Safety, Tolerability, and Pharmacokinetics of Nebulized Hydroxychloroquine: A Pilot Study in Healthy Volunteers.

Background: Early in the coronavirus disease 2019 (COVID-19) pandemic, hydroxychloroquine (HCQ) drew substantial attention as a potential COVID-19 treatment based on its antiviral and immunomodulatory effects in vitro. However, HCQ showed a lack of efficacy in vivo, and different groups of researchers attributed this failure to the insufficient drug concentration in the lung following oral administration (HCQ is only available in the market in the tablet form). Delivering HCQ by inhalation represents a more efficient route of administration to increase HCQ exposure in the lungs while minimizing systemic toxicity. In this pilot study, the safety, tolerability, and pharmacokinetics of HCQ nebulizer solution were evaluated in healthy volunteers. Methods: Twelve healthy participants were included in this study and were administered 2 mL of HCQ01 solution (equivalent to 25 mg of HCQ sulfate) through Aerogen® Solo, a vibrating mesh nebulizer. Local tolerability and systemic safety were assessed by forced expiratory volume in the first and second electrocardiograms, clinical laboratory results (e.g., hematology, biochemistry, and urinalysis), vital signs, and physical examinations. Thirteen blood samples were collected to determine HCQ01 systemic exposure before and until 6 hours after inhalation. Results: The inhalation of HCQ01 was well tolerated in all participants. The mean value of Cmax for the 12 participants was 9.66 ng/mL. Tmax occurred at around 4.8 minutes after inhalation and rapidly decreased thereafter. The reported systemic exposure was very low with a mean value of 5.28 (0.6-15.6) ng·h/mL. Conclusion: The low systemic concentrations of HCQ01 of 9.66 ng/mL reported by our study compared with 1 µg/mL previously predicted after 200 mg BID oral administration, and the safety and tolerability of HCQ01 administered as a single dose through nebulization, support the assessment of its efficacy, safety, and tolerability in further studies for the treatment of COVID-19.

Study of preoperative diagnostic modalities in Chinese patients with superficial esophageal squamous cell carcinoma.

BACKGROUND: Endoscopic ultrasonography (EUS) and magnifying endoscopy (ME) reliably determine indications for endoscopic resection in patients with superficial esophageal squamous cell carcinoma (SESCC). ME is widely accepted for predicting the invasion depth of superficial esophageal cancer with satisfying accuracy. However, the addition of EUS is controversial. AIM: To evaluate the diagnostic efficiency of ME vs EUS for invasion depth prediction and investigate the influencing factors in patients with SESCC to determine the best diagnostic model in China. METHODS: We retrospectively analyzed patients with suspected SESCC who completed both ME and EUS and then underwent endoscopic or surgical resection at Sun Yat-Sen University Cancer Center between January 2018 and December 2021. We evaluated and compared the diagnostic efficiency of EUS and ME according to histological results, and investigated the influencing factors. RESULTS: We included 152 lesions from 144 patients in this study. The diagnostic accuracies of ME and EUS in differentiating invasion depth were not significantly different (73.0% and 66.4%, P = 0.24); both demonstrated moderate consistency with the pathological results (ME: kappa = 0.58, 95% confidence interval [CI]: 0.48-0.68, P < 0.01; EUS: kappa = 0.46, 95%CI: 0.34-0.57, P < 0.01). ME was significantly more accurate in the diagnosis of high-grade intraepithelial (HGIN) or carcinoma in situ (odds ratio [OR] = 3.62, 95%CI: 1.43-9.16, P = 0.007) subgroups. Using a miniature probe rather than conventional EUS can improve the accuracy of lesion depth determination (82.3% vs 49.3%, P < 0.01). Less than a quarter of circumferential occupation and application of a miniature probe were independent risk factors for the accuracy of tumor invasion depth as assessed by EUS (< 1/4 circumferential occupation: OR = 3.07, 95%CI: 1.04-9.10; application of a miniature probe: OR = 5.28, 95%CI: 2.41-11.59, P < 0.01). Of the 41 lesions (41/152, 27.0%) that were misdiagnosed by ME, 24 were corrected by EUS (24/41, 58.5%). CONCLUSION: Preoperative diagnosis of SESCC should be conducted endoscopically using white light and magnification. In China, EUS can be added after obtaining patient consent. Use of a high-frequency miniature probe or miniature probe combined with conventional EUS is preferable.

Structural Characterization and Assessment of Anti-Inflammatory Activities of Polyphenols and Depsidone Derivatives from Melastoma malabathricum subsp. normale.

