was significantly greater than that of the brown R. kukunoris (P < 0.01), and significantly more mucous and granular glands were present on the dorsal skin of the khaki frog (P < 0.05). Meanwhile, the melanocytes on the dorsal skin of the brown frog were significantly larger than those on the khaki one (P < 0.05). Morphological changes in the expansion and aggregation of melanocytes seemed to deepen the skin color of R. kukunoris. Moreover, transcriptome sequencing identified tyrosine metabolism, melanogenesis, and riboflavin metabolism as the main pathways involved in melanin formation and metabolism in brown R. kukunoris. TYR, MC1R was upregulated as the skin color of R. kukunoris was deepened and contributed to melanin production and metabolism. In contrast, the khaki frog had significantly more upregulated genes and metabolic pathways related to autoimmunity. The khaki frog appeared to defend against ultraviolet (UV) radiation-induced damage by secreting mucus and small molecular peptides, whereas the brown frog protected itself by distributing a large amount of melanin. Hence, the different skin colors of R. kukunoris might represent different adaptation strategies for survival in the intense UV radiation environment of the Qinghai-Tibet Plateau.

Manifestation of the malignant progression of glioma following initial intracerebral hemorrhage: A case report.

BACKGROUND: Intracranial hemorrhage is extremely rare during the initial stages of glioma. Here, we report a case of glioma with unclassified pathology and intracranial bleeding. CASE SUMMARY: After the second surgery for intracerebral hemorrhage, the patient experienced weakness in the left arm and leg, but could walk unassisted. One month after discharge, the weakness in the left limbs had exacerbated and the patient also suffered from headaches and dizziness. A third surgery was ineffective against the rapidly growing tumor. Intracerebral hemorrhage may be the initial symptom of glioma in some rare cases, and atypical perihematomal edema can be used for diagnosis during an emergency. Certain histological and molecular features seen in our case were similar to that of glioblastoma with a primitive neuronal component, which is termed diffuse glioneuronal tumor with features similar to oligodendroglioma and nuclear clusters (DGONC). The patient underwent three surgeries to remove the tumor. The first tumor resection had been performed when the patient was 14-years-old. Resection of the hemorrhage and bone disc decompression were performed when the patient was 39-years-old. One month after the last discharge, the patient underwent neuronavigation-assisted resection of the right frontotemporal parietal lesion plus extended flap decompression. On the 50th d after the third operation, computed tomography imaging showed rapid tumor growth accompanied by brain hernia. The patient was discharged and died 3 d later. CONCLUSION: Glioma can present as bleeding in the initial stage and should be considered in such a setting. We have reported a case of DGONC, which is a rare molecular subtype of glioma with a unique methylation profile.

The transfrontal isthmus approach for insular glioma surgery.

OBJECTIVE: The classic transopercular or transsylvian approach to insular gliomas removes the tumor laterally through the insular cortex. This study describes a new anteroposterior approach through the frontal isthmus for insular glioma surgery. METHODS: The authors detailed the surgical techniques for resection of insular gliomas through the transfrontal isthmus approach. Fifty-nine insular gliomas with at least Berger-Sanai zone I involvement were removed with the new approach, and extent of resection and postoperative neurological outcomes were assessed. RESULTS: Fifty-nine patients were enrolled in the study, including 35 men and 24 women, with a mean (range) age 44.3 (19-75) years. According to the Berger-Sanai classification system, the most common tumor was a giant glioma (67.8%), followed by involvement of zones I and IV (18.6%). Twenty-two cases were Yasargil type 3A/B, and 37 cases were Yasargil type 5A/B. The average angle between the lateral plane of the putamen and sagittal line was 33.53°, and the average width of the isthmus near the anterior insular point was 33.33 mm. The average angle between the lateral plane of the putamen and the sagittal line was positively correlated with the width of the isthmus near the anterior insular point (r = 0.935, p < 0.0001). The median (interquartile range [IQR]) preoperative tumor volume was 67.82 (57.64-92.19) cm3. Of 39 low-grade gliomas, 26 (66.67%) were totally resected; of 20 high-grade gliomas, 19 (95%) were totally resected. The median (IQR) extent of resection of the whole group was 100% (73.7%-100%). Intraoperative diffusion-weighted imaging showed no cases of middle cerebral artery- or lenticulostriate artery-related stroke. Extent of insular tumor resection was positively correlated with the angle of the lateral plane of the putamen and sagittal line (r = -0.329, p = 0.011) and the width of the isthmus near the anterior insular point (r = -0.267, p = 0.041). At 3 months postoperatively, muscle strength grade exceeded 4 in all cases, and all patients exhibited essentially normal speech. The median (IQR) Karnofsky performance score at 3 months after surgery was 90 (80-90). CONCLUSIONS: The transfrontal isthmus approach changes the working angle from lateral-medial to anterior-posterior, allowing for maximal safe removal of insular gliomas.

