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G-Quadruplex nucleic acids or G-quadruplexes (G4s) are four-stranded DNA or RNA secondary structures that are formed in guanine-rich sequences. They are widely distributed in functional regions of the human genome, such as telomeres, ribosomal DNA (rDNA), transcription start sites, promoter regions and untranslated regions of mRNA, suggesting that G-quadruplex structures may play a pivotal role in the control of a variety of cellular processes. G-Quadruplexes are viewed as valid therapeutic targets in human cancer diseases. Small molecules, from naturally occurring to synthetic, are exploited to specifically target G-quadruplexes and have proven to be a new class of anticancer agents. Notably, alkaloids are an important source of G-quadruplex ligands and have significant bioactivities in anticancer therapy. In this review, the authors provide a brief, up-to-date summary of heterocyclic alkaloids and their derivatives targeting G-quadruplexes. [ABSTRACT FROM AUTHOR]

Based on the significantly synergistic effects of CDK4 and VEGFR2 inhibitors on growth of cancer cells, a series of novel multi-kinase inhibitors targeting CDK4 and VEGFR2 were designed, synthesized and evaluated, among which Roxyl-ZV-5J exhibited potent and balanced activities against both CDK4 and VEGFR2 with half-maximal inhibitory concentration at the nanomolar level. It effectively induced breast and cervical cancer cell cycle arrest and cell apoptosis. Roxyl-ZV-5J also inhibited the proliferation, tube formation and VEGFR2 downstream signaling pathways of HUVECs. Oral administration of Roxyl-ZV-5J led to significant tumor regression and anti-angiogenesis without obvious toxicity in SiHa xenograft mouse model. In addition, this compound showed good pharmacokinetics. This study confirmed a new tool for dual CDK-VEGFR2 pathways inhibition achieved with a single molecule, which provided valuable leads for further structural optimization and anti-angiogenesis and anti-tumor mechanism study. Image 1 • A series of novel inhibitors targeting CDK4 and VEGFR2 were designed and synthesized. • Roxyl-ZV-5J with both CDK4 and VEGFR2 at nanomolar level, exhibited potent anti-proliferative and anti-angiogenesis activities in vitro and in vivo. • Dual CDK-VEGFR2 pathways inhibition with a single molecule could be a promising agent applicable for cancer therapy. [ABSTRACT FROM AUTHOR]

Inhibiting the decomposition of carbohydrates into glucose or promoting glucose conversion is considered to be an effective treatment for type 2 diabetes. Herein, a series of novel xanthone-triazole derivatives were designed, synthesized, and their α-glucosidase inhibitory activities and glucose uptake in HepG2 cells were investigated. Most of the compounds showed better inhibitory activities than the parental compound a (1,3-dihydroxyxanthone, IC 50 = 160.8 μM) and 1-deoxynojirimycin (positive control, IC 50 = 59.5 μM) towards α-glucosidase. Compound 5e was the most potent inhibitor, with IC 50 value of 2.06 μM. The kinetics of enzyme inhibition showed that compounds 5e , 5g , 5h , 6c , 6d , 6g and 6h were noncompetitive inhibitors, and molecular docking results were consistent with the noncompetitive property that these compounds bind to allosteric sites away from the active site (Asp214, Glu276 and Asp349). On the other hand, the glucose uptake assays exhibited that compounds 5e , 6a , 6c and 7g displayed high activities in promoting the glucose uptake. The cytotoxicity assays showed that most compounds were low-toxic to human normal hepatocyte cell line (LO2). These novel xanthone triazole derivatives exhibited dual therapeutic effects of α-glucosidase inhibition and glucose uptake promotion, thus they could be use as antidiabetic agents for developing novel drugs against type 2 diabetes. Image 1 • Twenty-four novel xanthone-triazole derivatives were designed and synthesized. • Xanthone-triazole derivatives significantly increased α-glucosidase inhibition. • 5e , 6a , 6c and 7g had dual effects on α-glycosidase inhibition and glucose uptake. • Most of xanthone-triazole derivatives had low toxicity. [ABSTRACT FROM AUTHOR]