The roots of Melastoma malabathricum subsp. normale (D. Don) Karst. Mey have been used in traditional ethnic medicine systems in China to treat inflammation-triggered ailments, such as trauma, toothache, and fever. Therefore, the aim of this study is to screen for compounds with anti-inflammatory activity in the title plant. The extract of M. malabathricum subsp. normale roots was separated using various chromatographic methods, such as silica gel, ODS C18, MCI gel, and Sephadex LH-20 column chromatography, as well as semi-preparative HPLC. One new complex tannin, named whiskey tannin D (1), and an undescribed tetracyclic depsidone derivative, named guanxidone B (2), along with nine known polyphenols (2-10) and three known depsidone derivatives (12-14) were obtained from this plant. The structures of all compounds were elucidated by extensive NMR and CD experiments in conjunction with HR-ESI-MS data. All these compounds were isolated from this plant for the first time. Moreover, compounds 1-4, 8, and 10-14 were obtained for the first time from the genus Melastoma, and compounds 1, 2, and 11-14 have not been reported from the family Melastomataceae. This is the first report of complex tannin and depsidone derivatives from M. malabathricum subsp. normale, indicating their chemotaxonomic significance to this plant. Compounds 1-12 were investigated for their anti-inflammatory activities on the production of the nitric oxide (NO) in lipopolysaccharide (LPS)-stimulated RAW264.7 cells, and compounds 1, 11, and 12 showed anti-inflammatory activities with IC50 values of 6.46 ± 0.23 µM, 8.02 ± 0.35 µM, and 9.82 ± 0.43 µM, respectively. The structure-activity relationship showed that the catechin at glucose C-1 in ellagitannin was the key to its anti-inflammatory activity, while CH3O- at C-16 of aromatic ring A in depsidone derivatives had little effect on its anti-inflammatory activity. The study of structure-activity relationships is helpful to quickly discover new anti-inflammatory drugs. The successful isolation and structure identification of these compounds, especially complex tannin 1, not only provide materials for the screening of anti-inflammatory compounds, but also provide a basis for the study of chemical taxonomy of the genus Melastoma.

Live in Front of Students Teaching Sessions (LISTS): a Novel Learning Experience from Jordan During the COVID-19 Pandemic.

Objective: The COVID-19 pandemic uncovered innovative approaches in medical education. Modifications are needed to overcome the drawbacks of pure online teaching. Our study aimed at testing a hybrid method of live online practical anatomy sessions in which an element of face-to-face teacher-student interaction is maintained. Methods: We performed an experiment with a one-group design in which medical and medical laboratory sciences students were taught different practical anatomy topics using either purely online or live in front of students teaching sessions (LISTS). Students' performance and perceptions were quantitatively assessed. Results: For 108 medical laboratory sciences students, the mean quiz scores were significantly higher for the topics taught by the LISTS approach (p = 0.025). For two groups of 13 and 17 medical students, the performance in exams was significantly higher for the topics taught using the LISTS method (p = 0.000 and 0.011, respectively) with large effect sizes. Students' perceptions of preference, enjoyment, and satisfaction were all in favor of LISTS. Conclusions: Our results confirmed that keeping at least a minimum of interaction between the teacher and students can have a significant improvement in the performance and engagement in practical anatomy sessions for health professionals. The results indicate that the extra effort of LISTS was worth it.

Identification of the First "Two Digit Nano-molar" Inhibitors of the Human Glyoxalase-I Enzyme as Potential Anticancer Agents.

BACKGROUND: Glyoxalase-I (Glo-I) enzyme is recognized as an indispensable druggable target in cancer treatment. Its inhibition will lead to the accumulation of toxic aldehyde metabolites and cell death. Paramount efforts were spent to discover potential competitive inhibitors with the aim to eradicate cancer. OBJECTIVE: Based on our previous work on this target for discovering potent inhibitors of this enzyme, herein, we address the discovery of the most potent Glo-I inhibitors reported in the literature with two digits nano-molar activity. METHODS: Molecular docking and in vitro assay were performed to discover these inhibitors and explore the binding pattern within the active site. A detailed SAR scheme was generated, which identifies the major functionalities responsible for the observed activity. RESULTS: Compound 1 with an IC50 of 16.5 nM exhibited the highest activity, which possess catechol moiety as an essential zinc chelating functionality. It has been shown by using molecular modeling techniques that the catechol moiety is responsible for chelation zinc atom at the active site; an essential feature for enzyme inhibition. CONCLUSION: Catechol derivatives are successful zinc chelators in Glo-I enzyme while showing exceptional activity against the enzyme to nanomolar level.