Anticancer mechanisms on pyroptosis induced by Oridonin: New potential targeted therapeutic strategies.

Pyroptosis is a type of inflammatory cell death that is triggered by the formation of pores on the cell membrane by gasdermin (GSDM) family proteins. This process activates inflammasomes and leads to the maturation and release of proinflammatory cytokines such as interleukin-1ß (IL-1ß) and interleukin-18 (IL-18). Pyroptosis, a form of programmed cell death, has been found to be associated with various biomolecules such as caspases, granzymes, non-coding RNA (lncRNA), reactive oxygen species (ROS), and NOD-like receptor protein 3 (NLRP3). These biomolecules have been shown to play a dual role in cancer by affecting cell proliferation, metastasis, and the tumor microenvironment (TME), resulting in both tumor promotion and anti-tumor effects. Recent studies have found that Oridonin (Ori) has anti-tumor effects by regulating pyroptosis through various pathways. Ori can inhibit pyroptosis by inhibiting caspase-1, which is responsible for activating pyroptosis of the canonical pathway. Additionally, Ori can inhibit pyroptosis by inhibiting NLRP3, which is responsible for activating pyroptosis of the noncanonical pathway. Interestingly, Ori can also activate pyroptosis by activating caspase-3 and caspase-8, which are responsible for activating pyroptosis of the emerging pathway; Ori has been found to be effective in inhibiting pyroptosis by blocking the action of perforin, which is responsible for facilitating the entry of granzyme into cells and activating pyroptosis. Additionally, Ori plays a crucial role in regulating pyroptosis by promoting the accumulation of ROS while inhibiting the ncRNA and NLRP3 pathways. It is worth noting that all of these pathways ultimately regulate pyroptosis by influencing the cleavage of GSDM, which is a key factor in the process. These studies concludes that Ori has extensive anti-cancer effects that are related to its potential regulatory function on pyroptosis. The paper summarizes several potential ways in which Ori participates in the regulation of pyroptosis, providing a reference for further study on the relationship between Ori, pyroptosis, and cancer.

Molecular biological mechanism of action in cancer therapies: Juglone and its derivatives, the future of development.

Juglone (5 - hydroxy - 1, 4 - naphthalene diketone) is a kind of natural naphthoquinone, present in the roots, leaves, nut-hulls, bark and wood of walnut trees. Recent studies have found that Juglone has special significance in the treatment of cancer, which plays a significant role in the resistance of cancer cell proliferation, induction of cancer cell apoptosis, induction of autophagy, anti-angiogenesis and inhibition of cancer cell migration and invasion, etc. Additionally, its derivatives also play a tumor suppressive effect. In conclusion, Juglone and its derivatives have been identified as effective anticancer drugs. This paper reviews action mechanisms of Juglone and its derivatives in cancer treatment.

Anticancer activity of oleanolic acid and its derivatives: Recent advances in evidence, target profiling and mechanisms of action.

Oleanolic acid (OA, 3 ß - hydroxyoleanolic acid-12-en-28-oic acid) is a pentacyclic triterpenoid present in many plants. As a new framework for development of semi synthetic triterpenoids, OA is of great significance in the discovery of anticancer drugs. Some of these derivatives, such as CDDO (2-cyano-3,12-dioxooleana-1, 9 (11)-dien-28-oic acid) have been verified in clinical trials, while other derivatives studied previously, such as SZC014, SZC015 and SZC017 (OA derivatives respectively), are also candidate drugs for cancer treatment. This paper reviews the preclinical studies, literature evidence, target analysis and anticancer mechanism of OA and its derivatives. The mechanism of action of its derivatives mainly includes anti-cancer cell proliferation, inducing tumor cell apoptosis, inducing autophagy, regulating cell cycle regulatory proteins, inhibiting vascular endothelial growth, anti angiogenesis, inhibiting tumor cell migration and invasion. In recent years, the molecular mechanism of OA and its derivatives has been elucidated. These effects seem to be mediated by the alterations in a variety of signaling pathways induced by OA and its derivatives. In conclusion, OA and its derivatives are considered as important candidate drugs for the treatment of cancer, indicating that OA and its derivatives have the potential to be used as anticancer drugs in practice.

