%0 Journal Article
%T Discovery of Potent DAG-Lactone Derivatives as HIV Latency Reversing Agents.
%A Ishii T
%A Kobayakawa T
%A Matsuda K
%A Nigorikawa K
%A Bolah P
%A Noborio A
%A Tsuji K
%A Ohashi N
%A Yoshimura K
%A Nomura W
%A Mitsuya H
%A Maeda K
%A Tamamura H
%J ACS Infect Dis
%V 10
%N 6
%D 2024 Jun 14
%M 38771724
%F 5.578
%R 10.1021/acsinfecdis.4c00194
%X 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.