Pharmaceuticals

Research

11 pages, 2239 KiB

Open AccessCommunication

Microwave-Assisted Synthesis of Potential Bioactive Benzo-, Pyrido- or Pyrazino-thieno[3,2-d]pyrimidin-4-amine Analogs of MPC-6827

by Yvonnick Loidreau, Marie-Renée Nourrisson, Corinne Fruit, Cécile Corbière, Pascal Marchand and Thierry Besson

Pharmaceuticals 2020, 13(9), 202; https://doi.org/10.3390/ph13090202 - 19 Aug 2020

Cited by 10 | Viewed by 2764

Abstract

Efficient microwave-assisted chemical processes were applied to the synthesis of an array of novel N-(4-methoxyphenylamino)-2-methyl benzo-, pyrido- or pyrazino-thieno[3,2-d]pyrimidin-4-amine derivatives. These heteroaromatic systems were envisioned as potent bioisosteric analogues of MPC-6827, an anticancer agent previously developed until phase II [...] Read more.

Efficient microwave-assisted chemical processes were applied to the synthesis of an array of novel N-(4-methoxyphenylamino)-2-methyl benzo-, pyrido- or pyrazino-thieno[3,2-d]pyrimidin-4-amine derivatives. These heteroaromatic systems were envisioned as potent bioisosteric analogues of MPC-6827, an anticancer agent previously developed until phase II clinical studies. A brief evaluation and comparison of their antiproliferative activity on HT-29 and Caco-2, two human colorectal cancer cell lines, were also reported. At the tested concentrations (5 and 10 µM), thieno[3,2-d]pyrimidin-4-amines 4a and 4c exhibited an inhibitory effect similar to MPC-6827 on human colorectal cancer cell proliferation. Full article

(This article belongs to the Special Issue Recent Contributions in Medicinal Chemistry Within European GP2A Network)

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12 pages, 1364 KiB

Open AccessCommunication

Exploring Kinase Inhibition Properties of 9H-pyrimido[5,4-b]- and [4,5-b]indol-4-amine Derivatives

by Yvonnick Loidreau, Carole Dubouilh-Benard, Marie-Renée Nourrisson, Nadège Loaëc, Laurent Meijer, Thierry Besson and Pascal Marchand

Pharmaceuticals 2020, 13(5), 89; https://doi.org/10.3390/ph13050089 - 9 May 2020

Cited by 9 | Viewed by 3484

Abstract

We previously highlighted the interest in 6,5,6-fused tricyclic analogues of 4-aminoquinazolines as kinase inhibitors in the micromolar to the nanomolar range of IC₅₀ values. For the generation of chemical libraries, the formamide-mediated cyclization of the cyanoamidine precursors was carried out under microwave [...] Read more.

We previously highlighted the interest in 6,5,6-fused tricyclic analogues of 4-aminoquinazolines as kinase inhibitors in the micromolar to the nanomolar range of IC₅₀ values. For the generation of chemical libraries, the formamide-mediated cyclization of the cyanoamidine precursors was carried out under microwave irradiation in an eco-friendly approach. In order to explore more in-depth the pharmacological interest in such tricyclic skeletons, the central five member ring, i.e., thiophène or furan, was replaced by a pyrrole to afford 9H-pyrimido[5,4-b]- and [4,5-b]indol-4-amine derivatives inspired from harmine. The inhibitory potency of the final products was determined against four protein kinases (CDK5/p25, CK1δ/ε, GSK3α/β, and DYRK1A). As a result, we have identified promising compounds targeting CK1δ/ε and DYRK1A and displaying micromolar and submicromolar IC₅₀ values. Full article

(This article belongs to the Special Issue Recent Contributions in Medicinal Chemistry Within European GP2A Network)

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22 pages, 6763 KiB

Open AccessArticle

Structure–Activity Relationships (SARs) of α-Ketothioamides as Inhibitors of Phosphoglycerate Dehydrogenase (PHGDH)

by Quentin Spillier, Séverine Ravez, Judith Unterlass, Cyril Corbet, Charline Degavre, Olivier Feron and Raphaël Frédérick

Pharmaceuticals 2020, 13(2), 20; https://doi.org/10.3390/ph13020020 - 22 Jan 2020

Cited by 18 | Viewed by 5457

Abstract

For many years now, targeting deregulation within cancer cells’ metabolism has appeared as a promising strategy for the development of more specific and efficient cancer treatments. Recently, numerous reports highlighted the crucial role of the serine synthetic pathway, and particularly of the phosphoglycerate [...] Read more.

