Novel Isoxazolidine and γ-Lactam Analogues of Homonucleosides

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Abstract

Homonucleoside analogues cis- 16 and trans- 17 having a (5-methoxycarbonyl)isoxazolidine framework were synthesized via the 1,3-dipolar cycloaddition of nucleobase-derived nitrones with methyl acrylate. Hydrogenolysis of the isoxazolidines containing thymine, dihydrouracil, theophylline and adenine moieties efficiently led to the formation of the respective γ-lactam analogues. γ-Lactam analogues having 5-bromouracil and 5-chlorouracil fragments were synthesized by treatment of uracil-containing γ-lactams with NBS and NCS. Isoxazolidine and γ-lactam analogues of homonucleosides obtained herein were evaluated for activity against a broad range of DNA and RNA viruses. None of the compounds that were tested exhibited antiviral or cytotoxic activity at concentrations up to 100 µM. The cytostatic activities of all compounds toward nine cancerous cell lines was tested. γ-Lactams trans- 15e (Cl-Ura) and cis- 15h (Theo) appeared the most active toward pancreatic adenocarcinoma cells (Capan-1), showing IC ₅₀ values 21.5 and 18.2 µM, respectively. Isoxazolidine cis- 15e (Cl-Ura) inhibited the proliferation of colorectal carcinoma (HCT-116).

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Most cited references 59

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Lars Petter Jordheim, David Durantel, Fabien Zoulim … (2013)

Nucleoside analogues have been in clinical use for almost 50 years and have become cornerstones of treatment for patients with cancer or viral infections. The approval of several additional drugs over the past decade demonstrates that this family still possesses strong potential. Here, we review new nucleoside analogues and associated compounds that are currently in preclinical or clinical development for the treatment of cancer and viral infections, and that aim to provide increased response rates and reduced side effects. We also highlight the different approaches used in the development of these drugs and the potential of personalized therapy.

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Nucleoside analogs are structurally similar antimetabolites that have a broad range of action and are clinically active in both solid tumors and hematological malignancies. Many of these agents are incorporated into DNA by polymerases during normal DNA synthesis, an action that blocks further extension of the nascent strand and causes stalling of replication forks. The molecular mechanisms that sense stalled replication forks activate cell cycle checkpoints and DNA repair processes, which may contribute to drug resistance. When replication forks are not stabilized by these molecules or when subsequent DNA repair processes are overwhelmed, apoptosis is initiated either by these same DNA damage sensors or by alternative mechanisms. Recently, strategies aimed at targeting DNA damage checkpoints or DNA repair processes have demonstrated effectiveness in sensitizing cells to nucleoside analogs, thus offering a means to elude drug resistance. In addition to their DNA synthesis-directed actions many nucleoside analogs trigger apoptosis by unique mechanisms, such as causing epigenetic modifications or by direct activation of the apoptosome. A review of the cellular and molecular responses to clinically relevant agents provides an understanding of the mechanisms that cause apoptosis and may provide rationale for the development of novel therapeutic strategies.

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A new compound has been found, (S)-9-(3-hydroxy-2-phosphonylmethoxypropyl)adenine ((S)-HPMPA), that has potent and selective activity against a broad spectrum of DNA viruses, including herpes simplex virus (types 1 and 2); varicella zoster virus; thymidine kinase-deficient (TK-) mutants of herpes simplex and varicella zoster virus; human cytomegalovirus; phocid, simian, suid, bovid and equid herpesviruses; African swine fever virus; vaccinia virus; and human adenoviruses. It is also active against retroviruses. We also report that, in mice and rabbits in vivo, the compound is effective against both local and systemic infections with herpes simplex virus type 1, including herpetic keratitis caused by a TK- mutant which is resistant to the classical anti-herpes drugs.

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Author and article information

Journal

Journal ID (nlm-ta): Molecules

Journal ID (iso-abbrev): Molecules

Journal ID (publisher-id): molecules

Title: Molecules

Publisher: MDPI

ISSN (Electronic): 1420-3049

Publication date (Electronic): 06 November 2019

Publication date Collection: November 2019

Volume: 24

Issue: 22

Electronic Location Identifier: 4014

Affiliations

[1 ]Bioorganic Chemistry Laboratory, Faculty of Pharmacy, Medical University of Lodz, Muszynskiego 1, 90-151 Lodz, Poland; iwona.glowacka@ 123456umed.lodz.pl (I.E.G.); joanna.gotkowska@ 123456umed.lodz.pl (J.G.)

[2 ]Rega Institute for Medical Research, KU Leuven, Herestraat 49, B-3000 Leuven, Belgium

Author notes

[* ]Correspondence: dorota.piotrowska@ 123456umed.lodz.pl ; Tel.: +48-42-677-92-33; Fax: +48-42-678-83-98

Author information

Dorota G. Piotrowska https://orcid.org/0000-0003-3792-8796

Iwona E. Głowacka https://orcid.org/0000-0001-7567-5860

Graciela Andrei https://orcid.org/0000-0003-2609-4896

Article

Publisher ID: molecules-24-04014

DOI: 10.3390/molecules24224014

PMC ID: 6891762

PubMed ID: 31698778

SO-VID: 83b7b0f1-84e0-4e6d-b952-d655cf38fae3

License:

Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

Novel Isoxazolidine and γ-Lactam Analogues of Homonucleosides

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Abstract

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MDPI: Coronavirus

Most cited references 59

Advances in the development of nucleoside and nucleotide analogues for cancer and viral diseases.

Nucleoside analogs: molecular mechanisms signaling cell death.

A novel selective broad-spectrum anti-DNA virus agent.

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