scholarly journals Design and Synthesis of a New Soluble Natural β-Carboline Derivative for Preclinical Study by Intravenous Injection

2019 ◽  
Vol 20 (6) ◽  
pp. 1491 ◽  
Author(s):  
Sébastien Marx ◽  
Laurie Bodart ◽  
Nikolay Tumanov ◽  
Johan Wouters
Keyword(s):  
Cell Lines ◽  
Intravenous Injection ◽  
Biological Activities ◽  
Preclinical Study ◽  
Antitumoral Activity ◽  
Significant Activity ◽  
Physiological Conditions ◽  
Design And Synthesis ◽  
Poorly Soluble

Harmine is a natural β-carboline compound showing several biological activities, including antiproliferative properties, but this soluble natural molecule lacks selectivity. Harmine derivatives were reported to overcome this problem, but they are usually poorly soluble. Here, we designed and synthesized a new 2, 7, 9-trisubstituted molecule (1-methyl-7-(3-methylbutoxy)-9-propyl-2-[(pyridin-2-yl)methyl]-9H-pyrido[3,4-b]indol-2-ium bromide) with a solubility of 1.87 ± 0.07 mg/mL in a simulated injection vehicle. This compound is stable for at least 72 h in acidic and physiological conditions (pH 1.1 and 7.4) as well as in a simulated injection vehicle (physiological liquid + 0.1% Tween80®). Solubility in those media is 1.06 ± 0.08 mg/mL and 1.62 ± 0.13 mg/mL at pH 7.4 and 1. The synthesized molecule displays a significant activity on five different cancer cell lines (IC50 range from 0.2 to 2 µM on A549, MDA-MB-231, PANC-1, T98G and Hs683 cell lines). This compound is also more active on cancer cells (MDA-MB-231) than on normal cells (MCF-10a) at IC50 concentrations. Due to its high activity at low concentration, such solubility values should be sufficient for further in vivo antitumoral activity evaluation via intravenous injection.

scholarly journals Targeting DDX3X Helicase Activity with BA103 Shows Promising Therapeutic Effects in Preclinical Glioblastoma Models

Cancers ◽  
2021 ◽  
Vol 13 (21) ◽  
pp. 5569
Author(s):  
Annalaura Brai ◽  
Valentina Riva ◽  
Letizia Clementi ◽  
Lucia Falsitta ◽  
Claudio Zamperini ◽  
...  
Keyword(s):  
Cell Lines ◽  
Antitumoral Activity ◽  
Therapeutic Effects ◽  
Helicase Activity ◽  
In Vivo Evaluation ◽  
Cancer Types ◽  
And Migration ◽  
Oncogenic Protein ◽  
New Compounds

DDX3X is an ATP-dependent RNA helicase that has recently attracted interest for its involvement in viral replication and oncogenic progression. Starting from hit compounds previously identified by our group, we have designed and synthesized a new series of DDX3X inhibitors that effectively blocked its helicase activity. These new compounds were able to inhibit the proliferation of cell lines from different cancer types, also in DDX3X low-expressing cancer cell lines. According to the absorption, distribution, metabolism, elimination properties, and antitumoral activity, compound BA103 was chosen to be further investigated in glioblastoma models. BA103 determined a significant reduction in the proliferation and migration of U87 and U251 cells, downregulating the oncogenic protein β-catenin. An in vivo evaluation demonstrated that BA103 was able to reach the brain and reduce the tumor growth in xenograft and orthotopic models without evident side effects. This study represents the first demonstration that DDX3X-targeted small molecules are feasible and promising drugs also in glioblastoma.

scholarly journals DESIGN AND SYNTHESIS OF NOVEL 1-((DIMETHYLAMINO)METHYL)-3-(4-(3-(SUBSTITUTE DPHENYL)-4-OXOTHIAZOLIDIN-2-YL)PHENYLIMINO)-5-NITROINDOLIN-2-ONES AS POTENT ANTITUBERCULAR AGENTS

2019 ◽  
pp. 200-207
Author(s):  
KOSARAJU LAHARI ◽  
RAJA SUNDARARAJAN
Keyword(s):  
Antimicrobial Activity ◽  
Antimicrobial Agents ◽  
Biological Activities ◽  
Antimicrobial Activities ◽  
Mannich Bases ◽  
Proton Nuclear Magnetic Resonance ◽  
Design And Synthesis ◽  
Group Variation