For many years now, targeting deregulation within cancer cells’ metabolism has appeared as a promising strategy for the development of more specific and efficient cancer treatments. Recently, numerous reports highlighted the crucial role of the serine synthetic pathway, and particularly of the phosphoglycerate dehydrogenase (PHGDH), the first enzyme of the pathway, to sustain cancer progression. Yet, because of very weak potencies usually in cell-based settings, the inhibitors reported so far failed to lay ground on the potential of this approach. In this paper, we report a structure–activity relationship study of a series of α-ketothioamides that we have recently identified. Interestingly, this study led to a deeper understanding of the structure–activity relationship (SAR) in this series and to the identification of new PHGDH inhibitors. The activity of the more potent compounds was confirmed by cellular thermal shift assays and in cell-based experiments. We hope that this research will eventually provide a new entry point, based on this promising chemical scaffold, for the development of therapeutic agents targeting PHGDH. Full article

(This article belongs to the Special Issue Recent Contributions in Medicinal Chemistry Within European GP2A Network)

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9 pages, 1687 KiB

Open AccessCommunication

Biological Characterization of 8-Cyclopropyl-2-(pyridin-3-yl)thiazolo[5,4-f]quinazolin-9(8H)-one, a Promising Inhibitor of DYRK1A

by Corinne Fruit, Florence Couly, Rahul Bhansali, Malini Rammohan, Mattias F. Lindberg, John D. Crispino, Laurent Meijer and Thierry Besson

Pharmaceuticals 2019, 12(4), 185; https://doi.org/10.3390/ph12040185 - 17 Dec 2019

Cited by 10 | Viewed by 4268

Abstract

Dual-specificity tyrosine phosphorylation-regulated kinases (DYRKs) hyperactivity has been linked to the development of a number of human malignancies. DYRK1A is the most studied family member, and the discovery of novel specific inhibitors is attracting considerable interest. The 8-cyclopropyl-2(pyridin-3-yl)thiazolo[5,4-f]quinazolin-9(8H)-one (also [...] Read more.

Dual-specificity tyrosine phosphorylation-regulated kinases (DYRKs) hyperactivity has been linked to the development of a number of human malignancies. DYRK1A is the most studied family member, and the discovery of novel specific inhibitors is attracting considerable interest. The 8-cyclopropyl-2(pyridin-3-yl)thiazolo[5,4-f]quinazolin-9(8H)-one (also called FC162) was found to be a promising inhibitor of DYRK1A and was characterized in biological experiments, by western transfer and flow cytometry on SH-SY5Y and pre-B cells. Here, the results obtained with FC162 are compared to well-characterized known DYRK1A inhibitors (e.g., Leucettine L41 and EHT1610). Full article

(This article belongs to the Special Issue Recent Contributions in Medicinal Chemistry Within European GP2A Network)

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22 pages, 7372 KiB

Open AccessArticle

Biological Evaluation of Arylsemicarbazone Derivatives as Potential Anticancer Agents

by Anne Cecília Nascimento da Cruz, Dalci José Brondani, Temístocles I´talo de Santana, Lucas Oliveira da Silva, Elizabeth Fernanda da Oliveira Borba, Antônio Rodolfo de Faria, Julianna Ferreira Cavalcanti de Albuquerque, Sylvie Piessard, Rafael Matos Ximenes, Blandine Baratte, Stéphane Bach, Sandrine Ruchaud, Francisco Jaime Bezerra Mendonça Junior, Marc-Antoine Bazin, Marcelo Montenegro Rabello, Marcelo Zaldini Hernandes, Pascal Marchand and Teresinha Gonçalves da Silva

Pharmaceuticals 2019, 12(4), 169; https://doi.org/10.3390/ph12040169 - 17 Nov 2019

Cited by 7 | Viewed by 4464

Abstract

Fourteen arylsemicarbazone derivatives were synthesized and evaluated in order to find agents with potential anticancer activity. Cytotoxic screening was performed against K562, HL-60, MOLT-4, HEp-2, NCI-H292, HT-29 and MCF-7 tumor cell lines. Compounds 3c and 4a were active against the tested cancer cell [...] Read more.