Restoring Rotation Center in Total Hip Arthroplasty for Developmental Dysplasia of the Hip with the Assistance of Three Dimensional Printing Technology: A Pilot Study.

OBJECTIVE: To develop a new method to restore hip rotation center exactly and rapidly in total hip arthroplasty (THA) with the assistance of three dimensional (3D) printing technology and evaluate its clinical and radiological outcomes. METHODS: From March 2014 to July 2018, a total of 17 patients (five hips of four men and 16 hips of 13 women) with end-stage osteoarthritis secondary to developmental dysplasia of the hip who underwent THA were analyzed and followed up retrospectively. The average age is 58.00 ± 8.12 years (range from 45 to 71 years). Simulated operations were performed on 3D printed hip models for preoperative planning. The morphology of Harris fossa and acetabular notches were recognized and restored to locate the acetabular center. The size of bone defect was measured by the bone wax method. The agreement on the size of acetabular cup and bone defect between simulated operations and actual operations were analyzed. Harris Hip Score (HHS) was used to evaluate the recovery of hip joint function. The vertical distance and horizontal distance of the rotation center on the pelvis plain radiograph were measured, which were used to assess the efficacy of restoring hip rotation center and acetabular cup migration. RESULTS: The mean sizes of bone defect in simulated operations and THA were 4.58 ± 2.47 cm2 and 4.55 ± 2.57 cm2 respectively. There was no significant difference statistically between the sizes of bone defect in simulated operations and the actual sizes of bone defect in THA (t = 0.03, P = 0.97). The sizes of the acetabular cup of simulated operations on 3D print models showed a high rate of coincidence with the actual sizes in the operations (ICC = 0.93). All 17 patients were available for clinical and radiological follow-up. The average follow-up time was 18.35 ± 6.86 months (range, 12-36 months. The average HHS of the patients was improved from (38.33 ± 6.07) preoperatively to the last follow-up (88.61 ± 3.44) postoperatively. The mean vertical and horizontal distances of hip rotation center on the pelvic radiographs were restored to 15.12 ± 1.25 mm and 32.49 ± 2.83 mm respectively. No case presented dislocation or radiological signs of loosening until last follow-up. CONCLUSIONS: The application of 3D printing technology facilitates orthopedists to recognize the morphology of Harris fossa and acetabular notches, locate the acetabular center and restore the hip rotation center rapidly and accurately.

Lung transcriptome analysis for the identification of genes involved in the hypoxic adaptation of plateau pika (Ochotona curzoniae).

The plateau pika, a typical hypoxia-tolerant mammal lives 3000-5000 m above sea level on the Qinghai-Tibet Plateau, has acquired many physiological and morphological characteristics and strategies in its adaptation to sustained, high-altitude hypoxia. Blunted hypoxic pulmonary vasoconstriction is one such strategy, but the genes involved in this strategy have not been elucidated. Here, we investigated the genes involved and their expression profiles in the lung transcriptome of plateau pikas subjected to different hypoxic conditions (using low-pressure oxygen cabins). A slight, right ventricular hypertrophy was observed in pikas of the control group (altitude: 3200 m) vs. those exposed to 5000 m altitude conditions for one week. Our assembly identified 67,774 genes; compared with their expression in the control animals, 866 and 8364 genes were co-upregulated and co-downregulated, respectively, in pikas subjected to 5000 m altitude conditions for 1 and 4 w. We elucidated pathways that were associated with pulmonary vascular arterial pressure, including vascular smooth muscle contraction, HIF-1 signalling, calcium signalling, cGMP-PKG signalling, and PI3K-Akt signalling based on the differentially expressed genes; the top-100 pathway enrichments were found between the control group and the group exposed to 5000 m altitude conditions for 4 w. The mRNA levels of 18 candidate gene showed that more than 83% of genes were expressed and the number of transcriptome The up-regulated genes were EPAS1, Hbα, iNOS, CX40, CD31, PPM1B, HIF-1α, MYLK, Pcdh12, Surfactant protein B, the down-regulated genes were RYR2, vWF, RASA1, CLASRP, HIF-3α. Our transcriptome data are a valuable resource for future genomic studies on plateau pika.

