Synthesis and evaluation of hybrid compounds based on antimalarial and anticancer pharmacophores

Includes bibliographical references.Malaria stills remains one of the leading causes of death in sub-Saharan Africa, with P. falciparum being the most virulent strain of Plasmodium. Due to the emergence of drug resistance, new antimalarial agents are needed to circumvent this. Similarly, in the treatment of cancer, there is an urgent need for the design and development of new antineoplastic agents. This work describes the design, synthesis and biological evaluation of chromone-aminoquinoline hybrids as potentially new chemotherapeutic agents

A perspective on the radiopharmaceutical requirements for imaging and therapy of glioblastoma

Despite numerous clinical trials and pre-clinical developments, the treatment of glioblastoma (GB) remains a challenge. The current survival rate of GB averages one year, even with an optimal standard of care. However, the future promises efficient patient-tailored treatments, including targeted radionuclide therapy (TRT). Advances in radiopharmaceutical development have unlocked the possibility to assess disease at the molecular level allowing individual diagnosis. This leads to the possibility of choosing a tailored, targeted approach for therapeutic modalities. Therapeutic modalities based on radiopharmaceuticals are an exciting development with great potential to promote a personalised approach to medicine. However, an effective targeted radionuclide therapy (TRT) for the treatment of GB entails caveats and requisites. This review provides an overview of existing nuclear imaging and TRT strategies for GB. A critical discussion of the optimal characteristics for new GB targeting therapeutic radiopharmaceuticals and clinical indications are provided. Considerations for target selection are discussed, i.e. specific presence of the target, expression level and pharmacological access to the target, with particular attention to blood-brain barrier crossing. An overview of the most promising radionuclides is given along with a validation of the relevant radiopharmaceuticals and theranostic agents (based on small molecules, peptides and monoclonal antibodies). Moreover, toxicity issues and safety pharmacology aspects will be presented, both in general and for the brain in particular.http://www.thno.orgdm2022Nuclear Medicin

Mechanistic Sequence of Histone Deacetylase Inhibitors and Radiation Treatment: An Overview

Histone deacetylases inhibitors (HDACis) have shown promising therapeutic outcomes in haematological malignancies such as leukaemia, multiple myeloma, and lymphoma, with disappointing results in solid tumours when used as monotherapy. As a result, combination therapies either with radiation or other deoxyribonucleic acid (DNA) damaging agents have been suggested as ideal strategy to improve their efficacy in solid tumours. Numerous in vitro and in vivo studies have demonstrated that HDACis can sensitise malignant cells to both electromagnetic and particle types of radiation by inhibiting DNA damage repair. Although the radiosensitising ability of HDACis has been reported as early as the 1990s, the mechanisms of radiosensitisation are yet to be fully understood. This review brings forth the various protocols used to sequence the administration of radiation and HDACi treatments in the different studies. The possible contribution of these various protocols to the ambiguity that surrounds the mechanisms of radiosensitisation is also highlighted

A perspective on the radiopharmaceutical requirements for imaging and therapy of glioblastoma

Despite numerous clinical trials and pre-clinical developments, the treatment of glioblastoma (GB) remains a challenge. The current survival rate of GB averages one year, even with an optimal standard of care. However, the future promises efficient patient-tailored treatments, including targeted radionuclide therapy (TRT). Advances in radiopharmaceutical development have unlocked the possibility to assess disease at the molecular level allowing individual diagnosis. This leads to the possibility of choosing a tailored, targeted approach for therapeutic modalities. Therapeutic modalities based on radiopharmaceuticals are an exciting development with great potential to promote a personalised approach to medicine. However, an effective targeted radionuclide therapy (TRT) for the treatment of GB entails caveats and requisites. This review provides an overview of existing nuclear imaging and TRT strategies for GB. A critical discussion of the optimal characteristics for new GB targeting therapeutic radiopharmaceuticals and clinical indications are provided. Considerations for target selection are discussed, i.e. specific presence of the target, expression level and pharmacological access to the target, with particular attention to blood-brain barrier crossing. An overview of the most promising radionuclides is given along with a validation of the relevant radiopharmaceuticals and theranostic agents (based on small molecules, peptides and monoclonal antibodies). Moreover, toxicity issues and safety pharmacology aspects will be presented, both in general and for the brain in particular

Using Facebook to Recruit Urban Participants for Smartphone-Based Travel Surveys

Social media has become an integral part of everyday life for many individuals, serving as a platform to express opinions, share memories and lifestyles, follow news, and adapt to social trends and norms. The wealth of user information and analytics on these platforms has facilitated the development and sale of tailored products and services, benefiting advertisers and researchers seeking survey participants. Social media advertising has demonstrated its effectiveness in reaching hard-to-reach populations. However, transport researchers have yet to capitalise on this potential fully. This paper presents our experience using social media to recruit participants for two smartphone travel surveys conducted in Australia. We demonstrate that social media recruitment and smartphone-based travel surveys are highly effective, adaptable, and can be rapidly deployed in response to research opportunities, such as during the early phase of the COVID-19 pandemic when traditional methods may be less suitable. This approach also holds great potential for travel surveys targeting the general population. This paper shares several lessons from this experiment, including our administrative approach and detailed technical instructions to utilise open-source software tools for conducting smartphone travel surveys like ours. This approach significantly reduces study costs compared to most commercial solutions

Novel receptor tyrosine kinase pathway inhibitors for targeted radionuclide therapy of glioblastoma