Effects of seasonal precipitation change on soil respiration processes in a seasonally dry tropical forest.

Precipitation is projected to change intensity and seasonal regime under current global projections. However, little is known about how seasonal precipitation changes will affect soil respiration, especially in seasonally dry tropical forests. In a seasonally dry tropical forest in South China, we conducted a precipitation manipulation experiment to simulate a delayed wet season (DW) and a wetter wet season (WW) over a three-year period. In DW, we reduced 60% throughfall in April and May to delay the onset of the wet season and irrigated the same amount water into the plots in October and November to extend the end of the wet season. In WW, we irrigated 25% annual precipitation into plots in July and August. A control treatment (CT) receiving ambient precipitation was also established. Compared with CT, DW significantly increased soil moisture by 54% during October to November, and by 30% during December to April. The treatment of WW did not significantly affect monthly measured soil moisture. In 2015, DW significantly increased leaf area index and soil microbial biomass but decreased fine root biomass. In contrast, WW significantly decreased fine root biomass and forest floor litter stocks. Soil respiration was not affected by DW, which could be attributed to the increased microbial biomass offsetting the decrease in fine root biomass. In contrast, WW significantly increased soil respiration from 3.40 to 3.90 µmol m-2 s-1 in the third year, mainly due to the increased litter decomposition and soil pH (from 4.48 to 4.68). The present study suggests that both a delayed wet season and a wetter wet season will have significant impacts on soil respiration-associated ecosystem components. However, the ecosystem components can respond in different directions to the same change in precipitation, which ultimately affected soil respiration.

Complexes of oxoplatin with rhein and ferulic acid ligands as platinum(iv) prodrugs with high anti-tumor activity.

We herein designed two new PtIV prodrugs of oxoplatin (cis,cis,cis-[PtCl2(NH3)2(OH)2]), [PtIVCl2(NH3)2(O2C-FA)2] (Pt-2) and [PtIVCl2(NH3)2(O2C-RH)2] (Pt-3), by conjugating with ferulic acid (FA-COOH) and rhein (RH-COOH) which have well-known biological activities. Three other Pt(iv) complexes of [PtIVCl2(NH3)2(O2C-BA)2] (Pt-1), [PtIVCl2(NH3)2(O2C-CA)2] (Pt-4) and [PtIVCl2(NH3)2(O2C-TCA)2] (Pt-5) (where BA-COOH = benzoic acid, CA-COOH = crotonic acid and TCA-COOH = trans-cinnamic acid) were also prepared for the comparative study. Like most PtIV prodrug complexes, the cytotoxicity of Pt-3 containing the biologically active rhein (RH-COOH) ligand against lung carcinoma (A549 and A549/DDP) cells was higher than those of Pt-1, Pt-2, Pt-4, cisplatin and Pt-5. Moreover, the cytotoxicity of Pt-3 in HL-7702 normal cells was lower than those of PtIV derivatives bearing BA-COOH, FA-COOH, TCA-COOH and CA-COOH ligands. The highly efficacious Pt-2 and Pt-3 were found to accumulate strongly in the A549/DDP cells, with the prodrug Pt-3 showing highest levels of penetration into the mitochondria. The prodrug Pt-3 effectively entered the A549/DDP cells and caused mitochondrial damage, significantly greater than Pt-2. In addition, the prodrug Pt-3 exhibited higher antitumor efficacy (inhibition rates (IR) = 67.45%) than Pt-2 (28.12%) and cisplatin (33.05%) in the A549/DDP xenograft mouse model. Thus, the prodrug Pt-3 containing the rhein (RH-COOH) ligand is a promising candidate drug targeting the mitochondria.

Attitudes and Knowledge of Adolescents in Jordan Regarding the Ethics of Social Media Data Use for Research Purposes.

This study assessed the awareness and attitudes of adolescents in Jordan concerning the ethics of using their social media data for scientific studies. Using an online survey, 393 adolescents were recruited (mean age: 17.2 years ± 1.8). The results showed that 88% of participants were using their real personal information on social media sites, with males more likely to provide their information than females. More than two thirds of participants (72.5%) were aware that researchers may use their data for research purposes, with the majority believing that informed consent must be obtained from both the adolescents and their parents. However, more than three quarters of those surveyed (76%) did not trust the results of research that depended on collecting data from social media. These findings suggest that adolescents in Jordan understood most of the ethical aspects related to the utilization of their data from social media websites for research studies.

