New Inhibitors of Breast Cancer Resistance Protein (ABCG2) Containing a 2,4-Disubstituted Pyridopyrimidine Scaffold

Multidrug resistance (MDR) occurring during cancer chemotherapy is a major obstacle for effectiveness and response to therapy and is often caused by ATP-binding cassette (ABC) efflux transporters. Belonging to the family of ABC transporters, breast cancer resistance protein is getting more and more in the spotlight of research. As a strategy to overcome MDR, inhibitors of ABC transporters were synthesized, which could be applied in combination with cytostatic drugs. For this purpose, 2,4-disubstituted pyridopyrimidine derivatives were synthesized. The investigations confirmed three key characteristics of good inhibitors: a low intrinsic cytotoxicity and a high potency and selectivity toward ABCG2. For selected compounds the interaction with ABCG2 was elucidated and their effect on ATPase activity and conformation sensitive 5D3 antibody binding was investigated. Their ability to reverse MDR in coadministration with the active metabolite of irinotecan and mitoxantron was confirmed

New Inhibitors of Breast Cancer Resistance Protein (ABCG2) Containing a 2,4-Disubstituted Pyridopyrimidine Scaffold

Multidrug resistance (MDR) occurring during cancer chemotherapy is a major obstacle for effectiveness and response to therapy and is often caused by ATP-binding cassette (ABC) efflux transporters. Belonging to the family of ABC transporters, breast cancer resistance protein is getting more and more in the spotlight of research. As a strategy to overcome MDR, inhibitors of ABC transporters were synthesized, which could be applied in combination with cytostatic drugs. For this purpose, 2,4-disubstituted pyridopyrimidine derivatives were synthesized. The investigations confirmed three key characteristics of good inhibitors: a low intrinsic cytotoxicity and a high potency and selectivity toward ABCG2. For selected compounds the interaction with ABCG2 was elucidated and their effect on ATPase activity and conformation sensitive 5D3 antibody binding was investigated. Their ability to reverse MDR in coadministration with the active metabolite of irinotecan and mitoxantron was confirmed

Solubility of Carvedilol in Ethanol + Propylene Glycol Mixtures at Various Temperatures

Solubilities of carvedilol (CVD) in binary mixtures of (ethanol + propylene glycol (PG)) at 298.2, 303.2, 308.2, and 313.2 K are reported. The modified versions of the van’t Hoff and Gibbs equations were used to calculate the thermodynamic properties (enthalpy (Δ<i>H</i>°), entropy (Δ<i>S</i>°), and Gibbs energy (Δ<i>G</i>°) standard changes of solutions) for CVD dissolved in (ethanol (1) + PG (2)) mixtures from the solubility data. The solubility data of CVD in (ethanol (1) + PG (2)) at different temperatures were correlated using different mathematical models, i.e., the Jouyban–Acree model, a combination of the Jouyban–Acree model with the van’t Hoff model, and two modified versions of the Jouyban–Acree model. Solubility data of seven drugs in (ethanol (1) + PG (2)) at different temperatures were used to develop a quantitative structure–property relationship model for predicting solubility in solvent mixtures. In addition, enthalpy–entropy compensation using Δ<i>H</i>° vs Δ<i>G</i>° and Δ<i>H</i>° vs <i>T</i>ΔS° which explains the mechanism of cosolvency at different temperatures was discussed