Synthesis and structure-activity relationship of novel diarylpyrimidines with hydromethyl linker (CH(OH)-DAPYs) as HIV-1 NNRTIs.

A series of 26 diarylpyrimidines, characterized by the hydroxymethyl linker between the left wing benzene ring and the central pyrimidine, were synthesized and evaluated for in vitro anti-HIV activity. Most of the compounds exhibited moderate to excellent activities against wild-type HIV-1. Among them, compound 10i, bearing a chlorine atom at the C-2 position of left benzene ring, was the best congener and showed potent activity against wild-type HIV-1 with an EC(50) value of 0.009 µM, along with moderate activities against the double RT mutant (K103N+Y181C) HIV-1(III(B)) and HIV-2(ROD) with an EC(50) value of 6.2 and 6.0 µM, respectively. The preliminary structure-activity relationship (SAR) of this new series of compounds was also investigated.

Synthesis and biological evaluation of naphthyl phenyl ethers (NPEs) as novel nonnucleoside HIV-1 reverse transcriptase inhibitors.

A novel series of naphthyl phenyl ether analogues (NPEs) have been synthesized and evaluated for their in vitro activities against HIV in C8166 cells. Most of the compounds exhibited moderate to excellent anti-HIV activities. Among them the most active compound 12o showed excellent activities against wild-type HIV-1 with an EC(50) value of 4.60 nM, along with moderate activities against the double mutant strain HIV-1(IIIB) A17 (K103N+Y181C) and HIV-2 strain ROD with an EC(50) value of 0.82 and 4.40 µM, respectively. Preliminary structure-activity relationship (SAR) among the newly synthesized NPEs was also investigated.

Synthesis and biological activity of naphthyl-substituted (B-ring) benzophenone derivatives as novel non-nucleoside HIV-1 reverse transcriptase inhibitors.

A novel series of benzophenone derivatives with B-ring substituted by naphthyl ring has been synthesized and evaluated as non-nucleoside HIV-1 reverse transcriptase inhibitors. Most of these compounds showed good to moderate activity against wild-type HIV-1 and mutated viruses. In particular, the analogue 10i demonstrated the most potent activity against wild-type HIV-1 with an EC50 value of 4.8 nM, and with a high selectivity index up to 10347.9, it also proved to be active against the HIV-1 double mutant strain A17 (K103N+Y181C) with an EC50 value of 2.1 µM. In addition, the molecular modeling study was used to explore the major interactions between the potent inhibitors with the HIV-1 RT. The investigation of the structure-activity relationships may serve as an important lead for the further optimization.

Synthesis and biological evaluation of HQCAs with aryl or benzyl substituents on N-1 position as potential HIV-1 integrase inhibitors.

A series of new 5-hydroxylquinolone-3-carboxylic acids (HQCAs) with various aryl or benzyl substituents on N-1 position were synthesized and evaluated for their anti-HIV activity in C8166 cell culture. Most of the target compounds displayed activity against wide-type HIV-1 in the low micromolar range in infected C8166 cells. The most active compound 5 g exhibited activity against wild-type HIV-1 and HIV-1 mutant virus A17 with an EC(50) value of 3.17 and 17.88 µM, respectively. The biological results and the docking study revealed that the substitution pattern on N-1 position of the quinolone core might contribute to physicochemical properties of HQCAs and resulted in great influence on their antiviral potency.

Synthesis and biological evaluation of (±)-benzhydrol derivatives as potent non-nucleoside HIV-1 reverse transcriptase inhibitors.

A series of (±)-benzhydrol derivatives featuring the essential sulfonamide group at the para position on the C-ring were synthesized and evaluated for the potential anti-HIV activity in C8166 cells. Most of these analogues demonstrated low concentration inhibitory activity with EC(50) values less than 1 µM against the wild-type HIV-1. In particular, compound 7h was identified as the highest active inhibitor of wild-type HIV-1 with an EC(50) value of 0.12 µM and selectivity index value of 312.73. Furthermore, some of them also exhibited moderate activity against the double mutant strain A(17) (K103N+Y181C) with EC(50) values lower than 5 µM. In addition, the binding modes with RT and the preliminary structure-activity relationships of these derivatives were also explored for further chemical modifications.