Glioblastoma (GB) remains the most fatal brain tumor characterized by a high infiltration rate and treatment resistance. Overexpression and/or mutation of receptor tyrosine kinases is common in GB, which subsequently leads to the activation of many downstream pathways that have a critical impact on tumor progression and therapy resistance. Therefore, receptor tyrosine kinase inhibitors (RTKIs) have been investigated to improve the dismal prognosis of GB in an effort to evolve into a personalized targeted therapy strategy with a better treatment outcome. Numerous RTKIs have been approved in the clinic and several radiopharmaceuticals are part of (pre)clinical trials as a non-invasive method to identify patients who could benefit from RTKI. The latter opens up the scope for theranostic applications. In this review, the present status of RTKIs for the treatment, nuclear imaging and targeted radionuclide therapy of GB is presented. The focus will be on seven tyrosine kinase receptors, based on their central role in GB: EGFR, VEGFR, MET, PDGFR, FGFR, Eph receptor and IGF1R. Finally, by way of analyzing structural and physiological characteristics of the TKIs with promising clinical trial results, four small molecule RTKIs were selected based on their potential to become new therapeutic GB radiopharmaceuticals.http://www.mdpi.com/journal/pharmaceuticalspm2022Nuclear Medicin

Perspective on the use of DNA repair inhibitors as a tool for imaging and radionuclide therapy of glioblastoma

Despite numerous innovative treatment strategies, the treatment of glioblastoma (GB) remains challenging. With the current state-of-the-art therapy, most GB patients succumb after about a year. In the evolution of personalized medicine, targeted radionuclide therapy (TRT) is gaining momentum, for example, to stratify patients based on specific biomarkers. One of these biomarkers is deficiencies in DNA damage repair (DDR), which give rise to genomic instability and cancer initiation. However, these deficiencies also provide targets to specifically kill cancer cells following the synthetic lethality principle. This led to the increased interest in targeted drugs that inhibit essential DDR kinases (DDRi), of which multiple are undergoing clinical validation. In this review, the current status of DDRi for the treatment of GB is given for selected targets: ATM/ATR, CHK1/2, DNA-PK, and PARP. Furthermore, this review provides a perspective on the use of radiopharmaceuticals targeting these DDR kinases to (1) evaluate the DNA repair phenotype of GB before treatment decisions are made and (2) induce DNA damage via TRT. Finally, by applying in-house selection criteria and analyzing the structural characteristics of the DDRi, four drugs with the potential to become new therapeutic GB radiopharmaceuticals are suggested.https://www.mdpi.com/journal/cancersdm2022Nuclear Medicin

A Validation Study on Immunophenotypic Differences in T-lymphocyte Chromosomal Radiosensitivity between Newborns and Adults in South Africa

Children have an increased risk of developing radiation-induced secondary malignancies compared to adults, due to their high radiosensitivity and longer life expectancy. In contrast to the epidemiological evidence, there is only a handful of radiobiology studies which investigate the difference in radiosensitivity between children and adults at a cellular level. In this study, the previous results on the potential age dependency in chromosomal radiosensitivity were validated again by means of the cytokinesis-block micronucleus (CBMN) assay in T-lymphocytes isolated from the umbilical cord and adult peripheral blood of a South African population. The isolated cells were irradiated with 60Co γ-rays at doses ranging from 0.5 Gy to 4 Gy. Increased radiosensitivities of 34%, 42%, 29%, 26% and 16% were observed for newborns compared to adults at 0.5, 1, 2, 3 and 4 Gy, respectively. An immunophenotypic evaluation with flow cytometry revealed a significant change in the fraction of naïve (CD45RA+) T-lymphocytes in CD4+ and CD8+ T-lymphocytes with age. Newborns co-expressed an average of 91.05% CD45RA+ (range: 80.80–98.40%) of their CD4+ cells, while this fraction decreased to an average of 39.08% (range: 12.70–58.90%) for adults. Similar observations were made for CD8+ cells. This agrees with previous published results that the observed differences in chromosomal radiosensitivity between newborn and adult T-lymphocytes could potentially be linked to their immunophenotypic profiles

Synthesis and evaluation of benzoylbenzofurans and isoflavone derivatives as sirtuin 1 inhibitors with antiproliferative effects on cancer cells

Isoflavone derivatives were prepared from benzoylbenzofuran precursors. The synthesized compounds were analyzed by 1D and 2D nuclear magnetic resonance (NMR) spectroscopy, as well as high-resolution mass spectrometry (HRMS) to confirm their structures. The benzoylbenzofuran and isoflavone analogues were evaluated for inhibition of sirtuin 1 (SIRT1) and cell proliferation in MDA-MB-231 triple-negative breast cancer (TNBC) cells. Several isoflavone and benzoylbenzofuran derivatives exhibited potent antiproliferative effects against the MDA-MB-231 cancer cell line. Most of the isoflavone derivatives attenuated SIRT1 activity to below 50%. The most active compounds were the isoflavone quinones 38, 39, and 40, at IC50 values of 5.58 ± 0.373, 1.62 ± 0.0720, and 7.24 ± 0.823 μM, respectively. Importantly, the most active compound, 6-methoxy-4′,6′-dimethylisoflavone-2′,5′-quinone (39) displayed SIRT1 inhibitory activity comparable to that of the reference compound, suramin. The in silico docking simulations in the active site of SIRT1 further substantiated the experimental results and explored the binding orientations of potent compounds in the active site of the target.The National Research Foundation of South Africa; the University of Pretoria and the South African Nuclear Energy Corporation (Necsa SOC Ltd).https://www.elsevier.com/locate/bioorghj2023ChemistryPhysiolog