Synthesis of HIV Protease Inhibitor ABT-378 (Lopinavir)

Cancer stem cells (CSCs) are a specific subset of cancer cells that sustain tumor growth and dissemination. They might represent a significant treatment target to reduce malignant progression and prevent tumor recurrence. In solid tumors, several hierarchically organized CSC clones coexist, even within a single tumor. Among them, CSCs displaying an embryonic stem cell ‘stemness' signature, based on the expression of Oct-4, Nanog and Sox2, are present in distinct high-grade tumor types associated with poor prognosis. We previously designed a model to isolate pure populations of these CSCs from distinct solid tumors and used it to screen for molecules showing selective toxicity for this type of CSC. Here we show that human immunodeficiency virus (HIV)-protease inhibitors (HIV-PIs) specifically target CSCs expressing an embryonic signature derived from tumors with distinct origins. They reduced proliferation in a dose-dependent manner with a higher specificity as compared with the total population of cancer cells and/or healthy stem cells, and they were efficient in inducing cell death. Lopinavir was the most effective HIV-PI among those tested. It reduced self-renewal and induced apoptosis of CSCs, subsequently impairing in vivo CSC-induced allograft formation. Two key pharmacophores in the LPV structure were also identified. They are responsible for the specificity of CSC targeting and also for the overall antitumoral activity. These results contribute to the identification of molecules presenting selective toxicity for CSCs expressing an embryonic stemness signature. This paves the way to promising therapeutic opportunities for patients suffering from solid cancer tumors of poor prognosis.

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“…The key intermediates used for SAR studies were synthesized according to a previously reported procedure. 53 …”

Section: Methodsmentioning

confidence: 99%

Targeting cancer stem cells expressing an embryonic signature with anti-proteases to decrease their tumor potential

et al. 2013

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“…Acid A4 was treated with SOCl 2 in EtOAc, and the resulting acyl chloride was reacted with 1 using the reported procedure. 25 Catalytic debenzylation of intermediate compounds 2-5 using Pd/C provided the free amines 6-9 that were subsequently a Abbreviations: EDCI, 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride; HOBt, N-hydroxybenzotriazole hydrate; DIPEA, diisopropylethylamine; FRET, fluorescence resonance energy transfer. reacted with the activated carboxylic acids 10 or 11a-f to provide the designed inhibitors 12-16.…”

Section: Chemistrymentioning

confidence: 99%

Design and Synthesis of HIV-1 Protease Inhibitors Incorporating Oxazolidinones as P2/P2‘ Ligands in Pseudosymmetric Dipeptide Isosteres

et al. 2007

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A series of novel HIV-1 protease inhibitors based on two pseudosymmetric dipeptide isosteres have been synthesized and evaluated. The inhibitors were designed by incorporating N-phenyloxazolidinone-5-carboxamides into the hydroxyethylene and (hydroxyethyl)hydrazine dipeptide isosteres as P2 and P2' ligands. Compounds with (S)-phenyloxazolidinones attached at a position proximal to the central hydroxyl group showed low nM inhibitory activities against wild-type HIV-1 protease. Selected compounds were further evaluated for their inhibitory activities against a panel of multidrug-resistant protease variants and for their antiviral potencies in MT-4 cells. The crystal structures of lopinavir (LPV) and two new inhibitors containing phenyloxazolidinone-based ligands in complex with wild-type HIV-1 protease have been determined. A comparison of the inhibitor-protease structures with the LPV-protease structure provides valuable insight into the binding mode of the new inhibitors to the protease enzyme. Based on the crystal structures and knowledge of structure-activity relationships, new inhibitors can be designed with enhanced enzyme inhibitory and antiviral potencies.

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“…Acyl chloride (8) was prepared by reaction of the corresponding acid (7) with thionyl chloride in the presence of a single drop DMF, 15 and then reacted with the compound (9), lithium di-n-propylcuprate(I), to get the appropriate ketone (10) possessing a npropyl group. 16 a-Phenoxyacetophenone (11) was synthesized from a-bromoacetophenone and phenol in the presence of potassium carbonate.…”

Section: Chemistrymentioning

confidence: 99%

Design, synthesis, and biological evaluation of novel 4-hydroxypyrone derivatives as HIV-1 protease inhibitors

Sun

Pang

Zhang

et al. 2005

Bioorganic & Medicinal Chemistry Letters

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Synthesis of HIV Protease Inhibitor ABT-378 (Lopinavir)

Cited by 57 publications

References 15 publications

Targeting cancer stem cells expressing an embryonic signature with anti-proteases to decrease their tumor potential

Targeting cancer stem cells expressing an embryonic signature with anti-proteases to decrease their tumor potential

Design and Synthesis of HIV-1 Protease Inhibitors Incorporating Oxazolidinones as P2/P2‘ Ligands in Pseudosymmetric Dipeptide Isosteres

Design, synthesis, and biological evaluation of novel 4-hydroxypyrone derivatives as HIV-1 protease inhibitors

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