FOXO3/TRIM22 axis abated the antitumor effect of gemcitabine in non-small cell lung cancer via autophagy induction.

BACKGROUND: Non-small cell lung cancer (NSCLC) accounts for more than 80% of the total lung cancer and gemcitabine (GEM)-based chemotherapy is the first-line therapeutic approach for NSCLC treatment. Owing to acquired chemo-resistance, the prognosis of NSCLC patients receiving GEM treatment is still poor. METHODS: Dysregulation of mRNAs in GEM-resistant (GR) NSCLC cells comparing to parental cells were profiled by analyzing GSEA6914 datasets from GEO database. Additionally, qRT-PCR were performed on clinically collected patient serum samples and transplanted tumor tissues and GEM-resistant (GR)/sensitive (GS) cell lines. In order to explore the functional role of tripartite motif protein 22 (TRIM22), gain and loss-of-function cell models were constructed in A549 and A549/GR respectively. MTT and Annexin V-FITC/propidium iodide (PI) staining assay were carried out to access the response to GEM of A549 and A549/GR cells. Observation of RFP-LC3 puncta and western blot detection of autophagy markers were used to evaluate autophagy. Bi-luciferase reporter assay was used to confirm the transcriptional regulatory relationship. Rescue experiments were carried out to confirm the FOXO3/TRIM22 regulatory axis in GEM susceptibility. RESULTS: TRIM22 was significantly upregulated in GR patient serum samples, transplanted tumor tissues and NSCLC cells which was negatively transcriptional regulated by FOXO3. TRIM22 overexpression attenuated the sensitivity of A549 to GEM and its depletion promoted the sensitivity of A549/GR to GEM. Additionally, TRIM22 promoted GEM-induced pro-survival autophagy to protected NSCLC cells from apoptosis. CONCLUSIONS: TRIM22 was significantly upregulated in GR lung adenocarcinoma cell line A549 which is negatively transcriptional regulated by FOXO3. Due to the enhancement of pro-survival autophagy induced by TRIM22, the A549 cells became less sensitive to GEM. This study may provide a basis for screening target of liquid biopsy for predicting GEM sensitivity in NSCLC.

Novel Quinoline-based Ir(III) Complexes Exhibit High Antitumor Activity in Vitro and in Vivo.

Eight novel Ir(III) complexes listed as [Ir(H-P)2(P)]PF6 (PyP-Ir), [Ir(H-P)2(dMP)]PF6 (PydMP-Ir), [Ir(H-P)2(MP)]PF6 (PyMP-Ir), [Ir(H-P)2(tMP)]PF6 (PytMP-Ir), [Ir(MPy)2(P)]PF6 (MPyP-Ir), [Ir(MPy)2(dMP)]PF6 (MPydMP-Ir), [Ir(MPy)2(MP)]PF6 (MPyMP-Ir), [Ir(MPy)2((tMP)]PF6 (MPytMP-Ir) with 2-phenylpyri-dine (H-P) and 3-methyl-2-phenylpyridine (MPy) as ancillary ligands and pyrido-[3,2-a]-pyrido[1',2':1,2]imidazo[4,5-c]phenazine (P), 12,13-dimethyl pyrido-[3,2-a]-pyrido[1',2':1,2]-imidazo-[4,5-c]-phenazine (dMP), 2-methylpyrido [3,2-a]-pyrido-[1',2':1,2]-imidazo-[4,5-c]-phenazine (MP), and 2,12,13-trimethylpyrido-[3,2-a]-pyrido-[1',2':1,2]-imidazo-[4,5-c]-phenazine (tMP) as main ligands, respectively, were designed and synthesized to fully characterize and explore the effect of their toxicity on cancer cells. Cytotoxic mechanism studies demonstrated that the eight Ir(III) complexes exhibited highly potent antitumor activity selectively against cancer cell lines NCI-H460, T-24, and HeLa, and no activity against HL-7702, a noncancerous cell line. Among the eight Ir(III) complexes, MPytMP-Ir exhibited the highest cytotoxicity with an IC50 = 5.05 ± 0.22 nM against NCI-H460 cells. The antitumor activity of MPytMP-Ir in vitro could be contributed to the steric or electronic effect of the methyl groups, which induced telomerase inhibition and damaged mitochondria in NCI-H460 cells. More importantly, MPytMP-Ir displayed a superior inhibitory effect on NCI-H460 xenograft in vivo than cisplatin. Our work demonstrates that MPytMP-Ir could potentially be developed as a novel potent Ir-based antitumor drug.