Fourteen arylsemicarbazone derivatives were synthesized and evaluated in order to find agents with potential anticancer activity. Cytotoxic screening was performed against K562, HL-60, MOLT-4, HEp-2, NCI-H292, HT-29 and MCF-7 tumor cell lines. Compounds 3c and 4a were active against the tested cancer cell lines, being more cytotoxic for the HL-60 cell line with IC₅₀ values of 13.08 μM and 11.38 μM, respectively. Regarding the protein kinase inhibition assay, 3c inhibited seven different kinases and 4a strongly inhibited the CK1δ/ε kinase. The studied kinases are involved in several cellular functions such as proliferation, migration, cell death and cell cycle progression. Additional analysis by flow cytometry revealed that 3c and 4a caused depolarization of the mitochondrial membrane, suggesting apoptosis mediated by the intrinsic pathway. Compound 3c induced arrest in G1 phase of the cell cycle on HL-60 cells, and in the annexin V assay approximately 50% of cells were in apoptosis at the highest concentration tested (26 μM). Compound 4a inhibited cell cycle by accumulation of abnormal postmitotic cells at G1 phase and induced DNA fragmentation at the highest concentration (22 μM). Full article

(This article belongs to the Special Issue Recent Contributions in Medicinal Chemistry Within European GP2A Network)

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Review

Jump to: Research, Other

43 pages, 3965 KiB

Open AccessReview

Colchicine-Binding Site Inhibitors from Chemistry to Clinic: A Review

by Eavan C. McLoughlin and Niamh M. O’Boyle

Pharmaceuticals 2020, 13(1), 8; https://doi.org/10.3390/ph13010008 - 3 Jan 2020

Cited by 214 | Viewed by 11516 | Correction

Abstract

It is over 50 years since the discovery of microtubules, and they have become one of the most important drug targets for anti-cancer therapies. Microtubules are predominantly composed of the protein tubulin, which contains a number of different binding sites for small-molecule drugs. [...] Read more.

It is over 50 years since the discovery of microtubules, and they have become one of the most important drug targets for anti-cancer therapies. Microtubules are predominantly composed of the protein tubulin, which contains a number of different binding sites for small-molecule drugs. There is continued interest in drug development for compounds targeting the colchicine-binding site of tubulin, termed colchicine-binding site inhibitors (CBSIs). This review highlights CBSIs discovered through diverse sources: from natural compounds, rational design, serendipitously and via high-throughput screening. We provide an update on CBSIs reported in the past three years and discuss the clinical status of CBSIs. It is likely that efforts will continue to develop CBSIs for a diverse set of cancers, and this review provides a timely update on recent developments. Full article

(This article belongs to the Special Issue Recent Contributions in Medicinal Chemistry Within European GP2A Network)

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21 pages, 6620 KiB

Open AccessReview

A Decade of Antifungal Leads from Natural Products: 2010–2019

by Mohammed Aldholmi, Pascal Marchand, Isabelle Ourliac-Garnier, Patrice Le Pape and A. Ganesan

Pharmaceuticals 2019, 12(4), 182; https://doi.org/10.3390/ph12040182 - 12 Dec 2019

Cited by 63 | Viewed by 7840

Abstract

In this review, we discuss novel natural products discovered within the last decade that are reported to have antifungal activity against pathogenic species. Nearly a hundred natural products were identified that originate from bacteria, algae, fungi, sponges, and plants. Fungi were the most [...] Read more.

In this review, we discuss novel natural products discovered within the last decade that are reported to have antifungal activity against pathogenic species. Nearly a hundred natural products were identified that originate from bacteria, algae, fungi, sponges, and plants. Fungi were the most prolific source of antifungal compounds discovered during the period of review. The structural diversity of these antifungal leads encompasses all the major classes of natural products including polyketides, shikimate metabolites, terpenoids, alkaloids, and peptides. Full article

(This article belongs to the Special Issue Recent Contributions in Medicinal Chemistry Within European GP2A Network)

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Other

Jump to: Research, Review

54 pages, 14948 KiB

Open AccessConference Report

30th Annual GP₂A Medicinal Chemistry Conference

by Niamh M. O’Boyle, Jean-Jacques Helesbeux, Mary J. Meegan, Astrid Sasse, Elizabeth O’Shaughnessy, Alina Qaisar, Aoife Clancy, Florence McCarthy and Pascal Marchand

Pharmaceuticals 2023, 16(3), 432; https://doi.org/10.3390/ph16030432 - 12 Mar 2023

Viewed by 5621

Abstract

The Group for the Promotion of Pharmaceutical Chemistry in Academia (GP₂A) held their 30th annual conference in August 2022 in Trinity College Dublin, Ireland. There were 9 keynote presentations, 10 early career researcher presentations and 41 poster presentations. Full article

(This article belongs to the Special Issue Recent Contributions in Medicinal Chemistry Within European GP2A Network)

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53 pages, 19431 KiB

Open AccessConference Report

29th Annual GP2A Medicinal Chemistry Conference

by Jean-Jacques Helesbeux, Laura Carro, Florence O. McCarthy, Vânia M. Moreira, Francesca Giuntini, Niamh O’Boyle, Susan E. Matthews, Gülşah Bayraktar, Samuel Bertrand, Christophe Rochais and Pascal Marchand

Pharmaceuticals 2021, 14(12), 1278; https://doi.org/10.3390/ph14121278 - 7 Dec 2021

Viewed by 6613

Abstract

The 29th Annual GP₂A (Group for the Promotion of Pharmaceutical chemistry in Academia) Conference was a virtual event this year due to the COVID-19 pandemic and spanned three days from Wednesday 25 to Friday 27 August 2021. The meeting brought together [...] Read more.

