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In this study, 37 derivatives of phorbol esters were synthesized and their anti-HIV-1 activities evaluated, building upon our previous synthesis of 51 phorbol derivatives. 12-Para-electron-acceptor- trans -cinnamoyl-13-decanoyl phorbol derivatives stood out, demonstrating remarkable anti-HIV-1 activities and inhibitory effects on syncytia formation. These derivatives exhibited a higher safety index compared with the positive control drug. Among them, 12-(trans -4-fluorocinnamoyl)-13-decanoyl phorbol, designated as compound 3c , exhibited the most potent anti-HIV-1 activity (EC 50 2.9 nmol·L−1, CC 50 /EC 50 11 117.24) and significantly inhibited the formation of syncytium (EC 50 7.0 nmol·L−1, CC 50 /EC 50 4891.43). Moreover, compound 3c is hypothesized to act both as an HIV-1 entry inhibitor and as an HIV-1 reverse transcriptase inhibitor. Isothermal titration calorimetry and molecular docking studies indicated that compound 3c may also function as a natural activator of protein kinase C (PKC). Therefore, compound 3c emerges as a potential candidate for developing new anti-HIV drugs. [ABSTRACT FROM AUTHOR]

Metabolic alterations within mitochondria, encompassing processes such as autophagy and energy metabolism, play a pivotal role in facilitating the swift proliferation, invasion, and metastasis of cancer cells. Despite this, there is a scarcity of currently available medications with proven anticancer efficacy through the modulation of mitochondrial dysfunction in a clinical setting. Here, we introduce the structural characteristics of RN0D, a galactoglucan isolated and purified from Panax notoginseng flowers, mainly composed of β-1,4-galactan and β-1,3/1,6-glucan. RN0D demonstrates the capacity to induce mitochondrial impairment in cancer cells, leading to the accumulation of reactive oxygen species, initiation of mitophagy, and reduction in both mitochondrial number and size. This sequence of events ultimately results in the inhibition of mitochondrial and glycolytic bioenergetics, culminating in the demise of cancer cells due to adenosine triphosphate (ATP) deprivation. Notably, the observed bioactivity is attributed to RN0D's direct targeting of Galectin-3, as affirmed by surface plasmon resonance studies. Furthermore, RN0D is identified as an activator of the PTEN-induced kinase 1 (PINK1)/Parkin pathway, ultimately instigating cytotoxic mitophagy in tumor cells. This comprehensive study substantiates the rationale for advancing RN0D as a potentially efficacious anticancer therapeutic. [Display omitted] [ABSTRACT FROM AUTHOR]