Strong in vitro and vivo cytotoxicity of novel organoplatinum(II) complexes with quinoline-coumarin derivatives.

A series of novel organoplatinum(II) complexes, [PtII(QC1)(H-QC1)Cl] (Pt1), [PtII(QC2)(H-QC2)Cl] (Pt2), [PtII(QC3)(H-QC3)Cl] (Pt3), [PtII(QC4)(H-QC4)Cl]⋅CH3OH (Pt4), [PtII(QC5)(H-QC5)Cl] (Pt5), [PtII(H-QC6)(DMSO)Cl2] (Pt6), [PtII(H-QC7)(DMSO)Cl2]⋅H2O (Pt7), [PtII(H-QC8)(DMSO)Cl2] (Pt8), [PtII(H-QC9)(DMSO)Cl2]⋅CH3OH (Pt9), [PtII(H-QC10)(DMSO)Cl2] (Pt10) and [PtII(H-QC11)(DMSO)Cl2] (Pt11), bearing quinoline-coumarin derivatives (H-QC1-H-QC11) have been first designed. Complexes Pt1-Pt11 selectively displayed obvious cytotoxicities in comparison to cisplatin for A549/DDP (cisplatin-resistant human lung adenocarcinoma) cells and HeLa cervical carcinoma cells, with IC50 values as low as 100 nM-10.33 µM. In addition, Pt4 and Pt5 display a green-colored luminescent properties, targeted mitochondrial membrane and, thereby induced mainly mitochondria-mediated cell apoptosis was in the following order: Pt4 > Pt5. The different anti-cancer activity of quinoline-coumarin complexes Pt4 (100 nM) and Pt5 (250 nM) were correlate with the presence of 3-(2'-quinolyl)-6-hydroxy-coumarin (H-QC4) ligand. The quinoline-coumarin complex Pt4 (2.0 mg/kg per 2 days) also displayed potent in vivo anti-tumor effect after 21 days-treated. In contrast, the H-QC4 ligand highly enhances the anti-tumor activity and selectivity of organoplatinum(II) complexes in comparison to other previously reported coumarin derivatives metal complexes.

Two telomerase-targeting Pt(ii) complexes of jatrorrhizine and berberine derivatives induce apoptosis in human bladder tumor cells.

Two novel Pt(ii) complexes, [Pt(B-TFA)Cl]Cl (Pt1) and [Pt(J-TFA)Cl]Cl (Pt2) with jatrorrhizine and berberine derivatives (B-TFA and J-TFA) were first prepared as desirable luminescent agents for cellular applications and potent telomerase inhibitors, which can induce bladder T-24 tumor cell apoptosis by targeting telomerase, together with induction of mitochondrial dysfunction, telomere DNA damage and cell-cycle arrest. Importantly, T-24 tumor inhibition rate (TIR) was 50.4% for Pt2, which was higher than that of Pt1 (26.4%) and cisplatin (37.1%). Taken together, all the results indicated that jatrorrhizine and berberine derivatives Pt1 and Pt2 show low toxicity and could be novel Pt-based anti-cancer drug candidates.

Changes in seasonal precipitation distribution but not annual amount affect litter decomposition in a secondary tropical forest.

In the tropics of South China, climate change induced more rainfall events in the wet season in the last decades. Moreover, there will be more frequently spring drought in the future. However, knowledge on how litter decomposition rate would respond to these seasonal precipitation changes is still limited. In the present study, we conducted a precipitation manipulation experiment in a tropical forest. First, we applied a 60% rainfall exclusion in April and May to defer the onset of wet season and added the same amount of water in October and November to mimic a deferred wet season (DW); second, we increased as much as 25% mean annual precipitation into plots in July and August to simulate a wetter wet season (WW). Five single-species litters, with their carbon to nitrogen ratio ranged from 27 to 49, and a mixed litter were used to explore how the precipitation change treatments would affect litter decomposition rate. The interaction between precipitation changes and litter species was not significant. The DW treatment marginally accelerated litter decomposition across six litter types. Detailed analysis showed that DW increased litter decomposition rate in the periods of January to March and October to December, when soil moisture was increased by the water addition in the dry season. In contrast, WW did not significantly affect litter decomposition rate, which was consistent with the unchanged soil moisture pattern. In conclusion, the study indicated that regardless of litter types or litter quality, the projected deferred wet season would increase litter decomposition rate, whereas the wetter wet season would not affect litter decomposition rate in the tropical forests. This study improves our knowledge of how tropical forest carbon cycling in response to precipitation change.

