Design, Synthesis, and SAR of C-3 Benzoic Acid, C-17 Triterpenoid Derivatives. Identification of the HIV-1 Maturation Inhibitor 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-Dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoic Acid (GSK3532795, BMS-955176)

Regueiro‐Ren, Alicia; Swidorski, Jacob J.; Liu, Zheng; Chen, Yan; Sin, Nancy L.; Sit, Sing‐Yuen; Chen, Jie; Venables, Brian L.; Zhu, Juliang; Nowicka-Sans, Beata; Protack, Tricia; Lin, Zheng‐Zhe; Terry, Brian; Samanta, Himadri; Zhang, Sharon; Li, Zhufang; Easter, John A.; Beno, Brett R.; Arora, Vinod; Huang, Xiaohua; Rahematpura, Sandhya; Parker, Dawn D.; Haskell, Roy; Santone, Kenneth S.; Cockett, Mark I.; Krystal, Mark; Meanwell, Nicholas A.; Jenkins, Susan; Hanumegowda, Umesh; Dicker, Ira B.

doi:10.1021/acs.jmedchem.8b00854

Cited by 22 publications

(19 citation statements)

References 57 publications

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“…BA and 23‐OH‐BA are frequently used as templates for the design of novel anticancer or antiviral agents. New derivatives are regularly proposed 94–100 . Impressic acid and ACK are two natural sapogenins structurally close to BA that could be further considered as scaffolds for the design of bioactive products.…”

Section: Discussionmentioning

confidence: 99%

Acankoreagenin and acankoreosides, a family of lupane triterpenoids with anti‐inflammatory properties: an overview

Bailly¹

2021

Annals of the New York Academy of Sciences

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Acankoreagenin (ACK, also known as acankoreanogenin and HLEDA) and impressic acid are two lupane‐type triterpenes that can be isolated from various Acanthopanax and Schefflera species. They efficiently block activation of the NF‐κB signaling pathway and the release of proinflammatory cytokines and/or the action of inflammation mediators (HMGB1, iNOS, and NO). These effects are the basis for the antiviral and anticancer activities reported with these pentacyclic compounds or their various glycoside derivatives. More than 15 acankoreosides (Ack‐A to ‐O, and ‐R) and a few other mono‐ and bidesmosidic saponins (acantrifoside A and acangraciliside S) derive from the ACK aglycone. Compounds like Ack‐A and ‐B are remarkable anti‐inflammatory agents, inhibiting cytokine release from activated macrophages. Despite their effectiveness, ACK and impressic acid are far much less known and studied than the structurally related compounds betulinic acid and 23‐hydroxybetulinic acid (anemosapogenin). The structural differences (notably the R/S stereoisomerism of the 3‐hydroxyl group) and functional similarities of these compounds are discussed. The complete series of acankoreosides is presented for the first time. These natural products deserve further attention as anti‐inflammatory agents, and ACK is recommended as a template for the design of new anticancer and antiviral drugs.

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Section: Discussionmentioning

confidence: 99%

Acankoreagenin and acankoreosides, a family of lupane triterpenoids with anti‐inflammatory properties: an overview

Bailly¹

2021

Annals of the New York Academy of Sciences

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“…Betulonic acid, a triterpenoid, has an anti-SARS-CoV activity through the ketoxime backbone (Kazakova et al, 2011). The betulonic acid has a −OH and a COOH with a double bond at position C-20, 3-OH and 28-COOH groups (Regueiro-Ren et al, 2018), and C-3 and C-17 positions are crucial for the activity. Polyphenolic tannins show different binding capacities to the 3CLpro due to their SAR activities.…”

Section: Relationship Between Structures and Activities Of Natural Productsmentioning

confidence: 99%

Anti–SARS-CoV-2 Natural Products as Potentially Therapeutic Agents

Kim

2021

Front. Pharmacol.

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Severe acute respiratory syndrome–related coronavirus-2 (SARS-CoV-2), a β-coronavirus, is the cause of the recently emerged pandemic and worldwide outbreak of respiratory disease. Researchers exchange information on COVID-19 to enable collaborative searches. Although there is as yet no effective antiviral agent, like tamiflu against influenza, to block SARS-CoV-2 infection to its host cells, various candidates to mitigate or treat the disease are currently being investigated. Several drugs are being screened for the ability to block virus entry on cell surfaces and/or block intracellular replication in host cells. Vaccine development is being pursued, invoking a better elucidation of the life cycle of the virus. SARS-CoV-2 recognizes O-acetylated neuraminic acids and also several membrane proteins, such as ACE2, as the result of evolutionary switches of O-Ac SA recognition specificities. To provide information related to the current development of possible anti–SARS-COV-2 viral agents, the current review deals with the known inhibitory compounds with low molecular weight. The molecules are mainly derived from natural products of plant sources by screening or chemical synthesis via molecular simulations. Artificial intelligence–based computational simulation for drug designation and large-scale inhibitor screening have recently been performed. Structure–activity relationship of the anti–SARS-CoV-2 natural compounds is discussed.

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“…SARs led to the design of specific C‐17 amine moieties and ultimately enabled the discovery of BMS‐955176, also known as GSK3532795 ( 64 ; Figure 8), as a second‐generation maturation inhibitor that combines broad coverage of polymorphic viruses (EC 50 < 15 nM toward a panel of common polymorphisms representative of 96.5% HIV‐1 subtype B virus) with a favorable PK profile in preclinical species 62 . Compound 64 exhibited potent activity (EC 50 = 3.9 nM) toward a library ( n = 87) of gag/pr recombinant viruses representing 96.5% of subtype B polymorphic Gag diversity near the CA/SP1 cleavage site and a median EC 50 of 21 nM toward a library of subtype B clinical isolates assayed in PBMCs (Table 7).…”

Section: Pentacyclic Triterpenoidmentioning

confidence: 99%

Recent advances in natural anti‐HIV triterpenoids and analogs

Morris‐Natschke

et al. 2020

Medicinal Research Reviews

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The human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) epidemic is one of the world's most serious health challenges. Although combination antiretroviral therapy provides effective viral suppression, current medicines used against HIV cannot completely eradicate the infectious disease and often have associated toxicities and severe side effects in addition to causing drug resistance. Therefore, the continued development of new antiviral agents with diverse structures and novel mechanisms of action remains a vital need for the management of HIV/AIDS. Natural products are an important source of drug discovery, and certain triterpenes and their analogs have demonstrated potential as pharmaceutical precursors for the treatment of HIV. Over the past decade, natural triterpenoids and analogs have been extensively studied to find new anti-HIV drugs. This review discusses

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Cited by 22 publications

References 57 publications

Acankoreagenin and acankoreosides, a family of lupane triterpenoids with anti‐inflammatory properties: an overview

Acankoreagenin and acankoreosides, a family of lupane triterpenoids with anti‐inflammatory properties: an overview

Anti–SARS-CoV-2 Natural Products as Potentially Therapeutic Agents

Recent advances in natural anti‐HIV triterpenoids and analogs

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