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23 pages, 17693 KB

Open AccessArticle

Design, Synthesis and Anticancer Evaluation of Nitroimidazole Radiosensitisers

by Lydia P. Liew, Avik Shome, Way W. Wong, Cho R. Hong, Kevin O. Hicks, Stephen M. F. Jamieson and Michael P. Hay

Molecules 2023, 28(11), 4457; https://doi.org/10.3390/molecules28114457 - 31 May 2023

Cited by 6 | Viewed by 2390

Abstract

The role of hypoxic tumour cells in resistance to radiotherapy, and in suppression of immune response, continues to endorse tumour hypoxia as a bona fide, yet largely untapped, drug target. Radiotherapy innovations such as stereotactic body radiotherapy herald new opportunities for classical oxygen-mimetic radiosensitisers. Only nimorazole is used clinically as a radiosensitiser, and there is a dearth of new radiosensitisers in development. In this report, we augment previous work to present new nitroimidazole alkylsulfonamides and we document their cytotoxicity and ability to radiosensitise anoxic tumour cells in vitro. We compare radiosensitisation with etanidazole and earlier nitroimidazole sulfonamide analogues and we identify 2-nitroimidazole and 5-nitroimidazole analogues with marked tumour radiosensitisation in ex vivo assays of surviving clonogens and with in vivo tumour growth inhibition. Full article

(This article belongs to the Special Issue Heterocycles in Medicinal Chemistry II)

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14 pages, 3900 KB

Open AccessArticle

Activity of Drug Combinations against Mycobacterium abscessus Grown in Aerobic and Hypoxic Conditions

by Alessio Lanni, Emanuele Borroni, Angelo Iacobino, Cristina Russo, Leonarda Gentile, Lanfranco Fattorini and Federico Giannoni

Microorganisms 2022, 10(7), 1421; https://doi.org/10.3390/microorganisms10071421 - 14 Jul 2022

Cited by 14 | Viewed by 2873

Abstract

Infections caused by Mycobacterium abscessus (Mab), an environmental non-tuberculous mycobacterium, are difficult to eradicate from patients with pulmonary diseases such as cystic fibrosis and bronchiectasis even after years of antibiotic treatments. In these people, the low oxygen pressure in mucus and biofilm may restrict Mab growth from actively replicating aerobic (A) to non-replicating hypoxic (H) stages, which are known to be extremely drug-tolerant. After the exposure of Mab A and H cells to drugs, killing was monitored by measuring colony-forming units (CFU) and regrowth in liquid medium (MGIT 960) of 1-day-old A cells (A1) and 5-day-old H cells (H5). Mab killing was defined as a lack of regrowth of drug-exposed cells in MGIT tubes after >50 days of incubation. Out of 18 drugs tested, 14-day treatments with bedaquiline-amikacin (BDQ-AMK)-containing three-drug combinations were very active against A1 + H5 cells. However, drug-tolerant cells (persisters) were not killed, as shown by CFU curves with typical bimodal trends. Instead, 56-day treatments with the nitrocompounds containing combinations BDQ-AMK-rifabutin-clarithromycin-nimorazole and BDQ-AMK-rifabutin-clarithromycin-metronidazole-colistin killed all A1 + H5 Mab cells in 42 and 56 days, respectively, as shown by lack of regrowth in agar and MGIT medium. Overall, these data indicated that Mab persisters may be killed by appropriate drug combinations. Full article

(This article belongs to the Special Issue Nontuberculous Mycobacteria: Recent Advancements in Infection, Diagnosis and Therapy)

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16 pages, 3157 KB

Open AccessArticle

Bound Electron Enhanced Radiosensitisation of Nimorazole upon Charge Transfer

by Sarvesh Kumar, Islem Ben Chouikha, Boutheïna Kerkeni, Gustavo García and Paulo Limão-Vieira

Molecules 2022, 27(13), 4134; https://doi.org/10.3390/molecules27134134 - 28 Jun 2022

Cited by 4 | Viewed by 2118

Abstract

This novel work reports nimorazole (NIMO) radiosensitizer reduction upon electron transfer in collisions with neutral potassium (K) atoms in the lab frame energy range of 10–400 eV. The negative ions formed in this energy range were time-of-flight mass analyzed and branching ratios were obtained. Assignment of different anions showed that more than 80% was due to the formation of the non-dissociated parent anion NIMO^•− at 226 u and nitrogen dioxide anion NO₂⁻ at 46 u. The rich fragmentation pattern revealed that significant collision induced the decomposition of the 4-nitroimidazole ring, as well as other complex internal reactions within the temporary negative ion formed after electron transfer to neutral NIMO. Other fragment anions were only responsible for less than 20% of the total ion yield. Additional information on the electronic state spectroscopy of nimorazole was obtained by recording a K⁺ energy loss spectrum in the forward scattering direction (θ ≈ 0°), allowing us to determine the most accessible electronic states within the temporary negative ion. Quantum chemical calculations on the electronic structure of NIMO in the presence of a potassium atom were performed to help assign the most significant lowest unoccupied molecular orbitals participating in the collision process. Electron transfer was shown to be a relevant process for nimorazole radiosensitisation through efficient and prevalent non-dissociated parent anion formation. Full article

(This article belongs to the Special Issue Molecular Reactivity: Theoretical Study and Interpretation of Experimental Results)

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