The 29th Annual GP₂A (Group for the Promotion of Pharmaceutical chemistry in Academia) Conference was a virtual event this year due to the COVID-19 pandemic and spanned three days from Wednesday 25 to Friday 27 August 2021. The meeting brought together an international delegation of researchers with interests in medicinal chemistry and interfacing disciplines. Abstracts of keynote lectures given by the 10 invited speakers, along with those of the 8 young researcher talks and the 50 flash presentation posters, are included in this report. Like previous editions, the conference was a real success, with high-level scientific discussions on cutting-edge advances in the fields of pharmaceutical chemistry. Full article

(This article belongs to the Special Issue Recent Contributions in Medicinal Chemistry Within European GP2A Network)

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2 pages, 315 KiB

Open AccessCorrection

Correction: McLoughlin, E.C.; O’Boyle, N.M. Colchicine-Binding Site Inhibitors from Chemistry to Clinic: A Review. Pharmaceuticals 2020, 13, 8

by Eavan C. McLoughlin and Niamh M. O’Boyle

Pharmaceuticals 2020, 13(4), 72; https://doi.org/10.3390/ph13040072 - 20 Apr 2020

Cited by 10 | Viewed by 2310

Abstract

We, the authors, wish to make the following corrections to our paper [...] Full article

(This article belongs to the Special Issue Recent Contributions in Medicinal Chemistry Within European GP2A Network)

47 pages, 11734 KiB

Open AccessMeeting Report

27th Annual GP2A Medicinal Chemistry Conference

by Shailesh N. Mistry, Pascal Marchand and Barrie Kellam

Pharmaceuticals 2019, 12(4), 179; https://doi.org/10.3390/ph12040179 - 6 Dec 2019

Viewed by 7595

Abstract

The 27th annual GP2A (Groupement des Pharmacochimistes de l′Arc Atlantique/Group of Medicinal Chemists in the Atlantic Arc) conference took place from 21 to 23 August 2019, at the East Midlands Conference Centre (University Park, Nottingham, United Kingdom) and was hosted by the Division [...] Read more.

The 27th annual GP2A (Groupement des Pharmacochimistes de l′Arc Atlantique/Group of Medicinal Chemists in the Atlantic Arc) conference took place from 21 to 23 August 2019, at the East Midlands Conference Centre (University Park, Nottingham, United Kingdom) and was hosted by the Division of Biomolecular Science and Medicinal Chemistry (BSMC), within the School of Pharmacy at the University of Nottingham. The event brought together an international delegation of researchers with interests in medicinal chemistry and interfacing disciplines. In addition, a pre-conference workshop provided an opportunity for younger researchers to develop their theoretical knowledge in quantitative pharmacology. Abstracts of presentations by the 14 invited speakers and 6 young researchers, in addition to 41 posters, are included in this report. Full article

(This article belongs to the Special Issue Recent Contributions in Medicinal Chemistry Within European GP2A Network)

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42 pages, 12024 KiB

Open AccessMeeting Report

26th Annual GP2A Medicinal Chemistry Conference & 32nd Journées Franco-Belges de Pharmacochimie

by Patrick Dallemagne, Christophe Rochais, Pascal Marchand and Thierry Besson

Pharmaceuticals 2019, 12(2), 73; https://doi.org/10.3390/ph12020073 - 16 May 2019

Viewed by 7450

Abstract

As a joint meeting, the 26th Medicinal Chemistry Conference of GP2A and 32nd Journées Franco-Belges de Pharmacochimie took place between 13th and 15th June at Asnelles sur Mer (Normandie, France), providing a unique opportunity for a wide group of European medicinal chemists to [...] Read more.

As a joint meeting, the 26th Medicinal Chemistry Conference of GP2A and 32nd Journées Franco-Belges de Pharmacochimie took place between 13th and 15th June at Asnelles sur Mer (Normandie, France), providing a unique opportunity for a wide group of European medicinal chemists to engage. Topics included chemical tools for medicinal chemistry, protein-protein interactions, epigenetics, natural product-inspired molecules, computer-aided drug design, and new strategies for the design and development of drugs. Abstracts of invited lectures, proffered young researcher communications, flash communications and posters presented during the meeting are collected in this report. Full article

(This article belongs to the Special Issue Recent Contributions in Medicinal Chemistry Within European GP2A Network)

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