Abstract Drug-resistant bacteria associated with biofilm formation are rapidly on the rise, requiring novel therapeutic options to combat biofilm induced drug-resistance. In this study, a class of 3-hydroxy-2-(phenylhydroxy-methyl)-6-methyl-4 H -pyran-4-one derivatives (1a - 1e) were found by screening of an in-house compound library to be potential Pseudomonas aeruginosa biofilm inhibitors. Thirty one novel 2-substituted 3-hydroxy-6-methyl-4 H -pyran-4-one derivatives were synthesized and assayed for their biofilm inhibitory activity. A promising biofilm inhibitor 6a was identified, and showed an obvious biofilm inhibitory effect even at a concentration of 2.5 μM. Further mechanism studies revealed that 6a only shows inhibitory effects on the expression of pqsA-gfp in a fluorescent reporter strain, and the production of a PQS- regulated virulence factor, pyocyanin. This indicates that this type of compound exercises its anti-biofilm activity specifically through the PQS pathway. Novel chemical biofilm inhibitors are described here and guard against biofilm formation associated with Pseudomonas aeruginosa infections. Graphical abstract Image 1 Highlights • Four series of 2-substituted 3-hydroxy-6-methyl-4 H -pyran-4-one derivatives were synthesized. • Potent biofilm inhibitor 6a exhibited excellent Pseudomonas aeruginosa biofilm inhibitory effect were identified. • The PQS pathway specific anti-biofilm mechanism of this type of compound was uncovered. [ABSTRACT FROM AUTHOR]

The C797S mutation in EGFR is a leading mechanism of clinically acquired resistance against osimertinib for non-small cell lung cancer (NSCLC). In this study, we identified a potent and oral EGFRL858R/T790M/C797S tyrosine kinase inhibitor, 14aj with a novel chemical scaffold. Compound 14aj showed low nanomolar activity against EGFRL858R/T790M/C797S mutant with IC 50 value as 0.010 μM. In vitro assays, compound 14aj exhibited high potency against NSCLC cells harboring EGFRL858R/T790M/C797S and induced tumor cell cycle arrest and cell apoptosis. 14aj inhibited cellular phosphorylation of EGFR. In vivo xenograft mouse model, oral administration of compound 14aj led to significant tumor regression without obvious toxicity. In addition, this compound showed good pharmacokinetics. A novel potent and orally EGFRL858R/T790M/C797S inhibitor 14aj (IC 50 = 0.010 μM) showed good bioactivity in vitro and in vivo and exhibited good pharmacokinetics. [Display omitted] • A novel EGFRL858R/T790M/C797S inhibitor 14aj was identified with IC 50 value as 0.010 μM. • 14aj exhibited good antitumor activity against NSCLC in vitro and in vivo. • 14aj induced cell cycle arrest and cell apoptosis, and inhibited the EGFR signal pathway. • 14aj showed good pharmacokinetics. [ABSTRACT FROM AUTHOR]

Obesity, a global pandemic posing a growing threat to human health, necessitates the development of effective and safe anti-obesity agents. Our previous studies highlighted the lipid-lowering effects of indolylquinazoline Bouchardatine and its derivatives. In this study, we employed scaffold hopping and simplification strategies to design and synthesize two new series derivatives by modifying the D ring. Extensive discussions have been conducted regarding the structure-activity relationship between lipid-lowering activity and the new compounds. These discussions have resulted in the discovery of 2-pyrimidinylindole derivatives as a promising scaffold for anti-obesity treatment. The new 2-pyrimidinylindole derivatives exhibited comparable lipid-lowering activity to the previously reported indolylquinazoline derivatives, including SYSU-3d and R17 , with reduced toxicity. The most potent compound, 5a , demonstrated a larger therapeutic index, improved aqueous solubility and oral bioavailability compared to the previous lead compounds. In vivo evaluation indicated that 5a effectively reduced lipid accumulation in adipose tissue, improved glucose tolerance, and mitigated insulin resistance and liver function damage caused by a high-fat and high-cholesterol diet. Mechanism studies indicated that 5a may regulate lipid metabolism through the modulation of the PPARγ signaling pathway. Overall, our study has identified a highly active compound 5a , and provided the basis for further development of 2-pyrimidinylindole as a promising scaffold for obesity treatment. [Display omitted] • Novel pyrimidinylindole derivatives have been developed as potential anti-obesity agents through the modification of indoloquinazoline. • The SAR was explored and promising compound 5a was figured out. • 5a could attenuate HFC-induced obesity and related metabolic syndrome. • 5a may regulate lipid metabolism through the modulation of the PPARγ signaling pathway. • 5a exhibits favorable water solubility and oral bioavailability, thereby presenting valuable avenues and prospects for future applications. [ABSTRACT FROM AUTHOR]

