Coumarin carboxylic acids as monocarboxylate transporter 1 inhibitors: In vitro and in vivo studies as potential anticancer agents

Abstract

Novel N,N-dialkyl carboxy coumarins have been synthesized as potential anticancer agents via inhibition of monocarboxylate transporter 1 (MCT1). These coumarin carboxylic acids have been evaluated for their in vitro MCT1 inhibition, MTT cancer cell viability, bidirectional Caco-2 cell permeability, and stability in human and liver microsomes. These results indicate that one of the lead candidate compounds 4a has good absorption, metabolic stability, and a low drug efflux ratio. Systemic toxicity studies with lead compound 4a in healthy mice demonstrate that this inhibitor is well tolerated based on zero animal mortality and normal body weight gains compared to the control group. In vivo tumor growth inhibition studies in mice show that the candidate compound 4a exhibits significant single agent activity in MCT1 expressing GL261-luc2 syngraft model but doesn’t show significant activity in MCT4 expressing MDA-MB-231 xenograft model, indicating the selectivity of 4a for MCT1 expressing tumors.

Synthesis of Hydrazone Derivatives of 4-[4-Formyl-3-(2-oxochromen-3-yl)pyrazol-1-yl]benzoic acid as Potent Growth Inhibitors of Antibiotic-resistant Staphylococcus aureus and Acinetobacter baumannii

“…Coumarin derivatives are well-known oxygenated fused bicyclic molecules. These molecules are known for their wide range of biological activities [8,9,10] including activity against Gram-positive [11] bacteria ( S. aureus , [12] Bacillus subtilis [13,14]) and Gram-negative [11] ( E. coli , [12,14] P. aeruginosa [15] and other bacterial species [16]). Coumarin derivatives as anti- A. baumannii agents are rare [17].…”

Nanoparticles Based on Novel Carbohydrate-Functionalized Polymers

“…For the mannoconjugate 25, it was observed that it formed irregular films, with multiple cracks, and a high degree of convolution of neighboring agglomerates either by the polymer's preferential formation of films, or due to film deposition on top of those agglomerates. Dynamic Light Scattering (DLS) technique (results presented in Figure 2), where the particles are suspended in water in a colloidal manner, showed average particle size of 253 (20), 118 (24), and 193 nm (25), peak size of 219 (20), 105 (24), and 171 nm (25) and high polydispersity indexes of 5.828 (20), 0.440 (24), and 0.682 (25). These results confirmed that PEG derivatives formed polydisperse samples, with aggregates.…”

“…Monosaccharides (glucose, galactose, mannose, and thymidine) were bonded to these polymers to allow specific interactions between cell receptors and drug delivery agents. Coumarins were also included to potentially increase the pharmaceutical activity of these polymers, since they are known for their biological properties [23][24][25][26], but also to exploit their use as traceable probes due to their fluorescence character. In some cases, the click chemistry methodology [27] was used to establish the covalent bonds between these building blocks.…”

Identification of a selective inhibitor of human monocarboxylate transporter 4

“…The human monocarboxylate transporters (hMCTs/SLC16As) belong to solute carrier family 16 and mediate the uptake of various monocarboxylates (1). Among the hMCTs, hMCT1 and hMCT4 are prominently expressed in cancerous tissue, and transport energetic metabolites, such as L-lactate and pyruvate (2)(3)(4)(5).…”

“…Hence, these compounds are not suited as a pharmacological tool for distinguishing hMCT1 and hMCT4 in native cells. Although pteridine derivatives and coumarin derivatives have been created as selective hMCT1 inhibitors, no selective hMCT4 inhibitor has yet been developed (15,16). Tokyo Chemical Industry (Tokyo, Japan).…”