Isosteres of ester derived glucose uptake inhibitors

Dennis A Roberts; Liyi Wang; Weihe Zhang; Yi Liu; Pratik Shriwas; Yanrong Qian; Xiaozhuo Chen; Stephen C Bergmeier

doi:10.1016/j.bmcl.2020.127406

Isosteres of ester derived glucose uptake inhibitors

Bioorg Med Chem Lett. 2020 Sep 15;30(18):127406. doi: 10.1016/j.bmcl.2020.127406. Epub 2020 Jul 15.

Authors

Dennis A Roberts¹, Liyi Wang¹, Weihe Zhang¹, Yi Liu², Pratik Shriwas³, Yanrong Qian⁴, Xiaozhuo Chen⁵, Stephen C Bergmeier⁶

Affiliations

¹ Department of Chemistry and Biochemistry, Ohio University, Athens, OH 45701, USA.
² Department of Biomedical Science, Ohio University, Athens, OH 45701, USA; Program of Molecular and Cellular Biology, Ohio University, Athens, OH 45701, USA.
³ Program of Molecular and Cellular Biology, Ohio University, Athens, OH 45701, USA.
⁴ Department of Chemistry and Biochemistry, Ohio University, Athens, OH 45701, USA; Edison Biotechnology Institute, Ohio University, Athens, OH 45701, USA; Program of Molecular and Cellular Biology, Ohio University, Athens, OH 45701, USA.
⁵ Department of Chemistry and Biochemistry, Ohio University, Athens, OH 45701, USA; Edison Biotechnology Institute, Ohio University, Athens, OH 45701, USA; Department of Biomedical Science, Ohio University, Athens, OH 45701, USA; Program of Molecular and Cellular Biology, Ohio University, Athens, OH 45701, USA.
⁶ Department of Chemistry and Biochemistry, Ohio University, Athens, OH 45701, USA; Program of Molecular and Cellular Biology, Ohio University, Athens, OH 45701, USA. Electronic address: bergmeis@ohio.edu.

PMID: 32736210
DOI: 10.1016/j.bmcl.2020.127406

Abstract

Glucose transporters (GLUTs) facilitate glucose uptake and are overexpressed in most cancer cells. Inhibition of glucose transport has been shown to be an effective method to slow the growth of cancer cells both in vitro and in vivo. We have previously reported on the anticancer activity of an ester derived glucose uptake inhibitor. Due to the hydrolytic instability of the ester linkage we have prepared a series of isosteres of the ester moiety. Of all of the isosteres prepared, the amine linkage showed the most promise. Several additional analogues of the amine-linked compounds were also prepared to improve the overall activity.

Keywords: Bioisostere; Cancer; GLUT; Glucose uptake; Transporters.

Publication types

Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Amides / chemistry
Amines / chemistry
Antineoplastic Agents / chemical synthesis*
Antineoplastic Agents / pharmacology
Carbohydrate Metabolism
Cell Line, Tumor
Cell Membrane Permeability
Drug Screening Assays, Antitumor
Esters / chemical synthesis*
Esters / pharmacology
Glucose / metabolism*
Glucose Transport Proteins, Facilitative / antagonists & inhibitors*
Glycolysis / drug effects
Humans
Phosphorylation / drug effects
Phthalic Acids / chemistry
Structure-Activity Relationship
Sulfones / chemistry
Sulfoxides / chemistry

Substances

Amides
Amines
Antineoplastic Agents
Esters
Glucose Transport Proteins, Facilitative
Phthalic Acids
Sulfones
Sulfoxides
phthalic acid
Glucose