Our previous studies reveal that indolizinoquinolinedione scaffold is a base to develop novel DNA topoisomerase IB (TOP1) catalytic inhibitors. In this work, twenty-three novel indolizinoquinolinedione derivatives were synthesized. TOP1-mediated relaxation, nicking and unwinding assays revealed that three fluorinated derivatives 26 , 28 and 29 , and one N,N-trans derivative 46 act as TOP1 catalytic inhibitors with higher TOP1 inhibition (++++) than camptothecin (+++) and without TOP1-mediated unwinding effect. MTT assay against five human cancer cell lines indicated that the highest cytotoxicity is 20 for CCRF-CEM cells, 25 for A549 and DU-145 cells, 26 for HCT116 cells, and 33 for Huh7 cells with GI 50 values at nanomolar range. The drug-resistant cell assay indicated that compound 26 may mainly act to TOP1 in cells and are less of Pgp substrates. Flow cytometric analysis showed that compounds 26 , 28 and 29 can obviously induce apoptosis of HCT116 cells. Moreover, the structure-activity relationship (SAR) of indolizinoquinolinedione derivatives was analyzed. [ABSTRACT FROM AUTHOR]

Inhibition of the differentiation of adipocytes and reduced lipid synthesis are efficacious approaches for treating obesity-related metabolic disorders. Bouchardatine ( Bou ) is a natural alkaloid that has been reported to moderately inhibit the differentiation of 3T3-L1 cells without inducing toxicity. To explore the importance of aldehyde group at 8 a -position of Bou and optimize the activity, we synthesized 35 (31 novel) compounds by discarding or replacing aldehyde group with halogen and introducing different amine chains at 5-position of Bou . The lipid-lowering activity was evaluated using a cell-based screening system. The substitution of the group at the 8 a -position of compounds was important for its lipid-lowering activity, and the SAR was discussed. The selective compound 6e showed a 93-fold increase in its lipid-lowering effect (EC 50  = 0.24 μM) compared with Bou (EC 50  ≈ 25 μM). Further mechanistic studies revealed that compound 6e activated AMP-activated protein kinase (AMPK) pathway and inhibited MCE activity to block cell proliferation and induce cell cycle arrest at the early stage of differentiation, thus decreasing the expression of adipogenic factors and fatty acid synthesis-related proteins. [ABSTRACT FROM AUTHOR]

Novel topoisomerase II (Topo II) inhibitors have gained considerable interest for the development of anticancer agents. In this study, a series of carbazole derivatives containing chalcone analogs (CDCAs) were synthesized and investigated for their Topo II inhibition and cytotoxic activities. The results from Topo II mediated DNA relaxation assay showed that CDCAs could significantly inhibit the activity of Topo II, and the structure-activity relationship indicated the halogen substituent in phenyl ring play an important role in the activity. Further mechanism studies revealed that CDCAs function as non-intercalative Topo II catalytic inhibitors. Moreover, some CDCAs showed micromolar cytotoxic activities. The most potent compound 3h exhibited notable growth inhibition against four human cancer cell lines. Flow cytometric analysis revealed that compounds 3d and 3h arrested the HL-60 cells in sub G1 phase by induction of apoptosis. It was further confirmed by Annexin-V-FITC binding assay. Western blot analysis revealed that compound 3h induces apoptosis likely through the activation of caspase proteins. [ABSTRACT FROM AUTHOR]