Objective: Isatins have emerged as antimicrobial agents due to their broad spectrum of in vitro and in vivo antimicrobial activities. In addition, thiazolidinone also reported to possess various biological activities particularly antimicrobial activity. Due to the importance, we planned to synthesize compounds with isatin functionality coupled with thiazolidinone as possible antitubercular and antimicrobial agents which could furnish better therapeutic results. Methods: In vitro Mycobacterium tuberculosis method and agar streak dilution test are used to estimate antitubercular and antimicrobial potency of title analogs, respectively. Minimum inhibitory concentration of entire title compounds was determined against all tested microorganism such as M. tuberculosis, four Gram-positive, three Gram-negative bacteria, and two fungi. Results: A series of new thiazolidinone substituted Schiff and Mannich bases of 5-nitroisatins were designed and synthesized by a multistep synthesis from isatin. Structures of synthesized compounds are characterized using Fourier-transform infrared, proton nuclear magnetic resonance, mass spectroscopy, and bases of elemental analysis. Mild to good antitubercular and antimicrobial activity was showed by synthesized 5-nitroisatin analogs. The relationship between the biological activity and the functional group variation of the tested compounds was discussed. Conclusion: 3-(4-(3-(4-Aminophenyl)-4-oxothiazolidin-2-yl)phenylimino)-1-((dimethyl amino)methyl)-5-nitroindolin-2-one 6 and 3-(4-(3- (2-aminophenyl)-4-oxothiazolidin-2-yl)phenylimino)-1-((dimethylamino)methyl)-5-nitroindolin-2-one 13 were found to be the most potent compounds of this series which might be extended as a novel class of antimicrobial agents.

Design and Synthesis of Novel Thiosemicarbazones as Potent Anti-breast Cancer Agents

2019 ◽  
Vol 16 (4) ◽  
pp. 446-452 ◽  
Author(s):  
Mashooq Ahmad Bhat ◽  
M. Al-Tahhan ◽  
Mohamed A. Al-Omar ◽  
Ahmed M. Naglah ◽  
Abdullah Al-Dhfyan
Keyword(s):  
Breast Cancer ◽  
Cell Lines ◽  
Side Population ◽  
Biological Activities ◽  
Cancer Cell Line ◽  
Inhibition Assay ◽  
Reference Drug ◽  
Design And Synthesis ◽  
Pure Compounds ◽  
Mcf 7

Background: Thiosemicarbazones and its derivatives received a great pharmaceutical importance due to their prominent biological activities. Methods: A series of disubstituted thiosemicarbazone derivatives (1-12) were designed and synthesized as pure compounds in good yield. All the synthesized compounds were analyzed by spectral data. The anticancer activity of all the compounds was performed against breast cancer MCF-7 and MDA-MB-231 cell lines. Results: Most of the compounds showed activity against breast cancer MCF-7 and MDA-MB-231 cell lines with (IC50 = 12.25 µM ‒ 185.35 µM) and (IC50 = 12.97 µM ‒ 107.33 µM), respectively. Compound 9 presented (IC50 = 12.76 µM and 12.97 µM) against MCF-7 and MDA-MB-231 cell lines, respectively. Conclusion: Compound 9, was found to exhibit significant anti-breast cancer activity. This compound was further evaluated for side population percent inhibition assay on the breast cancer cell line MCF-7 at 5 and 10 µM concentration. It showed superiority to block side population by more than 80% at 5 μM concentration compared to the reference drug verapamil.

scholarly journals The Design, Synthesis, and Evaluation of Hypoxia-Activated Prodrugs of the KDAC Inhibitor Panobinostat

2020 ◽  
Author(s):  
Ewen Calder ◽  
Anna Skwarska ◽  
Deborah Sneddon ◽  
Lisa Folkes ◽  
Ishna N. Mistry ◽  
...  
Keyword(s):  
Cell Lines ◽  
Cancer Cell ◽  
Human Cancer ◽  
Parent Drug ◽  
Human Cancer Cell ◽  
Design Synthesis ◽  
Human Cancer Cell Lines ◽  
Design And Synthesis ◽  
Initial Validation

