Design of gp120 HIV-1 entry inhibitors by scaffold hopping via isosteric replacements

Iusupov, Ildar R.; Curreli, Francesca; Spiridonov, Evgeniy A.; Markov, Pavel O.; Ahmed, Shahad; Belov, Dmitry S.; Manasova, E. V.; Altieri, Andrea; Kurkin, Alexander V.; Debnath, Asim K.

doi:10.1016/j.ejmech.2021.113681

Cited by 5 publications

(7 citation statements)

References 34 publications

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“…The crude product was purified by silica gel column chromatography (PE/EA 5:1, v/v) to afford a yellowish solid (912 mg, 79.6%). 1 (31). To a cooled solution (0 °C) of compound 30 (500 mg, 2.28 mmol) in 20 mL of dry dichloromethane under N 2 , freshly distilled POCl 3 (565 μL, 6.16 mmol) was added slowly using a syringe.…”

Section: ■ Experimental Sectionmentioning

confidence: 99%

“…Scaffold hopping is an effective strategy for the discovery of structurally novel compounds, which has been widely used by medicinal chemists to optimize lead compounds with novel backbones. , In the process of designing novel analogues of Evo, we noted that CPT is a natural product of which Top1 is the only cellular target, and its derivative topotecan has been approved by the US Food and Drug Administration for treating ovarian and lung cancers . The quinoline core of CPT is vital because the nitrogen atom forms a hydrogen bond with Arg364 of Top1 to stabilize the Top1–DNA covalent complex .…”

Section: Introductionmentioning

confidence: 99%

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Discovery of Novel Polycyclic Heterocyclic Derivatives from Evodiamine for the Potential Treatment of Triple-Negative Breast Cancer

Yao

Qiu

et al. 2021

J. Med. Chem.

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Evodiamine (Evo) is a quinazolinocarboline alkaloid found in Evodia rutaecarpa and exhibits moderate antiproliferative activity. Herein, we report using a scaffold-hopping approach to identify a series of novel polycyclic heterocyclic derivatives based on Evo as the topoisomerase I (Top1) inhibitor for the treatment of triple-negative breast cancer (TNBC), which is an aggressive subtype of breast cancer with limited treatment options. The most potent compound 7f inhibited cell growth in a human breast carcinoma cell line (MDA-MB-231) with an IC50 value of 0.36 μM. Further studies revealed that Top1 was the target of 7f, which directly induced irreversible Top1–DNA covalent complex formation or induced an oxidative DNA lesion through an indirect mechanism mediated by reactive oxygen species. More importantly, in vivo studies showed that 7f exhibited potent antitumor activity in a TNBC-patient-derived tumor xenograft model. These results suggest that compound 7f deserves further investigation as a promising candidate for the treatment of TNBC.

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Section: ■ Experimental Sectionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Discovery of Novel Polycyclic Heterocyclic Derivatives from Evodiamine for the Potential Treatment of Triple-Negative Breast Cancer

Yao

Qiu

et al. 2021

J. Med. Chem.

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“…They interfere with the virus entry by disrupting the CD4-gp120 interaction, [9][10][15][16] and some of the third-generation potent entry inhibitors also inhibit HIV-1 RT. [17][18] Earlier, the structure-activity relationship (SAR) of NBDs and their structural modifications, including isosteric replacements of the thiazole ring with other aryl and heteroaryl rings, have been primarily investigated. [9][10][11][12][13][14]17,19] Therefore, this study focused on the possibility of topologically replacing the thiazole ring via positional isomers (Figure 2).…”

Section: Introductionmentioning

confidence: 99%

“…[17][18] Earlier, the structure-activity relationship (SAR) of NBDs and their structural modifications, including isosteric replacements of the thiazole ring with other aryl and heteroaryl rings, have been primarily investigated. [9][10][11][12][13][14]17,19] Therefore, this study focused on the possibility of topologically replacing the thiazole ring via positional isomers (Figure 2). The primary goal was to find whether that leads to any improvement in antiviral potency and cytotoxicity and derive a SAR on positional isomers.…”

Section: Introductionmentioning

confidence: 99%

“…They interfere with the virus entry by disrupting the CD4‐gp120 interaction, [9–10,15–16] and some of the third‐generation potent entry inhibitors also inhibit HIV‐1 RT [17–18] . Earlier, the structure‐activity relationship (SAR) of NBDs and their structural modifications, including isosteric replacements of the thiazole ring with other aryl and heteroaryl rings, have been primarily investigated [9–14,17,19] . Therefore, this study focused on the possibility of topologically replacing the thiazole ring via positional isomers (Figure 2).…”

Section: Introductionmentioning

confidence: 99%

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Design, Synthesis, and Antiviral Activity of the Thiazole Positional Isomers of a Potent HIV‐1 Entry Inhibitor NBD‐14270

Kurkin¹,

Curreli

Iusupov³

et al. 2022

ChemMedChem

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The envelope glycoprotein gp120 of human immunodeficiency virus type 1 (HIV‐1) plays a critical role in virus entry to the cells by binding to the host cellular protein CD4. Earlier, we reported the design and discovery of a series of highly potent small‐molecule entry antagonists containing a thiazole ring (Scaffold A). Since this thiazole ring connected with an ethyl amide linkage represents the molecule‘s flexible part, we decided to explore substituting Scaffold A with two other positional isomers of the thiazole ring (Scaffold B and C) to evaluate their effect on the antiviral potency and cellular toxicity. Here we report the novel synthesis of two sets of positional thiazole isomers of the NBD‐14270 by retrosynthetic analysis approach, their anti‐HIV‐1 activity, cellular toxicity, and structure‐activity relationships. The study revealed that Scaffold A provided the best HIV‐1 inhibitors with higher potency and better selectivity index (SI).

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Revealing the Indispensable Role of the RFamide Functionality using a Novel Acid Labile Benzofuranone based Amine (ALBA) Linker

Mudd,

Hendrikse,

Shave

et al. 2024

Helvetica Chimica Acta

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The RFamide family of peptides represents an important class of GPCR ligand neuropeptides covering a wide range of biological functions. While many analogues of the highly conserved C‐terminal RFamide motif within this peptide class have been synthesized and their functional significance elucidated, additional exploration of the structure activity relationship is of value. We have developed a novel linker for solid phase peptide synthesis (SPPS) which is able to anchor amine functionalised compounds for further elaboration. The acid labile benzofuranone based amine (ALBA) linker (5‐(3‐aminopropylcarbamoyl)‐2‐[[tert‐butyl(diphenyl)silyl]oxymethyl]benzoic acid) is compatible with Fmoc based SPPS and has two cleavage modes. As a proof of concept, the ALBA linker was used to successfully synthesise a novel analogue of Kisspeptin 10, the natural ligand for GPCR54, whereby the natural RFamide motif was replaced with an RFamine. Biological evaluation of the amine‐containing analogue revealed that the group is not compatible with receptor activation.

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Design of gp120 HIV-1 entry inhibitors by scaffold hopping via isosteric replacements

Cited by 5 publications

References 34 publications

Discovery of Novel Polycyclic Heterocyclic Derivatives from Evodiamine for the Potential Treatment of Triple-Negative Breast Cancer

Discovery of Novel Polycyclic Heterocyclic Derivatives from Evodiamine for the Potential Treatment of Triple-Negative Breast Cancer

Design, Synthesis, and Antiviral Activity of the Thiazole Positional Isomers of a Potent HIV‐1 Entry Inhibitor NBD‐14270

Revealing the Indispensable Role of the RFamide Functionality using a Novel Acid Labile Benzofuranone based Amine (ALBA) Linker

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