Two series of compounds (chalcones and bis-chalcones) were designed, synthesized, and evaluated as α -glucosidase inhibitors (AGIs) with 1-deoxynojirimycin as positive control in vitro . Most of the compounds with two or four hydroxyl groups showed better inhibitory activities than 1-deoxynojirimycin towards α -glucosidase with noncompetitive mechanism. Moreover, most of the hydroxy bis-chalcones exhibit good α -glucosidase inhibitory activities in enzyme test. Inspiringly, bis-chalcones 2g ( at 1 μ M concentration) has stronger effect than 1-deoxynojirimycin on reducing the glucose level in HepG-2 cells (human liver cancer cell line). [ABSTRACT FROM AUTHOR]

A series of 2-arylethenyl- N -methylquinolinium derivatives were designed and synthesized based on our previous research of 2-arylethenylquinoline analogues as multifunctional agents for the treatment of Alzheimer's disease (AD) (Eur. J. Med. Chem. 2015, 89, 349–361). The results of in vitro biological activity evaluation, including β-amyloid (Aβ) aggregation inhibition, cholinesterase inhibition, and antioxidant activity, showed that introduction of N -methyl in quinoline ring significantly improved the anti-AD potential of compounds. The optimal compound, compound a12 , dramatically attenuated the cell death of glutamate-induced HT22 cells by preventing the generation of ROS and increasing the level of GSH. Most importantly, intragastric administration of a12 •HAc was well tolerated at doses up to 2000 mg/kg and could traverse blood-brain barrier. [ABSTRACT FROM AUTHOR]

It has been shown that treatment of cancer cells with c-KIT G-quadruplex binding ligands can reduce their c-KIT expression levels thus inhibiting cell proliferation and inducing cell apoptosis. Herein, a series of new 7-substituted-5,6-dihydrobenzo[ c ]acridine derivatives were designed and synthesized. Subsequent biophysical evaluation demonstrated that the derivatives could effectively bind to and stabilize c-KIT G-quadruplex with good selectivity against duplex DNA. It was found that 12- N -methylated derivatives with a positive charge introduced at 12-position of 5,6-dihydrobenzo[ c ]acridine ring had similar binding affinity but lower stabilizing ability to c-KIT G-quadruplex DNA, compared with those of nonmethylated derivatives. Further molecular modeling studies showed possible binding modes of G-quadruplex with the ligands. RT-PCR assay and Western blot showed that compound 2b suppressed transcription and translation of c-KIT gene in K562 cells, which was consistent with the property of an effective G-quadruplex binding ligand targeting c-KIT oncogene promoter. Further biological evaluation showed that compound 2b could induce apoptosis through activation of the caspase-3 cascade pathway. [ABSTRACT FROM AUTHOR]

In our previous research, 9-bromo indolizinoquinoline-5,12-dione 1 has been found to be a good anti-MRSA agent. However, it had very low bioavailability in vivo possibly due to its low solubility in water. In order to obtain the derivatives with higher anti-MRSA activity and good water solubility, twenty eight bromo-substituted indolizinoquinoline-5,12-dione derivatives were synthesized in the present study. The antibacterial activity of the synthesized compounds was evaluated against one gram-negative and some gram-positive bacterial strains including 100 clinical MRSA strains. The UV assays were carried out to determine the solubility of six active compounds 16, 21, 23 and 27–29 . The most potent compound 28 exhibited strong activity against clinical MRSA strains with both MIC 50 and MIC 90 values lower than 7.8 ng/mL. Compound 27 had good water solubility of 1.98 mg/mL and strong activity against clinical MRSA strains with MIC 50 value of 63 ng/mL and MIC 90 value of 125 ng/mL, 16-fold higher than that of Vancomycin. [ABSTRACT FROM AUTHOR]

