Base-modified thymidines capable of terminating DNA synthesis are novel bioactive compounds with activity in cancer cells

Kayla M. Borland; Safnas F. AbdulSalam; Morwena J. Solivio; Matthew P. Burke; Patrick R. Wolfkiel; Sean M. Lawson; Courtney A. Stockman; Joel M. Andersen; Skyler Smith; Julia N. Tolstolutskaya; Purujit N. Gurjar; Aron P. Bercz; Edward J. Merino; Vladislav A. Litosh

doi:10.1016/j.bmc.2015.01.057

Base-modified thymidines capable of terminating DNA synthesis are novel bioactive compounds with activity in cancer cells

Kayla M. Borland, Safnas F. AbdulSalam, Morwena J. Solivio, Matthew P. Burke, Patrick R. Wolfkiel, Sean M. Lawson, Courtney A. Stockman, Joel M. Andersen, Skyler Smith, Julia N. Tolstolutskaya, Purujit N. Gurjar, Aron P. Bercz, Edward J. Merino, Vladislav A. Litosh

Research output: Contribution to journal › Article › peer-review

5 Scopus citations

Abstract

Current FDA-approved chemotherapeutic antimetabolites elicit severe side effects that warrant their improvement; therefore, we designed compounds with mechanisms of action focusing on inhibiting DNA replication rather than targeting multiple pathways. We previously discovered that 5-(α-substituted-2-nitrobenzyloxy)methyluridine-5′-triphosphates were exquisite DNA synthesis terminators; therefore, we synthesized a library of 35 thymidine analogs and evaluated their activity using an MTT cell viability assay of MCF7 breast cancer cells chosen for their vulnerability to these nucleoside derivatives. Compound 3a, having an α-tert-butyl-2-nitro-4-(phenyl)alkynylbenzyloxy group, showed an IC₅₀ of 9 ± 1 μM. The compound is more selective for cancer cells than for fibroblast cells compared with 5-fluorouracil. Treatment of MCF7 cells with 3a elicits the DNA damage response as indicated by phosphorylation of γ-H2A. A primer extension assay of the 5′-triphosphate of 3a revealed that 3aTP is more likely to inhibit DNA polymerase than to lead to termination events upon incorporation into the DNA replication fork.

Original language	English (US)
Pages (from-to)	1869-1881
Number of pages	13
Journal	Bioorganic and Medicinal Chemistry
Volume	23
Issue number	8
DOIs	https://doi.org/10.1016/j.bmc.2015.01.057
State	Published - Apr 15 2015

Bibliographical note

Funding Information:
We gratefully acknowledge the University of Cincinnati start-up and the University of Cincinnati Individual Faculty Research Grant funds to Prof. Litosh, and the NIH-NCI award ( R21CA185370 ) to Prof. Merino. We also acknowledge the National Cancer Institute Developmental Therapeutics Program for performing compound screening in a variety of cancer cell lines. Additionally, we would like to thank Prof. James Mack for granting access to his mechanochemistry facilities, making it possible to synthesize a key control compound that was inaccessible by conventional synthetic methods.

Publisher Copyright:
© 2015 Elsevier Ltd. All rights reserved.

Keywords

Antimetabolites
Cancer
Chemotherapeutics
DNA termination
Nucleosides
Nucleotides

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.bmc.2015.01.057

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Borland, K. M., AbdulSalam, S. F., Solivio, M. J., Burke, M. P., Wolfkiel, P. R., Lawson, S. M., Stockman, C. A., Andersen, J. M., Smith, S., Tolstolutskaya, J. N., Gurjar, P. N., Bercz, A. P., Merino, E. J., & Litosh, V. A. (2015). Base-modified thymidines capable of terminating DNA synthesis are novel bioactive compounds with activity in cancer cells. Bioorganic and Medicinal Chemistry, 23(8), 1869-1881. https://doi.org/10.1016/j.bmc.2015.01.057

Borland, KM, AbdulSalam, SF, Solivio, MJ, Burke, MP, Wolfkiel, PR, Lawson, SM, Stockman, CA, Andersen, JM, Smith, S, Tolstolutskaya, JN, Gurjar, PN, Bercz, AP, Merino, EJ & Litosh, VA 2015, 'Base-modified thymidines capable of terminating DNA synthesis are novel bioactive compounds with activity in cancer cells', Bioorganic and Medicinal Chemistry, vol. 23, no. 8, pp. 1869-1881. https://doi.org/10.1016/j.bmc.2015.01.057