The design and synthesis of four hypoxia-activated prodrugs of the KDAC inhibitor panobinostat is described. Initial validation of these compounds using isolated enzymes, and in two human cancer cell lines, reveals that the nitroimidazole-based prodrug (NI-Pano, CH-03) undergoes efficient bioreduction and fragmentation to release the parent drug, panobinostat. NI-Pano was identified as the optimum compound for use in further studies in cells, spheroid tumor models, and <i>in vivo</i>.

scholarly journals Synthesis and biological evaluation of heterocyclic 1,2,4-Triazole scaffolds as promising pharmacological agents

2020 ◽  
Author(s):  
Mukesh Kumari ◽  
Sumit Tahlan ◽  
Balasubramanian Narasimhan ◽  
Kalavathy Ramasamy ◽  
Siong Meng Lim ◽  
...  
Keyword(s):  
Antimicrobial Activity ◽  
Cell Lines ◽  
Biological Activities ◽  
Biological Evaluation ◽  
Dilution Method ◽  
Pharmacological Agents ◽  
Drug Candidates ◽  
Design And Synthesis ◽  
Hct 116

Abstract Background: Triazole is an important heterocyclic moiety that occupied a unique position in heterocyclic chemistry, due to its large number of biological activities. It exists in two isomeric forms i.e. 1,2,4-triazole and 1,2,3-triazole and used as core molecule for the design and synthesis of many medicinal compounds. 1,2,4-Triazole possess broad spectrum of therapeutically interesting drug candidates such as analgesic, antiseptic, antimicrobial, antioxidant, antiurease , anti-inflammatory, diuretics, anticancer, anticonvulsant, antidiabetic, antimigrain agents.Methods: The structure of all synthesized compounds were characterized by physicochemical properties and spectral means (IR and NMR). The synthesized compounds were evaluated for their in vitro antimicrobial activity against Gram-positive (B. subtilis), Gram-negative (P. aeruginosa and E. coli) bacterial and fungal (C. albicans and A. niger) strains by tube dilution method using ciprofloxacin, amoxicillin and fluconazole as standards. In-vitro antioxidant and anti-urease screening was done by DPPH assay and indophenol method, respectively. The in-vitro anticancer evaluation was carried out against MCF-7 and HCT116 cancer cell lines using 5-FU and cisplatin as standards.Results, discussion and conclusion: The biological screening results reveal that the compounds T5 (MICBS, EC = 24.7µM, MICPA, CA = 12.3 µM) and T17 (MICAN = 27.1µM) exhibited potent antimicrobial activity as comparable to standards ciprofloxacin, amoxicillin (MICCipro = 18.1µM, MICAmo = 17.1µM) and fluconazole (MICFlu = 20.4µM), respectively. The antioxidant evaluation showed that compounds T2 (IC50 = 34.83 µg/ml) and T3 (IC50 = 34.38 µg/ml) showed significant antioxidant activity and comparable to ascorbic acid (IC50 = 35.44 µg/ml). Compounds T3 (IC50 = 54.01µg/ml) was the most potent urease inhibitor amongst the synthesized compounds and compared to standard thiourea (IC50 = 54.25 µg/ml). The most potent anticancer activity showed by compounds T2 (IC50 = 3.84 μM) and T7 (IC50 = 3.25 μM) against HCT 116 cell lines as compared to standard 5-FU (IC50 = 25.36 μM).

scholarly journals A Novel Oncolytic Reovirus Immune Priming Strategy Dramatically Enhances the Efficacy of Anti-PD-L1 Antibody Therapy Against Multiple Myeloma

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3960-3960 ◽  
Author(s):  
Kevin R. Kelly ◽  
Claudia M. Espitia ◽  
Weiguo Zhao ◽  
Valeria Visconte ◽  
Matt Coffey ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Clinical Study ◽  
Cell Lines ◽  
Immune Checkpoint ◽  
Single Agent ◽  
Bone Destruction ◽  
The United States ◽  
Significant Activity ◽  
Immune Priming