The homologous recombination repair (HRR) pathway is critical for repairing double-strand breaks (DSB). Inhibition of the HRR pathway is usually considered a promising strategy for anticancer therapy. The Bloom's Syndrome Protein (BLM), a DNA helicase, is essential for promoting the HRR pathway. Previously, we discovered quinazolinone derivative 9h as a potential BLM inhibitor, which suppressed the proliferation of colorectal cancer (CRC) cell HCT116. Herein, a new series of quinazolinone derivatives with N3-substitution was designed and synthesized to improve the anticancer activity and explore the structure-activity relationship (SAR). After evaluating their BLM inhibitory activity, the SAR was discussed, leading to identifying compound 21 as a promising BLM inhibitor. 21 exhibited the potent BLM-dependent cytotoxicity against the CRC cells but weak against normal cells. Further evaluation revealed that 21 could disrupt the HRR level while inhibiting BLM located on the DSB site and trigger DNA damage in the CRC cells. This compound effectively suppressed the proliferation and invasion of CRC cells, along with cell cycle arrest and apoptosis. Consequently, 21 might be a promising candidate for treating CRC, and the BLM might be a new potential therapeutic target for CRC. [Display omitted] • New quinazolinone derivatives with N3-substitution was designed as BLM inhibitors. • The SAR was explored and promising compound 21 was figured out. • 21 disrupted the HRR level and trigger DNA damage in the CRC cells. • 21 suppressed CRC proliferation and invasion, along with cell cycle arrest and apoptosis. • 21 might be a promising candidate and BLM might be a new potential therapeutic target for CRC. [ABSTRACT FROM AUTHOR]

A series of 4-anilinoquinazoline derivatives were designed and synthesized as novel c-myc promoter G-quadruplex binding ligands. Subsequent biophysical and biochemical evaluation demonstrated that the introduction of aniline group at 4-position of quinazoline ring and two side chains with terminal amino group improved their binding affinity and stabilizing ability to G-quadruplex DNA. RT-PCR assay and Western blot showed that compound 7a could down-regulate transcription and expression of c-myc gene in Hela cells, which was consistent with the behavior of an effective G-quadruplex ligand targeting c-myc oncogene. More importantly, RTCA and colony formation assays indicated that 7a obviously inhibited Hela cells proliferation, without influence on normal primary cultured mouse mesangial cells. Flow cytometric assays suggested that 7a induced Hela cells to arrest in G0/G1 phase both in a time-dependent and dose-dependent manner. [ABSTRACT FROM AUTHOR]

In our previous work, indolizinoquinolinedione derivative 1 was identified as a Top1 catalytic inhibitor. Herein, a series of 6-substituted indolizinoquinolinedione derivatives were synthesized through modification of the parent compound 1 . Top1 cleavage and relaxation assays indicate that none of these novel compounds act as classical Top1 poison, and that the compounds with alkylamino terminus at C-6 side chain, including 8 , 11 – 16 , 18 – 21 , 25 , 26 and 28 – 30 , are the most potent Top1 catalytic inhibitors. Top1-mediated unwinding assay demonstrated that 14 , 22 and 26 were Top1 catalytic inhibitors without Top1-mediated unwinding effect. Moreover, MTT results showed that compounds 26 , 28 – 30 exhibit significant cytotoxicity against human leukemia HL-60 cells, and that compound 26 exerts potent cytotoxicity against A549 lung cancer cells at nanomolar range. [ABSTRACT FROM AUTHOR]

A novel series of benzo[a]phenazin derivatives bearing alkylamino side chains were designed, synthesized and evaluated for their topoisomerases inhibitory activity as well as cytotoxicity against four human cancer cell lines (HL-60, K-562, HeLa, and A549). These compounds were found to be dual inhibitors of topoisomerase (Topo) I and Topo II, and exhibited excellent antiproliferative activity, in particular against HL-60 cells with submicromolar IC 50 values. Further mechanistic studies showed that this class of compounds acted as Topo I poisons by stabilizing the Topo I-DNA cleavage complexes and Topo II catalytic inhibitors by inhibiting the ATPase activity of h Topo II. Molecular docking studies revealed the binding modes of these compounds for Topo I and Topo II. [ABSTRACT FROM AUTHOR]

