Pharmacology and in vivo efficacy of pyridine-pyrimidine amides that inhibit microtubule polymerization

Siddiqui‐Jain, Adam; Hoj, Jacob P.; Cescon, David W.; Hansen, Marc D.H.

doi:10.1016/j.bmcl.2018.01.053

Cited by 14 publications

(5 citation statements)

References 20 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In in vitro metabolism assays of ianthelliformisamines A–C ( 1 – 3 ), the results of the positive control verapamil were consistent with published data [ 50 ] and confirmed suitable activity of the microsomes under the conditions used. In this study, 1 underwent moderate degradation in mouse liver microsomes but displayed significant instability in the presence of human microsomes, while 2 was moderately degraded in microsomes from both species.…”

Section: Discussionsupporting

confidence: 88%

Bromotyrosine-Derived Metabolites from a Marine Sponge Inhibit Pseudomonas aeruginosa Biofilms

Tran

Addison

Davis

et al. 2023

IJMS

View full text Add to dashboard Cite

Pseudomonas aeruginosa forms stable biofilms, providing a major barrier for multiple classes of antibiotics and severely impairing treatment of infected patients. The biofilm matrix of this Gram-negative bacterium is primarily composed of three major exopolysaccharides: alginate, Psl, and Pel. Here, we studied the antibiofilm properties of sponge-derived natural products ianthelliformisamines A–C and their combinations with clinically used antibiotics. Wild-type P. aeruginosa strain and its isogenic exopolysaccharide-deficient mutants were employed to determine the interference of the compounds with biofilm matrix components. We identified that ianthelliformisamines A and B worked synergistically with ciprofloxacin to kill planktonic and biofilm cells. Ianthelliformisamines A and B reduced the minimum inhibitory concentration (MIC) of ciprofloxacin to 1/3 and 1/4 MICs, respectively. In contrast, ianthelliformisamine C (MIC = 53.1 µg/mL) alone exhibited bactericidal effects dose-dependently on both free-living and biofilm populations of wild-type PAO1, PAO1ΔpslA (Psl deficient), PDO300 (alginate overproducing and mimicking clinical isolates), and PDO300Δalg8 (alginate deficient). Interestingly, the biofilm of the clinically relevant mucoid variant PDO300 was more susceptible to ianthelliformisamine C than strains with impaired polysaccharide synthesis. Ianthelliformisamines exhibited low cytotoxicity towards HEK293 cells in the resazurin viability assay. Mechanism of action studies showed that ianthelliformisamine C inhibited the efflux pump of P. aeruginosa. Metabolic stability analyses indicated that ianthelliformisamine C is stable and ianthelliformisamines A and B are rapidly degraded. Overall, these findings suggest that the ianthelliformisamine chemotype could be a promising candidate for the treatment of P. aeruginosa biofilms.

show abstract

Section: Discussionsupporting

confidence: 88%

Bromotyrosine-Derived Metabolites from a Marine Sponge Inhibit Pseudomonas aeruginosa Biofilms

Tran

Addison

Davis

et al. 2023

IJMS

View full text Add to dashboard Cite

show abstract

“…Tumor cells proliferate rapidly through cycles of tubulin polymerization and depolymerization of tubulin. Compounds that inhibit tubulin polymerization have thus been developed as cytotoxic drugs and are an integral part of chemotherapy [ 31 ]. Colchicine was the first compound that was identified to target microtubules, which binds to tubulin and inhibits microtubule polymerization [ 32 ].…”

Section: Tubulin Polymerization Inhibitorsmentioning

confidence: 99%

Recent Advances in the Development of Pyrazole Derivatives as Anticancer Agents

Zhang

et al. 2023

IJMS

View full text Add to dashboard Cite

Pyrazole derivatives, as a class of heterocyclic compounds, possess unique chemical structures that confer them with a broad spectrum of pharmacological activities. They have been extensively explored for designing potent and selective anticancer agents. In recent years, numerous pyrazole derivatives have been synthesized and evaluated for their anticancer potential against various cancer cell lines. Structure–activity relationship studies have shown that appropriate substitution on different positions of the pyrazole ring can significantly enhance anticancer efficacy and tumor selectivity. It is noteworthy that many pyrazole derivatives have demonstrated multiple mechanisms of anticancer action by interacting with various targets including tubulin, EGFR, CDK, BTK, and DNA. Therefore, this review summarizes the current understanding on the structural features of pyrazole derivatives and their structure-activity relationships with different targets, aiming to facilitate the development of potential pyrazole-based anticancer drugs. We focus on the latest research advances in anticancer activities of pyrazole compounds reported from 2018 to present.

show abstract

“…IMB5046 was not a P‐gp substrate and displayed potent cytotoxicity against a panel of tumor cell lines and multidrug‐resistant cell lines that were resistant to colchicine, vincristine, and paclitaxel treatment . D4‐9‐31, a pyridine‐pyrimidine amide, showed strong efficacy in isogenic paclitaxel‐resistant breast cancer cells and also evaded P‐gp‐mediated drug efflux . Another major mechanism of drug resistance to tubulin inhibitors that is a critical clinical concern is due to the overexpression of certain β tubulin isoforms.…”

Section: Mechanisms Of Multidrug Resistancementioning

confidence: 99%

“…128 D4-9-31, a pyridine-pyrimidine amide, showed strong efficacy in isogenic paclitaxel-resistant breast cancer cells and also evaded P-gp-mediated drug efflux. 129 Another major mechanism of drug resistance to tubulin inhibitors that is a critical clinical concern is due to the overexpression of certain β tubulin isoforms. As stated above, humans have at least seven expressed β tubulin isoforms, and alterations in their expression is linked to acquired drug resistance.…”

mentioning

confidence: 99%

Current advances of tubulin inhibitors as dual acting small molecules for cancer therapy

Arnst

Banerjee

Chen

et al. 2019

Medicinal Research Reviews

122

107

View full text Add to dashboard Cite

Microtubule (MT)‐targeting agents are highly successful drugs as chemotherapeutic agents, and this is attributed to their ability to target MT dynamics and interfere with critical cellular functions, including, mitosis, cell signaling, intracellular trafficking, and angiogenesis. Because MT dynamics vary in the different stages of the cell cycle, these drugs tend to be the most effective against mitotic cells. While this class of drug has proven to be effective against many cancer types, significant hurdles still exist and include overcoming aspects such as dose limited toxicities and the development of resistance. Newer generations of developed drugs attack these problems and alternative approaches such as the development of dual tubulin and kinase inhibitors are being investigated. This approach offers the potential to show increased efficacy and lower toxicities. This review covers different categories of MT‐targeting agents, recent advances in dual inhibitors, and current challenges for this drug target.

show abstract

Pharmacology and in vivo efficacy of pyridine-pyrimidine amides that inhibit microtubule polymerization

Cited by 14 publications

References 20 publications

Bromotyrosine-Derived Metabolites from a Marine Sponge Inhibit Pseudomonas aeruginosa Biofilms

Bromotyrosine-Derived Metabolites from a Marine Sponge Inhibit Pseudomonas aeruginosa Biofilms

Recent Advances in the Development of Pyrazole Derivatives as Anticancer Agents

Current advances of tubulin inhibitors as dual acting small molecules for cancer therapy

Contact Info

Product

Resources

About