The discovery of allyltyrosine based tripeptides as selective inhibitors of the HIV-1 integrase strand-transfer reaction

Dalton, Neal; Gordon, Christopher P.; Boyle, Timothy P.; Vandegraaf, Nicholas; Deadman, John; Rhodes, David; Coates, Jonathan; Pyne, Stephen G.; Keller, P. A.; Bremner, John B.

doi:10.1039/c6ob00950f

Cited by 11 publications

(2 citation statements)

References 43 publications

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“…The remaining solution was acidified with 1M aqueous HCl, extracted with EtOAc (3 × 25 mL), the organic extracts dried over Na 2 SO 4 and solvent removed in vacuo to yield 26 (2.4 g, 82%) as a colourless solid, mp 70–71 °C (lit. [63] mp 73–75 °C). δ H (CDCl 3 ) 10.72 (1H, br s, OH), 8.21 (1H, dd, J = 7.8, 1.8 Hz, H-6), 7.56 (1H, ddd, J = 9.2, 7.4, 1.8 Hz, H-4), 7.46–7.38 (5H, m, Ar-H), 7.18–7.11 (2H, m, H-5, H-3) 5.30 (2H, s, CH 2 ).…”

Section: Methodsmentioning

confidence: 99%

Studies Towards Hypoxia-Activated Prodrugs of PARP Inhibitors

et al. 2019

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Poly(ADP-ribose)polymerase (PARP) inhibitors (PARPi) have recently been approved for the treatment of breast and ovarian tumors with defects in homologous recombination repair (HRR). Although it has been demonstrated that PARPi also sensitize HRR competent tumors to cytotoxic chemotherapies or radiotherapy, normal cell toxicity has remained an obstacle to their use in this context. Hypoxia-activated prodrugs (HAPs) provide a means to limit exposure of normal cells to active drug, thus adding a layer of tumor selectivity. We have investigated potential HAPs of model PARPi in which we attach a bioreducible “trigger” to the amide nitrogen, thereby blocking key binding interactions. A representative example showed promise in abrogating PARPi enzymatic activity in a biochemical assay, with a ca. 160-fold higher potency of benzyl phthalazinone 4 than the corresponding model HAP 5, but these N-alkylated compounds did not release the PARPi upon one-electron reduction by radiolysis. Therefore, we extended our investigation to include NU1025, a PARPi that contains a phenol distal to the core binding motif. The resulting 2-nitroimidazolyl ether provided modest abrogation of PARPi activity with a ca. seven-fold decrease in potency, but released the PARPi efficiently upon reduction. This investigation of potential prodrug approaches for PARPi has identified a useful prodrug strategy for future exploration.

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Section: Methodsmentioning

confidence: 99%

Studies Towards Hypoxia-Activated Prodrugs of PARP Inhibitors

et al. 2019

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“…Synthesis of nicotinoyl chloride ( 2 ) and glycyl-glycine-methyl-ester-hydrochloride : These compounds were prepared according to previously reported methods [ 38 , 39 ].…”

Section: Methodsmentioning

confidence: 99%

Synthesis, Molecular Docking Studies, In Vitro Antimicrobial and Antifungal Activities of Novel Dipeptide Derivatives Based on N-(2-(2-Hydrazinyl-2-oxoethylamino)-2-oxoethyl)-Nicotinamide

et al. 2018

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A series of linear dipeptide derivatives (4–10) were prepared and evaluated as antimicrobial agents via the synthesis of N-(2-(2-hydrazinyl-2-oxoethylamino)-2-oxoethyl) nicotinamide (4). Compound 4 was reacted with 4-chlorobenzaldehyde or 4-hydroxybenzaldehyde, to give the hydrazones 5 and 6, respectively. On the other hand, Compound 4 was coupled with phenylisocyanate or methylisothiocyanate to give Compounds 7 and 8, respectively. The latter compounds (7 and 8) were coupled with chloroacetic acid to give oxazolidine (9) and thiazolidine (10), respectively. The newly synthesized dipeptide compounds were confirmed by means of their spectral data. The antimicrobial activity of the newly synthesized compounds 4–10 was evaluated by agar well diffusion, and they showed good activity. Compounds 4, 5, and 9 gave the most promising activity in this study. Most of the tested compounds possessed MIC values ranging from 50 to 500 µg/mL. Furthermore, docking studies were carried out on enoyl reductase from E. coli and cytochrome P450 14 α-sterol demethylase (Cyp51) from Candida albicans active sites. The MolDock scores of the seven tested compounds ranged between −117 and −171 and between −107 and −179, respectively.

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Highly Stereoselective Synthesis of γ,δ‐Unsaturated Quaternary α‐Amino Esters via the Tandem N‐Alkylation/Claisen Rearrangement of α‐Imino Allylesters

et al. 2023

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γ,δ‐Unsaturated amino acids are the backbone of various natural products and pharmaceuticals, while quaternary α‐amino acids are also powerful enzyme inhibitors, and both are very important compounds in bioorganic chemistry. A highly efficient synthesis of γ,δ‐unsaturated quaternary amino esters utilizing the tandem umpolung/Claisen rearrangement for α‐iminoallyl esters was developed. This method has a wide range of substrates taking account of the Hammett rule, and highly stereoselective Claisen rearrangement were achieved by the effect of DMSO or the ortho‐substituents of imino carbon. Furthermore, product functionalization also showed the usefulness of this reaction and the detailed reaction mechanism was elucidated from isotopic labeling experiments, kinetic isotope effects and crossover‐experiments.

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The discovery of allyltyrosine based tripeptides as selective inhibitors of the HIV-1 integrase strand-transfer reaction

Abstract: From library screening of synthetic antimicrobial peptides, an O-allyltyrosine-based tripeptide HIV-1 integrase (IN) inhibitor was identified. Subsequent optimisation afforded an analogue exhibiting an IC50 value of 2.5 μM.

Cited by 11 publications

References 43 publications

Studies Towards Hypoxia-Activated Prodrugs of PARP Inhibitors

Studies Towards Hypoxia-Activated Prodrugs of PARP Inhibitors

Synthesis, Molecular Docking Studies, In Vitro Antimicrobial and Antifungal Activities of Novel Dipeptide Derivatives Based on N-(2-(2-Hydrazinyl-2-oxoethylamino)-2-oxoethyl)-Nicotinamide

Highly Stereoselective Synthesis of γ,δ‐Unsaturated Quaternary α‐Amino Esters via the Tandem N‐Alkylation/Claisen Rearrangement of α‐Imino Allylesters

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