A series of new 2-arylethenylquinoline derivatives ( 4a 1 – 4a 12 , 4b 1 – 4b 8 , 4c 1 – 4c 4 , 4d 1 – 4d 3 and 4e 1 – 4e 9 ) were designed, synthesized, and evaluated as potential multifunctional agents for the treatment of Alzheimer's disease (AD). In vitro studies showed that these synthetic compounds inhibited self-induced Aβ 1–42 aggregation effectively ranged from 23.6% to 83.9% at the concentration of 20 μM, and acted as potential antioxidants and biometal chelators. Their structure–activity relationships were obtained and discussed. In particular, compound 4b 1 , the most active compound, displayed strong inhibitory activity with an IC 50 value of 9.7 μM for self-induced Aβ 1–42 aggregation, good antioxidative activity with a value of 3.9-fold of Trolox, potent inhibitory activity for cholinesterase with IC 50 values of 0.2 μM and 64.1 μM against butyrylcholinesterase (BuChE) and acetylcholinesterase (AChE), respectively. Besides, 4b 1 was also capable of disassembling the self-induced Aβ 1–42 aggregation fibrils with a ratio of 59.8% at 20 μM concentration, and had a good metal chelating activity. Taken together, these results suggest that compound 4b 1 might be a promising lead compound for AD treatment. [ABSTRACT FROM AUTHOR]

P-glycoprotein (P-gp)-mediated multidrug resistance (MDR) is a phenomenon in which cells become resistant to structurally and mechanistically unrelated drugs resulting in low intracellular drug concentrations. It is one of the noteworthy problems in malignant tumor clinical therapeutics. So P-gp protein is one of the ideal targets to solve MDR. Based on the lead compound 5m obtained from our previous work, a series of furan derivatives featuring alkyl-substituted phenols and 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline were designed and synthesized as reversal agents against P-gp in this paper. Compound 16 containing isopropoxy possessed good potency against P-gp mediated MDR in MCF-7/ADR (IC 50 (doxorubicin) = 0.73 μM, RF = 69.6 with 5 μM 16 treated). Western blot results and Rh123 accumulation assays showed that 16 effectively inhibited P-gp efflux function but not its expression. The preliminary structure–activity relationship and docking studies demonstrated that compound 16 would be a potential P-gp inhibitor. Most worthy of mention is that compound 16 has achieved satisfactory results in combination with a variety of anti-tumor drugs, such as doxorubicin, paclitaxel, and vincristine. This study forwards a hopeful P-gp inhibitor for withstanding malignant tumor cell with multidrug resistance setting the basis for further studies. [Display omitted] • Eighteen 5-alkoxyphenyl-2-(6,7-dimethoxy-1,2,3,4-tetrahydroiso- quinolinecarboxamide)furan derivatives were designed and synthesized. • Title compounds were tested as reversal agents against P-glycoprotein mediated multidrug resistance in MCF-7/ADR cells. • SARs demonstrated that the alkoxy-substituent effect was key in enhancing the P-gp inhibitory activity and corroborated by docking study. • P-gp efflux function was abrogated effectively by compound 16 without down-regulating P-gp expression. • >60 fold increase in intracellular concentration was achieved for doxorubicin and vincristine. [ABSTRACT FROM AUTHOR]

Discovery of novel anti-obesity agents is a challenging and promising research area. Based on our previous works, we synthesized 40 novel β -indoloquinazoline analogues by altering the skeleton and introducing preferential side chains, evaluated their lipid-lowering activity and summarized the structure-activity relationships. In combination with an evaluation of the lipid-lowering efficacies, AMP-dependent activated protein kinase (AMPK) activating ability and liver microsomal stability, compound 23 (named as IQZ23) was selected for further studies. IQZ23 exerted a high efficacy in decreasing the triglyceride level (EC 50 = 0.033 μM) in 3T3-L1 adipocytes. Mechanistic studies revealed the lipid-lowering activity of IQZ23 was dependent on the AMPK pathway by modulating ATP synthase activity. This activation was accompanied by mitochondrial biogenesis and oxidation capacity increased, and insulin sensitivity enhanced in pertinent cell models by various interventions. Correspondingly, IQZ23 (20 mg/kg, i.p.) treatment significantly reversed high fat and cholesterol diet (HFC)- induced body weight increases and accompanying clinical symptoms of obesity in mice but without indicative toxicity. These results indicate that IQZ23 could be a useful candidate for the treatment of obesity and related metabolic disorders. Image 1 • 40 novel novel β -indoloquinazoline analogues were designed and synthesized. • The lipid-lowering activity was evaluated based on 3T3-L1 adipocyte model. • Compound IQZ23 shows a good drug-like properties and effectiveness on obesity mice. • Compound IQZ23 activates AMPK pathway by modulating ATP synthase activity. [ABSTRACT FROM AUTHOR]