Abstract Multiple myeloma (MM) is the second most common adult hematologic malignancy in the United States and is characterized by a unique form of progressive bone destruction. Despite the development of new treatments such as proteasome inhibitors and immunomodulatory agents, patients with high-risk disease have a median survival of only 2-3 years, highlighting the demand for more effective therapeutic strategies. Oncolytic viral formulations represent a promising new class of anticancer agents that may have important applications in precision medicine. Recent studies have demonstrated that reoviruses specifically replicate only in cancer cells and this led to the development of a reovirus-based oncolytic viral therapy called Reolysin. We have demonstrated that reoviruses selectively replicate in MM cells and Reolysin possesses significant activity in preclinical in vitro and in vivo MM models. These findings established the framework for an ongoing investigator-initiated phase 1b clinical study of Reolysin in combination with bortezomib and dexamethasone in patients with relapsed/refractory MM. Recent gene ontology analyses of RPMI-8226 and U266 MM cells treated with Reolysin revealed that reovirus exposure triggers a highly significant transient increase in CD274(programmed death 1 ligand, PD-L1) in MM cell lines. Reolysin-mediated PD-L1 upregulation was confirmed by immunoblotting, qRT-PCR, and flow cytometric analyses in MM cell lines and primary patient specimens treated with Reolysin. Increased PD-L1 expression was also detected by immunohistochemistry in MM tumor samples collected from mice treated with Reolysin. Adaptive resistance mediated by inhibitory ligands such as PD-L1 has emerged as an important mechanism of malignant cell survival and has led to the development of new agents that disrupt the PD-L1/PD-1 immune checkpoint. These agents have exhibited dramatic efficacy in certain forms of cancer including melanoma and lung cancer. Analysis of specimens from patients treated on clinical trials with these agents indicates that high basal expression of PD-L1 on tumor cells may be necessary to elicit significant clinical benefit. Notably, most MM cell lines and primary CD138+ cells from MM patients do not overexpress PD-L1 compared to normal plasma cells and this may preclude patients with MM from optimally benefiting from immune checkpoint therapy. However, novel immune priming strategies that stimulate transient upregulation of PD-L1 on malignant cells could potentially render agents that target the PD-L1/PD-1 axis significantly more effective for a broader range of malignancies including MM. We hypothesized that Reolysin could be used as a precision immune priming agent to potentiate the anti-MM efficacy of PD-L1 targeted therapy by rendering MM cells vulnerable to PD-L1 inhibition through the transient upregulation of target expression. To investigate this therapeutic approach, 5TGM1-luc murine MM cells were injected IV into immunocompetent mice to generate MM bone disease. After disease was established, mice were randomized into groups and treated with vehicle, Reolysin (5 x 108 TCID50, Q7D), murine anti-PD-L1 antibody (200 mg/mouse, Q2D) or the combination for 5 weeks. Mice treated with the combination demonstrated decreased disease burden as measured by bioluminescent imaging and also showed reduced IgG2bk levels (specific IgG secreted by 5TGM1 cells) by ELISA. Importantly, the combination also led to increased overall animal survival compared to vehicle control and either single agent treatment (P<0.01). Analysis of bone marrow specimens from mice in all experimental groups showed that Reolysin stimulated elevated PD-L1 levels in vivo in a manner that was directly linked to the enhanced efficacy of the combination. Our findings demonstrate that Reolysin has dramatic PD-L1-related immune priming effects in clinically relevant models of MM and support its use as a precision agent to sensitize MM cells to immune checkpoint therapy. Based on these promising data, we are currently planning a clinical study of Reolysin in combination with bortezomib and a PD-1 inhibitor in patients with relapsed/refractory MM. Disclosures Kelly: Novartis: Consultancy, Speakers Bureau; Pharmacyclics: Consultancy, Speakers Bureau; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees. Coffey:Oncolytics Biotech: Employment.

