Synthesis and evaluation of new dinitrobenzamide mustards in human prostate cancer

Alireza Basiri; Wenting Zhang; Jered Garrison

doi:10.1016/j.bmcl.2020.127697

Synthesis and evaluation of new dinitrobenzamide mustards in human prostate cancer

Bioorg Med Chem Lett. 2021 Jan 1:31:127697. doi: 10.1016/j.bmcl.2020.127697. Epub 2020 Nov 18.

Authors

Alireza Basiri¹, Wenting Zhang¹, Jered Garrison²

Affiliations

¹ Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, 985830 Nebraska Medical Center, Omaha, NE 68198, United States; Center for Drug Delivery and Nanomedicine, University of Nebraska Medical Center, 985830 Nebraska Medical Center, Omaha, NE 68198, United States.
² Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, 985830 Nebraska Medical Center, Omaha, NE 68198, United States; Department of Biochemistry and Molecular Biology, College of Medicine, University of Nebraska Medical Center, 985870 Nebraska Medical Center, Omaha, NE 68198, United States; Center for Drug Delivery and Nanomedicine, University of Nebraska Medical Center, 985830 Nebraska Medical Center, Omaha, NE 68198, United States; Eppley Cancer Center, University of Nebraska Medical Center, 985950 Nebraska Medical Center, Omaha, NE 68198, United States. Electronic address: jcgarrison@unmc.edu.

Abstract

Tumor hypoxia has been widely explored over the years as a diagnostic and therapeutic marker. Herein, we have reported the design and synthesis of a series of dinitrobenzamide mustards (DNBM) based on the PR-104A hypoxia-selective prodrug. Specifically, we explored the impact of various leaving groups and the introduction of a carboxylic acid group on the biological performance of the DNBM constructs. Once in hand, the Log D values, cytotoxicity in PC-3 and DU-145 human prostate cancer cells lines and the hypoxia selectivities of the DNBM analogs were examined. Overall, the DNBM constructs were found to be tolerant to modifications with none of the explored modifications substantially degrading the cytotoxic potential of the constructs.

Keywords: DNBM; Hypoxia; Prodrug; Prostate cancer.

MeSH terms

Antineoplastic Agents, Alkylating / chemical synthesis
Antineoplastic Agents, Alkylating / chemistry
Antineoplastic Agents, Alkylating / pharmacology*
Cell Hypoxia / drug effects*
Cell Line, Tumor
Cell Proliferation / drug effects
Cell Survival / drug effects
Dose-Response Relationship, Drug
Drug Screening Assays, Antitumor
Humans
Male
Molecular Structure
Nitrogen Mustard Compounds / chemical synthesis
Nitrogen Mustard Compounds / chemistry
Nitrogen Mustard Compounds / pharmacology*
Prostatic Neoplasms / drug therapy*
Prostatic Neoplasms / pathology
Structure-Activity Relationship

Substances

2,4-dinitrobenzamide nitorgen mustard
Antineoplastic Agents, Alkylating
Nitrogen Mustard Compounds

Grants and funding

R01 CA179059/CA/NCI NIH HHS/United States