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abstract = "Current FDA-approved chemotherapeutic antimetabolites elicit severe side effects that warrant their improvement; therefore, we designed compounds with mechanisms of action focusing on inhibiting DNA replication rather than targeting multiple pathways. We previously discovered that 5-(α-substituted-2-nitrobenzyloxy)methyluridine-5′-triphosphates were exquisite DNA synthesis terminators; therefore, we synthesized a library of 35 thymidine analogs and evaluated their activity using an MTT cell viability assay of MCF7 breast cancer cells chosen for their vulnerability to these nucleoside derivatives. Compound 3a, having an α-tert-butyl-2-nitro-4-(phenyl)alkynylbenzyloxy group, showed an IC50 of 9 ± 1 μM. The compound is more selective for cancer cells than for fibroblast cells compared with 5-fluorouracil. Treatment of MCF7 cells with 3a elicits the DNA damage response as indicated by phosphorylation of γ-H2A. A primer extension assay of the 5′-triphosphate of 3a revealed that 3aTP is more likely to inhibit DNA polymerase than to lead to termination events upon incorporation into the DNA replication fork.",

keywords = "Antimetabolites, Cancer, Chemotherapeutics, DNA termination, Nucleosides, Nucleotides",

author = "Borland, {Kayla M.} and AbdulSalam, {Safnas F.} and Solivio, {Morwena J.} and Burke, {Matthew P.} and Wolfkiel, {Patrick R.} and Lawson, {Sean M.} and Stockman, {Courtney A.} and Andersen, {Joel M.} and Skyler Smith and Tolstolutskaya, {Julia N.} and Gurjar, {Purujit N.} and Bercz, {Aron P.} and Merino, {Edward J.} and Litosh, {Vladislav A.}",

note = "Funding Information: We gratefully acknowledge the University of Cincinnati start-up and the University of Cincinnati Individual Faculty Research Grant funds to Prof. Litosh, and the NIH-NCI award ( R21CA185370 ) to Prof. Merino. We also acknowledge the National Cancer Institute Developmental Therapeutics Program for performing compound screening in a variety of cancer cell lines. Additionally, we would like to thank Prof. James Mack for granting access to his mechanochemistry facilities, making it possible to synthesize a key control compound that was inaccessible by conventional synthetic methods. Publisher Copyright: {\textcopyright} 2015 Elsevier Ltd. All rights reserved.",

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AU - Borland, Kayla M.

AU - AbdulSalam, Safnas F.

AU - Solivio, Morwena J.

AU - Burke, Matthew P.

AU - Wolfkiel, Patrick R.

AU - Lawson, Sean M.

AU - Stockman, Courtney A.

AU - Andersen, Joel M.

AU - Smith, Skyler

AU - Tolstolutskaya, Julia N.

AU - Gurjar, Purujit N.

AU - Bercz, Aron P.

AU - Merino, Edward J.

AU - Litosh, Vladislav A.

N1 - Funding Information: We gratefully acknowledge the University of Cincinnati start-up and the University of Cincinnati Individual Faculty Research Grant funds to Prof. Litosh, and the NIH-NCI award ( R21CA185370 ) to Prof. Merino. We also acknowledge the National Cancer Institute Developmental Therapeutics Program for performing compound screening in a variety of cancer cell lines. Additionally, we would like to thank Prof. James Mack for granting access to his mechanochemistry facilities, making it possible to synthesize a key control compound that was inaccessible by conventional synthetic methods. Publisher Copyright: © 2015 Elsevier Ltd. All rights reserved.

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N2 - Current FDA-approved chemotherapeutic antimetabolites elicit severe side effects that warrant their improvement; therefore, we designed compounds with mechanisms of action focusing on inhibiting DNA replication rather than targeting multiple pathways. We previously discovered that 5-(α-substituted-2-nitrobenzyloxy)methyluridine-5′-triphosphates were exquisite DNA synthesis terminators; therefore, we synthesized a library of 35 thymidine analogs and evaluated their activity using an MTT cell viability assay of MCF7 breast cancer cells chosen for their vulnerability to these nucleoside derivatives. Compound 3a, having an α-tert-butyl-2-nitro-4-(phenyl)alkynylbenzyloxy group, showed an IC50 of 9 ± 1 μM. The compound is more selective for cancer cells than for fibroblast cells compared with 5-fluorouracil. Treatment of MCF7 cells with 3a elicits the DNA damage response as indicated by phosphorylation of γ-H2A. A primer extension assay of the 5′-triphosphate of 3a revealed that 3aTP is more likely to inhibit DNA polymerase than to lead to termination events upon incorporation into the DNA replication fork.

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KW - Nucleosides

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Base-modified thymidines capable of terminating DNA synthesis are novel bioactive compounds with activity in cancer cells

Abstract

Bibliographical note

Keywords

UN SDGs

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