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Special Issue "Targeted Prodrugs 2018"

A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Medicinal Chemistry".

Deadline for manuscript submissions: closed (30 June 2018)

Special Issue Editor

Guest Editor
Prof. William Robert Wilson

Auckland Cancer Society Research Centre, Faculty of Medical and Health Sciences, University of Auckland, Private Bag 92019, Auckland, New Zealand
Website | E-Mail
Phone: +64-9-9236883
Interests: tumour hypoxia; 3D cell culture models; radiation biology; drug discovery and development; CRISPR screens

Special Issue Information

Dear Colleagues,

Prodrug technologies are widely used to improve systemic drug delivery, but can also be used to target drugs to specific sites. This Special Issue focuses on prodrugs of the latter type, which are designed to increase drug exposure of disease targets relative to normal tissues.  This search for selectivity is a focus in cancer therapeutics in particular, but also in other diseases. Topics of relevance to this update and overview of prodrug technologies include design of compounds responsive to disease-specific triggering mechanisms (such as tumour hypoxia) and the biological evaluation of such prodrugs.

Prof. William Robert Wilson
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All papers will be peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Molecules is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 1800 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Prodrugs
  • Bystander effects
  • Targeted drug delivery
  • Tumor hypoxia
  • Prodrug-activating enzymes
  • Pharmacokinetics

Published Papers (3 papers)

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Research

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Open AccessCommunication Evaluation of Nitrobenzyl Derivatives of Camptothecin as Anti-Cancer Agents and Potential Hypoxia Targeting Prodrugs
Molecules 2018, 23(8), 2041; https://doi.org/10.3390/molecules23082041
Received: 30 June 2018 / Revised: 14 August 2018 / Accepted: 14 August 2018 / Published: 15 August 2018
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Abstract
As part of our initial efforts into developing a tumor-targeting therapy, C-10 substituted derivatives of a camptothecin analog (SN-38) have been synthesized (2-, 3- and 4-nitrobenzyl) for use as potential hypoxia-activated prodrugs and evaluated for their cytotoxicity, topoisomerase I inhibition and electrochemical (reductive)
[...] Read more.
As part of our initial efforts into developing a tumor-targeting therapy, C-10 substituted derivatives of a camptothecin analog (SN-38) have been synthesized (2-, 3- and 4-nitrobenzyl) for use as potential hypoxia-activated prodrugs and evaluated for their cytotoxicity, topoisomerase I inhibition and electrochemical (reductive) properties. All three derivatives were found to possess reduced toxicity towards human leukemia K562 cells compared to SN-38, validating a condition for prodrug action. Using an MTS assay, IC50’s were found to be 3.0, 25.9, 12.2 and 58.0 nM for SN-38, 2-nitro-, 3-nitro- and 4-nitrobenzyl-C10-substituted-SN-38, respectively, representing an 8-, 4- and 19-fold decrease in cytotoxicity. Using a topoisomerase I assay, one of the analogs (4-nitrobenzyl) was shown to inhibit the ability of this enzyme to relax supercoiled pBR322 DNA, at a similar concentration to the clinically-approved active metabolite SN-38. Cyclic voltammetry detailed the reductive nature of the analogs, and was used to infer the potential of these compounds to serve as hypoxia-targeting prodrugs. The electrochemical results also validated the quasi-reversible nature of the first reduction step, and served as a proof-of-principle that hypoxia-targeting prodrugs of SN-38 can participate in a redox-futile cycle, the proposed mechanism of activation and targeting. Chemical reduction of the 4-nitrobenzyl analog led to the formation/release of SN-38 and validated the prodrug ability of the C-10 substituted derivative. Full article
(This article belongs to the Special Issue Targeted Prodrugs 2018)
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Graphical abstract

Open AccessArticle Antitumor Effects and Delivery Profiles of Menahydroquinone-4 Prodrugs with Ionic or Nonionic Promoiety to Hepatocellular Carcinoma Cells
Molecules 2018, 23(7), 1738; https://doi.org/10.3390/molecules23071738
Received: 27 June 2018 / Revised: 14 July 2018 / Accepted: 15 July 2018 / Published: 16 July 2018
PDF Full-text (4006 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Hepatocellular carcinoma (HCC) shows poor prognosis owing to its very frequent recurrence even after curative treatment. Thus, an effective and safe long-term chemopreventive agent is strongly in demand. Menahydroquinone-4 (MKH) is an active form of menaquinone-4 (MK-4, vitamin K2) that is
[...] Read more.
Hepatocellular carcinoma (HCC) shows poor prognosis owing to its very frequent recurrence even after curative treatment. Thus, an effective and safe long-term chemopreventive agent is strongly in demand. Menahydroquinone-4 (MKH) is an active form of menaquinone-4 (MK-4, vitamin K2) that is involved in the synthesis of vitamin K-dependent proteins in the liver. We hypothesized that efficient delivery of MKH might be critical to regulate HCC proliferation. The discovery of a suitable prodrug targeting HCC in terms of delivery and activation could reduce the clinical dose of MK-4 and maximize efficacy and safety. We previously showed that MKH dimethylglycinate (MKH-DMG) enables effective delivery of MKH into HCC cells and exhibits strong antitumor effects compared with MK-4. In this study, we prepared anionic MKH hemi-succinate (MKH-SUC) and non-ionic MKH acetate (MKH-ACT), in addition to cationic MKH-DMG, and evaluated MKH delivery profiles and antitumor effects in vitro. MKH-SUC showed the highest uptake and the most efficient release of MKH among the examined compounds and exhibited rapid and strong antitumor effects. These results indicate that MKH-SUC might have a good potential as an MKH delivery system for HCC that overcomes the limitations of MK-4 as a clinical chemopreventive agent. Full article
(This article belongs to the Special Issue Targeted Prodrugs 2018)
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Review

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Open AccessReview Strategies for Enhancing the Permeation of CNS-Active Drugs through the Blood-Brain Barrier: A Review
Molecules 2018, 23(6), 1289; https://doi.org/10.3390/molecules23061289
Received: 3 April 2018 / Revised: 22 May 2018 / Accepted: 24 May 2018 / Published: 28 May 2018
Cited by 2 | PDF Full-text (1558 KB) | HTML Full-text | XML Full-text
Abstract
Background: The blood brain barrier (BBB) is a dynamic and functional structure which poses a vast challenge in the development of drugs acting on the central nervous system (CNS). While most substances are denied BBB crossing, selective penetration of substances mainly occurs through
[...] Read more.
Background: The blood brain barrier (BBB) is a dynamic and functional structure which poses a vast challenge in the development of drugs acting on the central nervous system (CNS). While most substances are denied BBB crossing, selective penetration of substances mainly occurs through diffusion, carrier mediated transport, or receptor mediated transcytosis. Methods: Strategies in enhancing BBB penetration have been reviewed and summarized in accordance with their type of formulation. Highlights in monoclonal antibodies, peptide-vectors, nanoparticles, and simple prodrugs were included. Conclusion: Nanoparticles and simple prodrugs, for example, can be used for efficient BBB penetration through inhibition of efflux mechanisms, however, monoclonal antibodies are the most promising strategy in BBB penetration. Close follow-up of future development in this area should confirm our expectation. Full article
(This article belongs to the Special Issue Targeted Prodrugs 2018)
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