High in vitro and in vivo antitumor activities of luminecent platinum(II) complexes with jatrorrhizine derivatives.

Two highly active anticancer Pt(II) complexes, [Pt(Jat1)Cl]Cl (Pt1) and [Pt(Jat2)Cl]Cl (Pt2), containing jatrorrhizine derivative ligands (Jat1 and Jat2) are described. Cell intake study showed high accumulation in cell nuclear fraction. Pt1 and Pt2 exhibited high selectivity for HeLa cancer cells (IC50 = 15.01 ±â€¯1.05 nM and 1.00 ±â€¯0.17 nM) comparing with HL-7702 normal cells (IC50 > 150 µM), by targeting p53 and telomerase. Pt2 containing Jat2 ligand was more potent and showed high selectivity for telomerase. It also caused mitochondria and DNA damage, sub-G1 phase arrest, and a high rate of cell apoptosis at the low dose of 1.00 nM. The HeLa tumor inhibition rate (TIR) of Pt2 was 48.8%, which was even higher than cisplatin (35.2%). In addition, Pt2 displayed green luminescent property and potent telomerase inhibition. Our findings demonstrated the promising development of platinum(II) complexes containing jatrorrhizine derivatives as novel Pt-based anti-cancer agents.

Complexes of lanthanides(iii) with mixed 2,2'-bipyridyl and 5,7-dibromo-8-quinolinoline chelating ligands as a new class of promising anti-cancer agents.

Five novel lanthanides(iii) complexes, [Lu(Me)(MBrQ)2NO3] (MeMBrQ-Lu), [Ho(MeO)(MBrQ)2NO3] (MeOMBrQ-Ho), [Ho(Me)(MBrQ)2NO3] (MeMBrQ-Ho), [La(Me)2(BrQ)2NO3] (MeBrQ-La) and [Sm(Me)(BrQ)2(CH3OH)NO3] (MeBrQ-Sm), have been synthesized, in which 2,2'-bipyridyl (4,4'-dimethyl-2,2'-bipyridyl (Me) and 4,4'-dimethoxy-2,2'-bipyridine (MeO)) and 5,7-dibromo-8-quinolinoline derivatives (5,7-dibromo-2-methyl-8-quinolinol (MBrQ-H) and 5,7-dibromo-8-quinolinol (BrQ-H)) act as the chelating ligands. The in vitro cytotoxic activities of the five Ln(iii) complexes have been studied with the SK-OV-3/DDP, NCI-H460 and HeLa cancer cells. MeMBrQ-Lu, MeOMBrQ-Ho, MeMBrQ-Ho, MeBrQ-La and MeBrQ-Sm show higher cytotoxicity against the HeLa cells (IC50 values of 1.00 nM-3.45 µM) than cisplatin (13.11 ± 0.53 µM). In particular, the MeOMBrQ-Ho and MeMBrQ-Ho complexes exhibit superior cytotoxic activity, with IC50 values at 1.00 ± 0.34 nM and 125.00 ± 1.08 nM. We further demonstrate that MeOMBrQ-Ho and MeMBrQ-Ho inhibit the proliferation of HeLa cells by inhibiting telomerase and targeting mitochondria to induce DNA damage-mediated apoptosis. In addition, MeOMBrQ-Ho significantly inhibits tumor growth with a tumor growth inhibition rate (IR) of 50.8% in a HeLa mouse xenograft model. Taken together, MeOMBrQ-Ho is a novel lanthanide(iii) complex with promising antitumor activity.

In vitro and in vivo antitumor activities of three novel binuclear platinum(II) complexes with 4'-substituted-2,2':6',2″-terpyridine ligands.