Evaluation of ON 01910.Na, a novel modulator of polo-like kinase 1 (Plk1) pathway, and development of a cyclin-B1-based predictive assay in pancreatic cancer

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 3569-3569
Author(s):  
A. Jimeno ◽  
A. Chan ◽  
X. Zhang ◽  
J. Wheelhouse ◽  
A. Solomon ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cell Lines ◽  
Ex Vivo ◽  
Cyclin B1 ◽  
Preclinical Model ◽  
Significant Activity ◽  
In Vivo Models ◽  
Pancreatic Cell ◽  
Ex Vivo Assay

3569 Background: Plk1 is a key mitotic regulator of the transition through the G2/M checkpoint in the cell cycle. This work aimed to evaluate the activity of ON 01910.Na, a Plk1 pathway modulator, in in vitro and in vivo models of pancreatic cancer (PaCa) and to discover biomarkers predictive of efficacy. Methods: ON 01910.Na was tested in 12 PaCa cell lines. Studies assessing Plk1 related markers were conducted to identify biomarkers. For validation a live collection of PaCa xenografts from fresh tumor samples obtained at the time of surgical resection was used (PancXenoBank). The ex vivo assay was based on fine-needle aspirate (FNA) biopsies. Results: ON 01910.Na showed equal activity to gemcitabine against PaCa cell lines. The activity of ON 01910.Na correlated with suppression of two downstream mediators of PLK1, CDC25C and cyclin B1 (by mRNA and protein). ON 01910.Na was tested in xenografts from representative pancreatic cell lines. The selected markers were evaluated in an ex vivo assay, using intra-tumor pharmacokinetics to select the dose of the assay. Cyclin B1 mRNA evaluation yielded the most optimal combination of accuracy and reproducibility. Knockdown of cyclin B1 by siRNA had no effect per se or in the response of the resistant MiaPaca2 to either of the drugs. We next used the ex vivo assay to profile ten patient-derived cases from the PancXenoBank. Two cases were catalogued as potential responders. From each of these ten cases, a group of mice bearing at least 20 tumors received vehicle or ON 01910.Na for 28 days. There was a correlation between the ex vivo cyclin B1 assay and the sensitivity to the tested agent, as the 2 cases prospectively identified as sensitive met pre-specified criteria for response. Of the 8 tumors predicted to be resistant, only one was sensitive. In IHC testing cases showing ex vivo cyclin B1 down-regulation had also decreases in cyclin B1 protein, and there was a correlation between activity and IHC changes in cyclin B1. Conclusions: ON 01910.Na demonstrated significant activity in a preclinical model of PaCa. A rationally designed ex vivo cyclin B1-based assay not only identified cases sensitive to ON 01910.Na, but also replicated the pharmacodynamic events occurring after in vivo exposure. No significant financial relationships to disclose.

Preclinical study of PD-0332991 on EBV-positive NPC cell lines and xenografts.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e17506-e17506
Author(s):  
Zhichao Xue
Keyword(s):  
Cell Lines ◽  
Tumor Size ◽  
In Vitro Study ◽  
Preclinical Study ◽  
Drug Study ◽  
Single Drug ◽  
Combination Study ◽  
Scan Data

e17506 Background: Originated from nasopharynx, nasopharyngeal carcinoma is a subtype of head and neck cancer, which is consistently associated with EBV infection. It is prevalent exclusively in south of China, Malaysia and southeast Asia. Previously, there was only one EBV positive cell line, c666-1, for NPC study, the new EBV positive cell lines and xenografts established by our lab recently represent better models for preclinical drug test. The objective of this preclinical study is to evaluate the therapeutic effect of specific CDK4/6 inhibitor PD-0332991 in our new established EBV positive NPC cell lines and Xenografts. Methods: Cell lines were cultured in both 2D and 3D condition, cytotoxic test was conduct by Resazurin in 2D and by cell titer-glo in 3D. Cell cycle was analyzed by Western blot and flow cytometry. In the animal study, PD-0332991 was first used as single drug administrated to xenograft mice daily by oral gavage. Secondly, SAHA as a HDAC inhibitor was used to combine with PD-0332991 in this study, which was i.p. injected into animal every other day. Tumor size, body weight well as micro-pets scan data was recorded. The data from each experiment was analyzed by ANOVA and unpaired t-test for significant drug responses. Results: PD-0332991 was first identified to be effective during in vitro study. Beside single drug effect, when combination with SAHA, a synergistic effect was observed both in vitro and in vivo. In single drug study, PD-0332991 can significantly inhibit tumor growth in 3 of our xenografts (XENO76: P < 0.0001, XENO32: P < 0.0001, XENO23: P = 0.0019). In combination study, through tumor size and micro-pets scan, combination treatment induced significant decrease in tumor size and tumor metabolism states in animal models compare to vehicle, PD-0332991 and SAHA treatment. Conclusions: PD-0332991 is identified to be effective in our preclinical test by using our new established EBV positive cell lines and xenografts, this could be a promising treatment for NPC patients after clinical trial.

