Cuviello_2018_Eur.J.Med.Chem_164_1

Reference

Title : The P-glycoprotein inhibitor diltiazem-like 8-(4-chlorophenyl)-5-methyl-8-[(2Z)-pent-2-en-1-yloxy]-8H-[1,2,4]oxadiazolo[3,4-c ][1,4]thiazin-3-one inhibits esterase activity and H3 histone acetylation - Cuviello_2018_Eur.J.Med.Chem_164_1
Author(s) : Cuviello F , Bisaccia F , Spinelli D , Armentano MF , Bufo SA , Cosimelli B , Ostuni A
Ref : Eur Journal of Medicinal Chemistry , 164 :1 , 2018
Abstract :

With the aim to reduce multidrug resistance several molecules were synthesized and tested for their ability to inhibit ATP-binding cassette (ABC) proteins, which are responsible for drugs transport out from cells. The compound 8-(4-chlorophenyl)-5-methyl-8-[(2Z)-pent-2-en-1-yloxy]-8H-[1,2,4]oxadiazolo[3,4-c ][1,4]thiazin-3-one namely 2c, is structurally related to the myocardial-calcium-channel-modulator diltiazem and is considered one of the most efficient P-glycoprotein inhibitors, able to induce apoptosis at low concentrations of doxorubicin in multidrug resistant ovarian cells. In this study experiments were carried out to evaluate other biological activities of compound 2c. We verified the ability of 2c to inhibit ABC transporters do not involved in drug resistance and considering the inhibitory effect of diltiazem on recombinant human carboxylesterase, we observed its inhibitory effect on the esterase activity. Our findings demonstrated that 2c exhibits broad-spectrum activity as ABC transporters inhibitor being able to inhibit ABCC6, a protein belonging to the ABC family although poorly involved in drug resistance. 2c also inhibits cell esterase activity, acetylcholine esterase activity in vitro and cell histone H3 acetylation according to its structural homology with some known HAT inhibitors. The results obtained provide new knowledge on the biological activities of 2c and represent useful information when it is used as an inhibitor of drug resistance.

PubMedSearch : Cuviello_2018_Eur.J.Med.Chem_164_1
PubMedID: 30583246

Related information

Substrate Diltiazem

Citations formats

Cuviello F, Bisaccia F, Spinelli D, Armentano MF, Bufo SA, Cosimelli B, Ostuni A (2018)
The P-glycoprotein inhibitor diltiazem-like 8-(4-chlorophenyl)-5-methyl-8-[(2Z)-pent-2-en-1-yloxy]-8H-[1,2,4]oxadiazolo[3,4-c ][1,4]thiazin-3-one inhibits esterase activity and H3 histone acetylation
Eur Journal of Medicinal Chemistry 164 :1

Cuviello F, Bisaccia F, Spinelli D, Armentano MF, Bufo SA, Cosimelli B, Ostuni A (2018)
Eur Journal of Medicinal Chemistry 164 :1