Herein, we report the design and synthesis of three novel binuclear platinum(II) complexes, [Pt(tpbtpy)Cl][Pt(DMSO)Cl3] (tpbtpy-Pt), [Pt(dthbtpy)Cl][Pt(DMSO)Cl3]⋅CH3OH (dthbtpy-Pt), and [Pt(qlbtpy)Cl][Pt(DMSO)Cl3]⋅CH3OH (qlbtpy-Pt) with 4'-(3-thiophenecarboxaldehyde)-2,2':6',2″-terpyridine (tpbtpy), 4'-(3,5-bis (1,1-dimethylethyl)-2-hydroxy-benzaldehyde)-2,2':6',2″-terpyridine (dthbtpy) and 4'-(2-quinolinecarboxaldehyde)-2,2':6',2″-terpyridine (qlbtpy) as ligands, respectively. All three novel binuclear platinum(II) complexes tpbtpy-Pt, dthbtpy-Pt, and qlbtpy-Pt were characterized by single-crystal X-ray diffraction analysis, spectroscopic analysis (ESI-MS, IR, 1H NMR), and elemental analysis. Additionally, the cytotoxicity of tpbtpy-Pt, dthbtpy-Pt and qlbtpy-Pt was assessed with human non-small cell lung cancer cell line (NCIH460 cells), yielding IC50 values in the range of 0.35-12.09 µM with tpbtpy-Pt as the most potent and qlbtpy-Pt as the least potent complexes. Mechanistic studies indicated that tpbtpy-Pt and dthbtpy-Pt induced apoptosis through mitochondrial dysfunction and telomerase inhibition. In a NCIH460 xenograft model, when administered at 10.0 mg kg-1 every 2 days, tpbtpy-Pt was shown to significantly reduce tumor growth (tumor growth inhibition rate (IR) = 70.1%, p < 0.05). Therefore, tpbtpy-Pt is a promising Pt(II) complex for further translational studies and clinical evaluation as an antitumor agent.

Synthesis of two platinum(II) complexes with 2-methyl-8-quinolinol derivatives as ligands and study of their antitumor activities.

Two platinum(II) complexes, [Pt(ClQ)(DMSO)Cl] (ClQ-Pt) and [Pt(BrQ)(DMSO)Cl] (BrQ-Pt), with 5,7-dichloro-2-methyl-8-quinolinol (H-ClQ) and 5,7-dibromo-2-methyl-8-quinolinol (H-BrQ) as ligands, respectively, have been synthesized and characterized. The single-crystal X-ray diffraction characterization as well as other spectroscopic and analytical studies of ClQ-Pt and BrQ-Pt revealed that the coordination geometry of Pt(II) can be described as a four-coordinated square planar geometry. By MTT assay, ClQ-Pt displayed the most potent activity, with IC50 values of 5.02-34.38 µM against MGC80-3, T-24, Hep-G2 and BEL-7402 tumor cells. Among them, the T-24 cells the highest sensitivity to ClQ-Pt and BrQ-Pt with IC50 value of 5.02 ±â€¯0.62 µM and 18.02 ±â€¯1.05 µM, respectively. In addition, ClQ-Pt caused a higher percentage of apoptotic T-24 cells (ca. 33.75%) than that of BrQ-Pt (ca. 23.85%) and cisplatin (ca. 12.82%). Mechanistic studies revealed that ClQ-Pt and BrQ-Pt caused T-24 cell cycle arrest at the S phase, as shown by the down-regulation of cyclin A and CDK2 expression levels. In addition, ClQ-Pt and BrQ-Pt also caused mitochondrial dysfunction. Interestingly, the in vitro anticancer activity of ClQ-Pt was higher than those of BrQ-Pt and cisplatin, more selective for T-24 tumor cells than for normal HL-7702 cells. Taken together, we concluded that the 5- and 7-substitution groups of the ClQ ligands play an important role in determining the anti-proliferation activity of the corresponding Pt(II) complexes.

Platinum(ii) complexes with rutaecarpine and tryptanthrin derivatives induce apoptosis by inhibiting telomerase activity and disrupting mitochondrial function.

Four new platinum(ii) complexes, [Pt(Rut)(DMSO)Cl2] (Rut-Pt), [Pt(Try)(DMSO)Cl2] (Try-Pt), [Pt(ITry)(DMSO)Cl2] (ITry-Pt) and [Pt(BrTry)(DMSO)Cl2] (BrTry-Pt), with rutaecarpine (Rut), tryptanthrin (Try), 8-iodine-tryptanthrin (ITry) and 8-bromo-tryptanthrin (BrTry) as ligands were synthesized and fully characterized. In these complexes, the platinum(ii) adopts a four-coordinated square planar geometry. The inhibitory activity evaluated by the MTT assay showed that BrTry-Pt (IC50 = of 0.21 ± 0.25 µM) could inhibit the growth of T-24 tumor cells (human bladder cancer cell line) more so than the other three complexes. In addition, all of these Pt complexes exhibited low toxicity against non-cancerous HL-7702 cells. BrTry-Pt induced cell cycle arrest in the S phase, leading to the down-regulation of cyclin A and CDK2 proteins. BrTry-Pt acts as a telomerase inhibitor targeting the c-myc promoter. In addition, BrTry-Pt also caused mitochondrial dysfunction. Importantly, the in vitro anticancer activity of BrTry-Pt was higher than those of Rut-Pt, Try-Pt and ITry-Pt, and it was more selective for T-24 cells than for non-cancerous HL-7702 cells.