The Nucleoside Analogue Acadesine Exerts Antitumoral Activity and Cooperates with Conventional Agents In In Vitro and In Vivo Models of Mantle Cell Lymphoma

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3918-3918
Author(s):  
Arnau Montraveta ◽  
Mercè de Frías ◽  
Clara Campàs ◽  
Elias Campo ◽  
Gael Roue ◽  
...  
Keyword(s):  
Mantle Cell Lymphoma ◽  
Cell Lines ◽  
Nucleoside Analogue ◽  
Cell Lymphoma ◽  
Primary Cultures ◽  
Antitumoral Activity ◽  
In Vivo Models ◽  
Mantle Cell

Abstract Abstract 3918 Mantle cell lymphoma (MCL) is a mature B-cell neoplasm characterized by the t(11;14)(q13:q32) that involves cyclin D1 overexpression and consequent cell cycle deregulation at the G1 phase. This entity is generally characterized by an aggressive course and a bad prognosis. Recently, a specific subtype of MCL has been described, showing best outcomes and that might be managed more conservatively than conventional MCL. These cases are characterized by non-nodal presentation, predominantly hypermutated IgVH, lack of genomic complexity, and absence of SOX11 expression. Acadesine is a nucleoside analogue initially developed as a cardioprotective agent, and which has shown a wide range of metabolic effects, including the activation of AMP-activated protein kinase (AMPK). Acadesine was shown to induce apoptosis in primary cells from several B lymphoid neoplasms and has been entered in a phase I/II clinical trial with relapsed/refractory chronic lymphocytic leukemia (CLL) patients. This clinical study has shown that acadesine plasmatic levels in the micro molar range are achievable and safe when CLL patients are treated with the drug. To evaluate the antitumoral properties of acadesine in MCL, we exposed a set of 11 MCL primary cultures and 9 MCL cell lines for up to 48h with increasing doses of the drug. Cytotoxicity and cytostatic effects were then assessed by flow cytometry detection of annexinV/propidium iodide labeling and MTT proliferation assay, respectively. In both MCL cell lines and MCL primary cultures, we observed a heterogeneous response to the drug, with no correlation to common genetic alterations such as deletion/mutation of P53, ATM or P16 genes. JVM2, Jeko-1, Rec-1 and UPN-1 were the more sensitive cell lines, with a mean lethal dose 50 (LD50) of 1.57 mM at 24 h and 0.95 mM at 48h, while 2 cell lines (HBL-2 and Granta-519) showed a primary resistance to the compound (LD50 > 50 mM). Among MCL primary cultures, acadesine showed selective cytotoxic activity against malignant B cells while sparing accompanying T cells. Of note, those cases corresponding to the indolent MCL group showed increased sensitivity to the drug at 24h of treatment, when compared to conventional MCL cases (p=0.03). We observed that acadesine efficiently activates the intrinsic apoptotic pathway in MCL cells by modulating Bcl-2 family protein levels, leading to conformational activation of Bax and Bak, mitochondrial depolarization, generation of reactive oxygen species and caspases processing. In drug combination assays, acadesine showed a synergistic effect when combined with Rituximab, being the Rituximab-acadesine combination more potent than other Rituximab-based polychemotherapies such as R-bendamustine and R-CHOP. Finally, a daily administration of 400mg/kg acadesine in mice previously inoculated with a MCL xenotransplant significantly reduced tumor burden when compared to control animals, as soon as 7 days of treatment. In summary, these results suggest that acadesine exerts significant antitumoral activity in both in vitro and in vivo model of MCL, and may represent an attractive model for the design of a new therapeutic approach for this entity, especially in patients presenting with the indolent form. Disclosures: de Frías: Advancell therapeutics: Employment. Campàs:Advancell therapeutics: Employment.

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