Design, Synthesis and Structure−Activity Relationships of Novel Taxane-Based Multidrug Resistance Reversal Agents

AbstractP-gp-associated multidrug resistance is a major impediment to the success of chemotherapy. With the aim of finding non-toxic and effective P-gp inhibitors, we investigated a panel of quinolin-2-one-pyrimidine hybrids. Among the active compounds, two of them significantly increased intracellular doxorubicin and rhodamine 123 accumulation by inhibiting the efflux mediated by P-gp and restored doxorubicin toxicity at nanomolar range. Structure–activity relationships showed that the number of methoxy groups, an optimal length of the molecule in its extended conformation, and at least one flexible methylene group bridging the quinolinone to the moiety bearing the pyrimidine favored the inhibitory potency of P-gp. The best compounds showed a similar binding pattern and interactions to those of doxorubicin and tariquidar, as revealed by MD and hybrid QM/MM simulations performed with the recent experimental structure of P-gp co-crystallized with paclitaxel. Analysis of the molecular interactions stabilizing the different molecular complexes determined by MD and QTAIM showed that binding to key residues from TMH 4–7 and 12 is required for inhibition.

Download Full-text

Quinolin-2-one-pyrimidine Hybrids Acting as Potent Reversal Agents on the P-gp-mediated Multidrug Resistance: Insights into Structure-activity Relationships and the Binding Mode

10.21203/rs.3.rs-451061/v1 ◽

2021 ◽

Author(s):

Jerónimo Laiolo ◽

Priscila Ailin Lanza ◽

Oscar Parravicini ◽

Cecilia Barbieri ◽

Daniel Insuasty ◽

...

Keyword(s):

Multidrug Resistance ◽

Molecular Complexes ◽

Binding Mode ◽

Reversal Agents ◽

Structure Activity Relationships ◽

Structure Activity ◽

Doxorubicin Toxicity ◽

Key Residues ◽

Nanomolar Range ◽

Experimental Structure

Abstract P-gp-associated multidrug resistance (MDR) is a major impediment to the success of chemotherapy. With the aim of finding non-toxic and effective P-gp inhibitors, we investigated a panel of quinolin-2-one-pyrimidine hybrids. Among the active compounds, two of them significantly increased intracellular doxorubicin and rhodamine 123 accumulation by inhibiting the efflux mediated by P-gp and restored doxorubicin toxicity at nanomolar range. Structure-activity relationships showed that the number of methoxy groups, an optimal length of the molecule in its extended conformation, and at least one flexible methylene group bridging the quinolinone moiety favored the inhibitory potency of P-gp. The best compounds showed a similar binding pattern and interactions to those of doxorubicin and tariquidar, as revealed by MD and hybrid QM/MM simulations performed with the recent experimental structure of P-gp co-crystallized with paclitaxel. Analysis of the molecular interactions stabilizing the different molecular complexes determined by MD and QTAIM showed that binding to key residues from TMH 4–7 and 12 is required for inhibition.

Download Full-text

Quantitative Structure-Activity Relationship of Multidrug Resistance Reversal Agents

Molecular Pharmacology ◽

10.1124/mol.52.2.323 ◽

1997 ◽

Vol 52 (2) ◽

pp. 323-334 ◽

Cited By ~ 88

Author(s):

Gilles Klopman ◽

Leming M. Shi ◽

Avner Ramu

Keyword(s):

Multidrug Resistance ◽

Quantitative Structure Activity Relationship ◽

Structure Activity Relationship ◽

Activity Relationship ◽

Quantitative Structure ◽

Reversal Agents ◽

Structure Activity ◽

Resistance Reversal ◽

Relationship Of

Download Full-text

Antitumor Agents 286. Design, Synthesis, and Structure−Activity Relationships of 3′R,4′R-Disubstituted-2′,2′-dimethyldihydropyrano[2,3-f]chromone (DSP) Analogues as Potent Chemosensitizers to Overcome Multidrug Resistance

Journal of Medicinal Chemistry ◽

10.1021/jm101249z ◽

2010 ◽

Vol 53 (24) ◽

pp. 8700-8708 ◽

Cited By ~ 20

Author(s):

Ting Zhou ◽

Qian Shi ◽

Kenneth F. Bastow ◽

Kuo-Hsiung Lee

Keyword(s):

Multidrug Resistance ◽

Antitumor Agents ◽

Design Synthesis ◽

Structure Activity Relationships ◽

Structure Activity

Download Full-text

Design, Synthesis and Biological Evaluation of Dimethyl Cardamonin (DMC) Derivatives as P-glycoprotein-mediated Multidrug Resistance Reversal Agents

Letters in Drug Design & Discovery ◽

10.2174/1570180817999200531162015 ◽

2020 ◽

Vol 17 (10) ◽

pp. 1270-1282

Author(s):

Ximeng Shi ◽

Yuyu Zhao ◽

Licheng Zhou ◽

Huanhuan Yin ◽

Jianwen Liu ◽

...

Keyword(s):

Multidrug Resistance ◽

Biological Evaluation ◽

Glycoprotein P ◽

Design Synthesis ◽

Reversal Agents ◽

Protein Levels ◽

P Glycoprotein ◽

Resistance Reversal ◽

Mcf 7

Background: P-glycoprotein (P-gp) has been regarded as an important factor in the multidrug resistance (MDR) of tumor cells within the last decade, which can be solved by inhibiting Pgp to reverse MDR. Thus, it is an effective strategy to develop inhibitor of P-gp. Objective: In this study, the synthesis of a series of derivatives had been carried out by bioisosterism design on the basis of Dimethyl Cardamonin (DMC). Subsequently, we evaluated their reversal activities as potential P-glycoprotein (P-gp)-mediated Multidrug Resistance (MDR) agents. Methods: Dimethyl cardamonin derivatives were synthesized from acetophenones and the corresponding benzaldehydes in the presence of 40% KOH by Claisen-Schmidt reaction. Their cytotoxicity and reversal activities in vitro were assessed with MTT. Moreover, the compound B4 was evaluated by Doxorubicin (DOX) accumulation, Western blot and wound-healing assays deeply. Results and Conclusion: The results showed that compounds B2, B4 and B6 had the potency of MDR reversers with little intrinsic cytotoxicity. Meanwhile, these compounds also demonstrated the capability to inhibit MCF-7 and MCF-7/DOX cells migration. Besides, the most compound B4 was selected for further study, which promoted the accumulation of DOX in MCF-7/DOX cells and inhibited the expressionof P-gp at protein levels. Conclusion: The above findings may provide new insights for the research and development of Pgp- mediated MDR reversal agents.

Download Full-text