Multidrug resistance (MDR) is a main cause of chemotherapy failure and patient death. This situation usually involves a glycoprotein (P-gp) mediated drug efflux, resulting in a low cellular drug concentration and insensitivity. Here we report the design, synthesis and evaluation of novel (+/−)-securinine bivalents as P-gp inhibitors in vitro and in vivo. MTT assays reflected that bivalent mimetics of securinine particularly the virosecurinine bivalent mimetic 8C showed promissing MDR reversal potential in both P-gp highly expressed cell line HepG2/DOX and MCF-7/ADM. At a 10 μM concentration, 8C can entirely reverse the resistance of HepG2/DOX to doxorubicin (DOX), and is more effective than the positive control verapamil (VRP). Fluorescence, flow cytometry, and DOX efflux assays demonstrated that 8C can facilitate the accumulation and diminish the efflux of intracellular DOX. Molecular docking analysis and western blot assays indicated that 8C accomplished this by competitively inhibiting the activity of P-gp rather than by affecting its expression. Compound 8C was also observed to reverse drug resistance effectively in xenograft models when combined with DOX. This study lays a foundation for the discovery of (+/−)-securinine ramifications as P-gp inhibitors and provides a promising lead compound 8C as a P-gp mediated MDR reversal agent. A virosecurinine bivalent compound (8C) has been identified as an effective P-gp modulator that blocks the P-gp mediated DOX efflux with no impact on the P-gp expression with effective in vivo multidrug resistance reverse activities. Image 1 • A series of novel virosecurinine bivalent mimetics were synthesized. • Compound 8C as a reversal agent against multidrug resistance in cancer both in vitro and in vivo was identified. • The mechanism of reversal activity of 8C was revealed. [ABSTRACT FROM AUTHOR]

A series of novel, highly potent, selective CDK9 inhibitors with cancer stem cells (CSCs) inhibition activity were designed and synthesized for non-small-cell lung cancer (NSCLC) therapy. Structure-activity relationship analysis based on enzymatic and cellular activities led to the discovery of a promising inhibitor 21e. 21e potently inhibited CDK9 with IC 50 value of 11 nM and suppressed the stemness properties of NSCLC effectively. It could decrease the stemness phenotypes of NSCLC cells, including tumor sphere formation, side-population and stemness markers abundance. 21e displayed good selectivity over the CDK family kinases and kinase profiling assay against 381 kinases. In addition, 21e inhibited cell proliferation, colony-formation, and cell cycle progression and induced apoptosis in NSCLC. In H1299 xenograft mouse model, a once-daily dose of compound 21e at 20 mg/kg significantly suppressed the tumor growth without obvious toxicity. Studies of mechanisms of action indicated that 21e efficiently inhibited CDK9 signaling pathway and stemness both in vitro and in vivo. Collectively, 21e as a novel CDK9 inhibitor with CSCs inhibition properties could be a promising agent for the treatment of NSCLC. A selective, potent and oral CDK9 inhibitor, 21e (IC 50 = 11 nM) with stemness suppression properties of NSCLC was discovered. In H1299 xenograft mouse model, 21e at 20 mg/kg led to significant tumor regression without obvious toxicity. Image 1 • A series of novel CDK9 inhibitors with cancer stem cells (CSCs) inhibition activity were designed and synthesized. • 21e inhibited CDK9 with IC 50 value of 11 nM and suppressed the stemness properties of NSCLC. • In H1299 xenograft mouse model, 21e led to significant tumor regression. [ABSTRACT FROM AUTHOR]