Novel tacrine platinum(II) complexes display high anticancer activity via inhibition of telomerase activity, dysfunction of mitochondria, and activation of the p53 signaling pathway.

In this work, we designed and synthesized tacrine platinum(II) complexes [PtClL(DMSO)]⋅CH3OH (Pt1), [PtClL(DMP)] (Pt2), [PtClL(DPPTH)] (Pt3), [PtClL(PTH)] (Pt4), [PtClL(PIPTH)] (Pt5), [PtClL(PM)] (Pt6) and [PtClL(en)] (Pt7) with 4,4'-dimethyl-2,2'-bipyridine (DMP), 4,7-diphenyl-1,10-phenanthroline (DPPTH), 1,10-phenanthroline (PTH), 2-(1-pyrenecarboxaldehyde) imidazo [4,5-f]-[1,10] phenanthroline (PIPTH), 2-picolylamine (PM) and 1,2-ethylenediamine (en) as telomerase inhibitors and p53 activators. Biological evaluations demonstrated that Pt1Pt7 exhibited cytotoxic activity against the tested NCIH460, Hep-G2, SK-OV-3, SK-OV-3/DDP and MGC80-3 cancer cell lines, with Pt5 displaying the highest cytotoxicity. Pt5 exhibited an IC50 value of 0.13 ±â€¯0.16 µM against SK-OV-3/DDP cancer cells and significantly reduced tumor growth in a Hep-G2 xenograft mouse model (tumor growth inhibition (TGI) = 40.8%, p < 0.05) at a dose of 15.0 mg/kg. Interestingly, Pt1Pt7 displayed low cytotoxicity against normal HL-7702 cells. Mechanistic studies revealed that these compounds caused cell cycle arrest at the G2/M and S phases, and regulated the expression of CDK2, cyclin A, p21, p53 and p27. Further mechanistic studies showed that Pt5 induced SK-OV3/DDP cell apoptosis via dysfunction of mitochondria, inhibition of the telomerase activity by directly targeting the c-myc promoter, and activation of the p53 signaling pathway. Taken together, Pt5 has the potential to be further developed as a new antitumor drug.

Synthesis, characterization and biological evaluation of six highly cytotoxic ruthenium(ii) complexes with 4'-substituted-2,2':6',2''-terpyridine.

Herein, six ruthenium(ii) terpyridine complexes, i.e. [RuCl2(4-EtN-Phtpy)(DMSO)] (Ru1), [RuCl2(4-MeO-Phtpy)(DMSO)] (Ru2), [RuCl2(2-MeO-Phtpy)(DMSO)] (Ru3), [RuCl2(3-MeO-Phtpy)(DMSO)] (Ru4), [RuCl2(1-Bip-Phtpy)(DMSO)] (Ru5), and [RuCl2(1-Pyr-Phtpy)(DMSO)] (Ru6) with 4'-(4-diethylaminophenyl)-2,2':6',2''-terpyridine (4-EtN-Phtpy), 4'-(4-methoxyphenyl)-2,2':6',2''-terpyridine (4-MeO-Phtpy), 4'-(2-methoxyphenyl)-2,2':6',2''-terpyridine (2-MeO-Phtpy), 4'-(3-methoxyphenyl)-2,2':6',2''-terpyridine (3-MeO-Phtpy), 4'-(1-biphenylene)-2,2':6',2''-terpyridine (1-Bip-Phtpy), and 4'-(1-pyrene)-2,2':6',2''-terpyridine (1-Pyr-Phtpy), respectively, were synthesized and fully characterized. The MTT assay demonstrates that the in vitro anticancer activity of Ru1 is higher than that of Ru2-Ru6 and more selective for Hep-G2 cells than for normal HL-7702 cells. In addition, various biological assays show that Ru1 and Ru6, especially the Ru1 complex, are telomerase inhibitors targeting c-myc G4 DNA and also cause apoptosis of Hep-G2 cells. With the same Ru center, the in vitro antitumor activity and cellular uptake ability of the 4-EtN-Phtpy and 1-Bip-Phtpy ligands follow the order 4-EtN-Phtpy > 1-Bip-Phtpy.