ABSTRACT
Toward human immunodeficiency virus type-1 (HIV-1) cure, cells latently infected with HIV-1 must be eliminated from people living with HIV-1. We previously developed a protein kinase C (PKC) activator, diacylglycerol (DAG)-lactone derivative 3, with high HIV-1 latency-reversing activity, based on YSE028 (2) as a lead compound and found that the activity was correlated with binding affinity for PKC and stability against esterase-mediated hydrolysis. Here, we synthesized new DAG-lactone derivatives not only containing a tertiary ester group or an isoxazole surrogate but also several symmetric alkylidene moieties to improve HIV-1 latency reversing activity. Compound 9a, with a dimethyl group at the α-position of the ester group, exerted twice higher HIV-1 latency reversing activity than compound 3, and compound 26, with the isoxazole moiety, was significantly active. In addition, DAG-lactone derivatives with moderate hydrophobicity and potent biostability showed high biological activity.
Subject(s)
Anti-HIV Agents , HIV-1 , Lactones , Virus Latency , Humans , HIV-1/drug effects , HIV-1/physiology , Virus Latency/drug effects , Lactones/pharmacology , Lactones/chemistry , Lactones/chemical synthesis , Anti-HIV Agents/pharmacology , Anti-HIV Agents/chemistry , Anti-HIV Agents/chemical synthesis , Diglycerides/chemistry , Diglycerides/pharmacology , Diglycerides/chemical synthesis , HIV Infections/drug therapy , HIV Infections/virology , Protein Kinase C/metabolism , Protein Kinase C/antagonists & inhibitorsABSTRACT
Cells latently infected with human immunodeficiency virus type 1 (HIV-1) prevent people living with HIV-1 from obtaining a cure to the infectious disease. Latency reversing agents (LRAs) such as protein kinase C (PKC) activators and histone deacetylase (HDAC) inhibitors can reactivate cells latently infected with HIV-1. Several trials based on treatment with HDAC inhibitors alone, however, failed to reduce the number of latent HIV-1 reservoirs. Herein, we have focused on a diacylglycerol (DAG)-lactone derivative, YSE028 (1), which is a PKC activator with latency reversing activity and no significant cytotoxicity. Caspase-3 activation of YSE028 (1) led to cell apoptosis, specifically in HIV-1 latently infected cells. Structure-activity relationship studies of YSE028 (1) have produced several useful derivatives. Among these, compound 2 is approximately ten times more potent than YSE028 (1) in reactivation of cells latently infected with HIV-1. The activity of DAG-lactone derivatives was correlated with the binding affinity for PKC and the stability against esterase-mediated hydrolysis.
